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  • The immunotherapy wave has finally hit the shores of the breast cancer landscape

    Immunotherapy is all the rage these days in oncology, and there is particular interest in those agents that target programmed death 1 (PD-1) and its ligand, PD-L1. In several solid tumors (and hematologic tumors as we saw at ASH last week) there is a race to market for this class of compounds by multiple competitors. Data presented in the past two years in melanoma have been impressive and have led to approvals of Keytruda® (pembrolizumab, Merck; U.S. FDA approval September 2014) and Opdivo® (nivolumab, BMS/Ono; Japanese MHLW approval July 2014 ) in advanced/metastatic disease and will likely lead to approvals in other indications in the near future (non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are nearest term). Robust research in this area continues to push into additional indications, including breast cancer. In general, breast cancer is seen as less responsive to immunotherapy, and there has been some skepticism about the ability of immunotherapy to deliver.  In particular, mutant proteins that serve as “neo-antigens” to the immune system are very low in breast cancer compared to other solid tumors.1 However, high levels of tumor-infiltrating lymphocytes (TILs) do seem to predict pathological complete response (pCR) in breast cancer patients,2 suggesting that the immune system is an important factor in the fight against this disease.

    The question as to whether or not immunotherapy can be successful in breast cancer began to be answered Wednesday, December 10, 2014, at the San Antonio Breast Cancer Symposium (SABCS) with two presentations demonstrating early signals of activity for PD-1 and PD-L1 inhibitors in triple-negative breast cancer (TNBC) patients. Wednesday’s oral general session was the venue for the first results of Keytruda in 32 advanced TNBC patients treated in the ongoing Phase Ib KEYNOTE-012 study.3 The trial enrolled heavily pretreated patients (47% had three or more prior lines of chemotherapy) with PD-L1+ disease and treated them with pembrolizumab monotherapy at 10 mg/kg every two weeks. In 27 evaluable patients, the objective response rate (ORR) was 18.5% (1 CR, 4 PR) and median duration of response (DoR) was not reached (range, 15-40+ weeks), with three of five responders remaining on therapy for 11+ months. Adverse events (AEs) were mostly Grade 1/2, including fatigue (18.8%), arthralgia (18.8%), myalgia (15.6%) and nausea (15.6%). Grade 3/4 treatment-related AEs occurred in four patients – anemia, headache, meningitis aseptic, decreased blood fibrinogen and pyrexia – with two patients discontinuing drug due to AEs. There was also one death due to disseminated intravascular coagulation (DIC). Based on this encouraging data, the presenter, Dr. Nanda, disclosed Merck’s plans to start a Phase II trial in TNBC in the first half of 2015 and hinted during the Q&A at plans to pursue the other breast cancer subtypes, such as HER2+ patients, who may also be susceptible to immunotherapy. Small trials, such as PANACEA (NCT02129556), which will examine Keytruda in combination with Herceptin® (trastuzumab, Genentech/Roche/Chugai) in advanced Herceptin-resistant HER2+ breast cancer, should start recruiting soon.

    Also on Wednesday, there was a poster presentation of data from a small cohort of 12 patients in the ongoing Phase Ia dose-escalation study of MPDL3280A (anti PD-L1, Genentech/Roche/Chugai), which evaluates doses of 0.3-20 mg/kg every three weeks in previously treated patients with advanced, PD-L1+ TNBC. 4 In nine evaluable patients, ORR was 33% (1 CR, 2 PR); however, there were an additional two responders who were initially pseudo-progressors and were not included in the calculated ORR. Grade 3/4 treatment-related AEs occurred in only one patient, and no dose-limiting toxicities occurred. Further evaluation of MPDL3280A is ongoing in both PD-L1-positive and -negative TNBC patients (NCT01375842).

    In both studies, response was measured by RECIST criteria, not immune-related-response criteria that take into account that some patients on immunotherapy initially progress before responding. Had these alternative criteria been used, perhaps the ORR would have been higher. Despite this, the ORR reported in these two studies (19% and 33%) are similar to the ORR reported for PD-1 / PD-L1 inhibitors in other solid tumors ( 31%-34% in melanoma,5,6 17%-21% in NSCLC,7,8,9 20% in RCC and head and neck10,11). Perhaps more important than the response rate is the extent to which the PD-1/PD-L1 inhibitors are able to slow the progression of disease and prolong survival. The duration of response data for Keytruda is the only piece of data that is yet available to guide toward an answer to this question in breast cancer, but it is a promising start – metastatic TNBC has a notoriously poor prognosis, and to see duration of response nearing one year in later lines of therapy is very encouraging. What will be more encouraging is to see an OS benefit extending beyond just those patients who achieve an objective response, as we have come to expect from immunotherapies in many tumors.

    Despite the small cohort of patients and limited data, discussant Dr. Disis was very positive on the results and called for researchers to move ahead and consider combination trials in breast cancer. This is a bit of a departure from typical breast cancer treatment strategies, which tend to focus on sequential monotherapies rather than combination regimens. The immunotherapy field is beginning to explore combination approaches in other solid tumors, so extending that idea to breast cancer isn’t novel. The approach Keytruda is taking (combining with Herceptin) is somewhat expected in breast cancer, although is limited to HER2+ patients. In TNBC patients, however, no targeted therapy options are yet developed with which to combine; chemotherapy thus becomes the de facto combination partner (Celgene is conducting a Phase I trial that includes study of Opdivo with Abraxane® (nab-paclitaxel) in second-line HER2-negative disease (NCT02309177)), although this approach negates the low-toxicity advantage that immunotherapy is meant to afford.  

    Breast cancer is the most commonly diagnosed cancer in the U.S. and Europe and is the second most commonly diagnosed cancer globally. Given the large number of patients involved, it is somewhat surprising that the checkpoint inhibitors haven’t been more widely developed in this disease. Perhaps higher unmet need drove early development of PD-1/PD-L1 inhibitors toward other malignancies, but the tides may now be shifting. It seems the immunotherapy wave has finally hit the shores of the breast cancer landscape.


    1. Disis M., Discussant Oral Session 1, SABCS 2014
    2. Loi S., Educational Session: Introduction to Immunotherapy, SABCS 2014
    3. Nanda R., Abstract S1-09, SABCS 2014
    4. Emens L.A., Abstract PD1-06, SABCS 2014
    5. Ribas, Abstract LBA9000, ASCO 2014
    6. Weber, Abstract LBA3, ESMO 2014
    7. Brahmer, Abstract 8030, ASCO 2013
    8. Rizvi, Abstract 8007, ASCO 2014
    9. Spigel, Abstract 8008, ASCO 2013
    10. Motzer, Abstract 5009, ASCO 2014
    11. Seiwert, Abstract 6011, ASCO 2014

    By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Mara Jeffress, Ph.D., Associate Consultant, Clinical and Scientific Assessment, Kantar Health

    The battlefield extends into hematologic malignancies – continuing the race between PD-1-targeted therapeutics

    Immune checkpoints in the Programmed Death-1 (PD-1) pathway have critical roles in balancing the co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T‑cell responses. PD-1 is a key immune checkpoint receptor expressed on activated T-cells. Binding of PD-1 to its ligand (PD-L1) results in suppression of the immune response, and tumor cells can manipulate this critical pathway to elude attack by tumor-infiltrating T-cells.

    The two front-runners for this class are Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals). Opdivo holds the title of being the first PD-1 inhibitor to gain regulatory approval when it was approved in Japan in July 2014 for malignant melanoma, while in September 2014 Keytruda became the first PD-1 inhibitor to gain FDA approval (accelerated approval for advanced and unresectable malignant melanoma). Both are currently in development in a number of other solid tumors and now are making a foray into the hematologic space. Both companies released the first-reported clinical results in hematologic malignancies in the same oral presentation session on Sunday, Dec. 8, 2014 at the 2014 American Society of Hematology (ASH) conference.

    Unlike solid tumors, in which data has demonstrated strong efficacy for this class in numerous abstracts across multiple tumor types, studies in the hematologic malignancies are still scarce (“disappointingly only four presentations at the 2014 ASH meeting” as elegantly expressed by Dr. Levy in his commentary presentation during a full house Sunday special session on Immune Checkpoint Blockade in Lymphoma).  

    Opdivo has two stories to tell from its Phase I trial in hematologic malignancies

    A Phase I study of Opdivo enrolled a total of 105 patients with relapsed/refractory hematologic malignancies. This trial supported two presentations: one focusing on results from the cohort of 23 patients with relapsed/refractory Hodgkin’s lymphoma1 and the second discussing the remaining 82 patients with other relapsed/refractory lymphoma malignancies (B-cell lymphoma, T-cell lymphoma and multiple myeloma.)2 Safety and tolerability were the primary endpoints, and best overall response, duration of response, progression-free survival (PFS) and biomarker studies were secondary endpoints.

    Story One: High overall response rates (87%) in heavily pre-treated relapsed or refractory Hodgkin’s lymphoma1,3

    Classical Hodgkin’s lymphoma (cHL) is unique, with Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies have suggested that Hodgkin’s RS cells may have developed mechanisms to exploit the PD-1 pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that correlates with elevated expression of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. The rationale behind this study is that Opdivo may confer antitumor activity in patients with relapsed or refractory (R/R) cHL who have elevated PD-L1 expression. The FDA granted nivolumab Breakthrough Therapy Status for Hodgkin’s lymphoma in May 2014, and this is the first presentation of the data that supported that designation. The results did not disappoint.

    In the cohort of 23 heavily pre-treated R/R cHL patients (one-third of patients received six or more prior treatments), the overall response rate (ORR) was an exciting 87%, including four patients with complete response (CR, 17%), and 100% clinical benefit rate. The onsets of response were relatively fast, with first responses (both CR and PR) observed for within the first eight weeks of treatment (60% of responses occurred by week 8). The 24-week PFS was 86%, indicating durable responses from this immune blockade drug. Importantly, durable responses were observed in patients who had failed after prior stem cell transplant and/or prior treatment with Adcetris® (brentuximab vedotin, Seattle Genetics/Takeda). The overall safety profile was found to be similar to that observed in solid tumors: drug-related Grade 3 adverse events (AEs) included lymphopenia, gastrointestinal inflammation, increased lipase, pneumonitis, colitis and stomatitis and occurred in 22% of patients.

    A large, multinational Phase II study (Registration; CheckMate 205, NCT02181738) was initiated in July 2014 and is ongoing in patients who relapsed after autologous stem cell transplantation (ASCT). If the clinical benefits observed in the Phase I study are confirmed in the CheckMate 205 trial, will PD-1 blockade introduce a paradigm shift in the treatment of cHL patients in the future in the same way that PD-1 blockade is doing now in solid tumors?

    Story Two: Mixed results in other relapsed or refractory hematologic malignancies2

    Results from the 69-patient cohort with non-Hodgkin’s lymphoma (NHL) malignancies (B-cell lymphoma, n=23; T-cell lymphoma, n=23; and multiple myeloma n=23) were reported separately. Most of the patients in this combined cohort were also heavily pre-treated (number of prior systemic treatments ranged from two to five, with over 20% of patients having received more than five prior treatments). The ORRs differed by patient subgroups. The ORR and CR rates in patients with B-NHL were 28% and 7%, respectively, with the highest objective ORRs observed in follicular lymphoma (40%) and peripheral T-cell lymphoma (40%). In the overall T-NHL population, the ORR was 17%. No responses were observed in multiple myeloma or in primary mediastinal B-cell lymphoma.

    Again, the overall safety profile was similar to other Opdivo trials. Fatigue (13%) and pneumonitis (11%) were the most frequently observed drug-related AEs (all grades); the majority of pneumonitis was Grade 1 or 2, although there was one fatal event. Overall, 18% of drug-related AEs were Grade 3 and 2% were Grade 4  in this cohort.

    This second part of the trial in hematologic malignancies demonstrated that Opdivo is safe and tolerable across many hematologic tumor types but that clinical benefit differs across the range of hematologic malignancies. The different responses from different hematologic malignancies may indicate that the PD-1 pathway may not function the same across all tumor types (genetic alteration of 9p24.1 was uncommon in the NHL population studied in this trial), or that tumor-specific mechanisms may affect the checkpoint blockade effect from PD-1 targeted drugs. The preliminary clinical data from this Phase I study are encouraging, but more studies are warranted before we can conclude that PD-1-targeted drugs will offer the same homerun/panacea effect in hematologic malignancies as many expect will be the case in solid tumors.

    Encouraging results from Keytruda in Hodgkin’s lymphoma (KEYNOTE-013 Study)4

    Merck presented the first results from a cohort of 31 R/R cHL patients enrolled in the KEYNOTE-013 study (the broader study population also included patients with myelodysplastic syndrome (MDS), mediastinal large B-cell lymphoma, multiple myeloma and NHL). The primary endpoint is CR rate, and secondary endpoints are ORR, PFS, overall survival and duration of response. Safety profiles of AEs with clinical interest to Keytruda were also part of the study objectives.

    Keytruda achieved an excellent ORR of 66%, including CR rate of 21%, in this cohort of 29 R/R cHL patients, 100% of whom had failed after prior Adcetris and 69% of whom (n=20) had failed after a prior transplant. Most patients were heavily pre-treated (more than half of patients received five prior treatments). The overall clinical benefit rate was 86%, with only four patients having progressive disease. The clinical benefit rate in the 20 patients who were transplant failures was 90%, higher than that observed in the nine patients who were transplant-ineligible or refused transplant (78%). The overall safety profile was found to be similar to that observed in solid tumors, with Grade 3/4 treatment-related AEs occurring rarely.

    These studies demonstrate that in cHL Opdivo and Keytruda are both active agents with similarly encouraging efficacy when measured by ORR (87% vs. 66%) or CR rate (17% vs. 21%). During a special session on immune checkpoint blockade, many questions were raised as to why there were such differences in response in different hematologic malignancies. The answers were mostly a straight and simple, “I don’t know.” Dr. Ansell from the Mayo Clinic provided excellent speculations on the biological reasons, namely, increased regulatory T-cells in lymphoma, presence of “exhausted” T-cells, increased immunosuppression ligands, and presence of intratumoral monocytes and follicular dendritic cells. Furthermore, the high responses to PD-1 drugs in cHL may be attributable to the genetic amplification at 9p24.1 and related PD-L1 overexpression that is common in cHL versus other hematologic malignancies. With these unique characteristics in mind, incorporating these promising immunologic agents into the current standards of care for lymphoma will present daunting clinical challenges for hematologists, immunotherapists and oncologists in the hematologic world.

    Opdivo may be a step ahead with its Breakthrough Therapy Status in Hodgkin’s lymphoma and the ongoing CheckMate 205 study initiated in July 2014. Who the winner will be on the battlefield of hematologic malignancies remains to be seen, but if durable responses translate into prolonged PFS and overall survival then the ultimate winner is the patient.


    1. Armand et al., Abstract 289, ASH 2014
    2. Lesokhin et al., Abstract 291, ASH 2014
    3. Ansell et al., New Engl J Med, 2014 (DOI: 10.1056/NEJMoa1411087)
    4. Moskowitz et al., Abstract 290, ASH 2014

    By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Linda Zhao, Ph.D., Director, Clinical and Scientific Assessment, Kantar Health

    Adcetris continues to advance outcomes in relapsed/refractory Hodgkin’s lymphoma

    Hodgkin’s lymphoma (HL) represents one of the more successful stories in oncology. The four-regimen combination of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) is the standard of care for newly diagnosed patients, and prognosis is excellent for patients who respond, demonstrating a five-year overall survival of approximately 80%.1 However, about 20% of patients relapse or are refractory to first-line therapy,2 and prognosis has traditionally been poor for this population, who typically receive salvage chemotherapy followed by autologous stem cell transplantation (auto-SCT), which provides a cure rate of about 50%.3 For patients who relapse after auto-SCT, allogeneic SCT or best supportive care was the only an option. The approval of Adcetris® (brentuximab vendotin, Seattle Genetics/Takeda) in 2011 after second-line relapse or transplant failure changed this grim landscape and provided an important and effective new treatment option for patients. The compelling results from its pivotal Phase II trial, which showed an objective response rate (ORR) of 75% and median progression-free survival (PFS) of 5.6 months,4 helped pave the way to make Adcetris the new standard of care in relapsed/refractory patients. Indeed, about one-third of patients receive Adcetris following SCT failure or as second-line systemic therapy. 5 Given the effectiveness of Adcetris following SCT failure, one salient question arises: Can Adcetris also be used to minimize the risk of relapse post-SCT if given early as part of consolidation therapy following auto-SCT?

    The AETHERA trial (SG035-0005; NCT01100502) was initiated to answer that very question, and interim efficacy data were presented at the American Society of Hematology (ASH) Conference held in San Francisco on Dec, 8, 2014.6  This trial enrolled 329 patients who had failed first-line therapy for newly diagnosed HL, treated them with salvage chemotherapy followed by auto-SCT, and then randomized them to consolidation therapy with Adcetris (1.8 mg/kg every three weeks for up to 12 months) plus best supportive care (BSC) versus placebo plus BSC. Patients were stratified into three high-risk groups at the time of enrollment/salvage chemotherapy: those with refractory HL, those who relapsed or progressed within one year from receiving front-line chemotherapy, and those who relapsed at or more than one year after front-line chemotherapy and had extranodal disease. Following completion of salvage chemotherapy, patients were restaged and stratified again based on response to salvage therapy prior to auto-SCT: complete response (CR), partial response (PR), or stable disease (SD); patients who had progressive disease following salvage therapy were excluded from the study.

    As determined by independent review, the trial met its primary endpoint, and the results are compelling. The PFS was 43 months in the Adcetris arm and 24 months in the placebo arm (HR 0.57; 95%CI: 0.40-0.81, p=0.001). There was also some suggestion of a durable response by the PFS rate at two years, which was 63% in the Adcetris arm and 51% in the placebo arm. Subgroup analysis showed that the PFS benefit favored Adcetris in all pre-specified patient stratification groups. The OS was not significantly different between the two arms (p=0.62); however, patients who progressed on study were unblinded and allowed to cross over to the Adcetris arm, thus confounding the OS results. Indeed, 85% of patients in the placebo arm went on to receive Adcetris as subsequent therapy. As was seen with the pivotal trial that led to its approval, peripheral neuropathy of any grade was a common adverse event in these patients (any grade: 67% vs. 19% with placebo), as were neutropenia (any grade: 35% vs. 12%; Grade 3: 13% vs. 1%), nausea (any grade: 22% vs. 8%) and fatigue (any grade: 24% vs. 18%).

    As with most therapeutics studied in a maintenance setting for patients in remission, an inevitable question is, “Does early maintenance therapy have a meaningful impact on the disease compared to treating the patient upon relapse?” The gold standard used across oncology to answer this question has been overall survival. The lack of survival benefit in AETHERA is concerning since it suggests that patients will do equally well (in the long run) whether they receive Adcetris in remission as maintenance or upon relapse. However, countering this stance is the argument that there is inherent value in delaying progression. In other tumors where this debate has occurred (e.g., non-small cell lung cancer, ovarian cancer), the PFS benefit has been in the range of two to four months. The 19-month improvement in median PFS seen in AETHERA is certainly more robust and supports enthusiasm among the hematologic oncology community. This level of PFS benefit is all the more exciting when we consider that many patients reached a point where they were enjoying a treatment-free remission since consolidation Adcetris was given for up to one year; at this interim analysis, one-half of patients who had discontinued therapy did so because they completed the 12 months of treatment in the absence of disease progression. Seattle Genetics has guided that it will seek approval for Adcetris in the maintenance/consolidation setting in early 2015, and the large level of benefit observed in this study is expected to support an expanded regulatory label.

    The encouraging results in the relapsed and now in post-SCT maintenance settings support continued development of Adcetris in earlier lines of therapy for HL. The Phase III ECHELON-1 trial (NCT01712490) is examining whether Adcetris in combination with AVD will yield better efficacy than ABVD alone. For now, it looks as if Adcetris’ “hold” in relapsed/refractory HL is assured. One emerging area of need in HL is in patients who have relapsed or are refractory to Adcetris. While there is evidence that re-treatment with Adcetris following progression is efficacious,7 the potential for cumulative neuropathy may not make this a feasible option. In that vein, the PD-1 inhibitors have made their entry into the hematological malignancies. Keytruda® (pembrolizumab, Merck) and Opdivo® (nivolumab, BMS)8,9 were shown at ASH to be effective in the relapsed setting for HL following Adcetris. The data were from Phase I trials, so any firm conclusions will need to be reserved until later-stage studies are conducted, but these preliminary results are interesting. Additionally, Opdivo was tested in patients post-transplantation, which would put it in direct competition with Adcetris and may set the stage for an “immunotherapeutics showdown” between Opdivo and Adcetris. The high response rates and tolerable safety profile of PD-1 inhibitors may prove to be substantial competition for Adcetris down the road if Opdivo or Keytruda ultimately enter the relapsed/refractory HL market. For the time being, however, Adcetris will continue to be the dominant choice on the market for patients with relapsed HL.


    1. Kantar Health, CancerMPact® Patient Metrics, accessed December 8, 2014
    2. Derenzi et al., Genome Med, 2011
    3. Majhail et al., Bio Blood Marrow Transplant, 2006
    4. Younes et al., J Clin Oncol, 2012
    5. Kantar Health, CancerMPact® Treatment Architecture, accessed December 8, 2014
    6. Moskowitz et al., ASH 2014 (Abstract 673)
    7. Barlett et al., J Hematol Oncol, 2014
    8. Arman et al., ASH 2014 (Abstract 289)
    9. Moskowitz et al., ASH 2014 (Abstract 290)

    By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Len Kusdra, Analyst, Clinical and Scientific Assessment, Kantar Health

    Something to ASPIRE to? Kyprolis + RevDex combination in relapsed/refractory multiple myeloma

    Proteasome inhibitors and immunomodulators (IMiDs) are the mainstay of therapy for multiple myeloma. For years, treatment has relied on Velcade® (bortezomib, Millennium/Takeda/Johnson & Johnson) and Revlimid® (lenalidomide, Celgene) as part of first-line and second-line therapy, usually in sequence. Recently, two advances have changed this paradigm. The first is the development of triplet therapy that combines both an IMiD and a proteasome inhibitor together with steroid: The RVD regimen (Revlimid, Velcade, dexamethasone) is now the most commonly used first-line regimen in the U.S. in transplant-eligible myeloma (37% of patients), and the similar VTD regimen (Velcade, thalidomide, dexamethasone) is most commonly used in these patients in Western Europe (25% of patients).1 The second recent advance is the introduction of next-generation agents within both of these classes – the proteasome inhibitor Kyprolis® (carfilzomib, Onyx/Amgen) was approved in the U.S. in July 2012 and the IMiD Pomalyst® (Imnovid® in Europe, pomalidomide, Celgene) was approved in the U.S. in February 2013 and in Europe in August 2013. Both Kyprolis and Pomalyst are currently approved for use in relapsed/refractory myeloma patients who have previously been treated with a proteasome inhibitor and an IMiD, but expectations are high that both drugs may ultimately be used in earlier lines of therapy.

    Kyprolis received an accelerated approval in the U.S. based on a single-arm study. Confirmation of activity and European regulatory submission would be based on two randomized Phase III trials – the FOCUS trial (which compared Kyprolis versus best supportive care in third-line or later myeloma) and the ASPIRE trial. As was reported at the 2014 European Society of Medical Oncology (ESMO) annual meeting, the FOCUS trial failed to show significantly prolonged overall survival or progression-free survival (PFS) for Kyprolis versus best supportive care and also highlighted acute renal failure as a significant toxicity in this patient population.2 The failure of the FOCUS study placed greater onus on the ASPIRE trial to confirm activity of Kyprolis. The first results of the ASPIRE trial were reported at the 2014 American Society of Hematology (ASH) conference.3

    ASPIRE randomized 792 patients to treatment with KRd (Kyprolis + Revlimid + low-dose dexamethasone) or Rd in myeloma patients who had received one to three prior regimens (median two prior lines). Unlike FOCUS, the ASPIRE trial did meet the primary endpoint, showing significantly prolonged PFS in favor of the KRd arm versus the Rd arm: 26.3 months versus 17.6 months, HR 0.69, p<0.0001. The triplet combination also significantly improved response rate (ORR 87.1% versus 66.7%; CR/VGPR 69.9% versus 40.4%; and CR/sCR 31.8% versus 9.3%), and there was a trend toward improved overall survival (two-year OS 73.3% versus 65.0%; medians not reached; HR 0.79, p=0.018, which did not cross the pre-specified stopping boundary for significance at this interim analysis). Although not reported in the presentation, Dr. Stewart noted during discussions that there was a low rate of post-study Kyprolis in both arms due to the lack of regulatory approval for Kyprolis in Europe. This lack of extensive crossover may prevent the OS analysis from being confounded and give us greater confidence when interpreting the data when final analysis is available.

    Encouragingly, there were no safety signals, including no significant increase in renal failure (all grades: 8.4% versus 7.2%) or cardiac failure (all grades: 6.4% versus 4.1%). One potential reason for discordance between the FOCUS and ASPIRE trials in terms of renal toxicity may be the trial enrollment criteria: The ASPIRE trial predominantly enrolled patients with creatinine clearance (CrCl) of at least 50 mL/min, whereas the FOCUS trial included some patients with CrCl of less than 30 mL/min. Other adverse events were similar or only mildly increased in the KRd arm, with those increases typically being in the incidence of Grade 1/2 toxicity, which likely contributed to the significant improvement in EORTC Global Health Status that was observed in the KRd arm versus the Rd arm (p<0.0001).

    Of note, in this study Kyprolis was administered for only the first 18 cycles, while the Rd regimen continued to be administered to patients until disease progression or intolerance (in both arms). The reasons for this are unclear although likely represent uncertainty with regard to long-term toxicity of the triplet regimen. Interestingly, the PFS curves reached maximal separation at the 18-month timepoint, after which they appeared to begin to converge. One wonders if an even greater level of PFS or OS benefit could have been achieved if Kyprolis had been maintained along with Rd until progression, especially in light of the safety data that suggest little concerning adverse events and the improved quality of life that was achieved during the 18-month period of triplet therapy.

    What will be the impact of these results? Most significantly, the ASPIRE trial should support regulatory approval of Kyprolis in Europe. With the FOCUS trial having failed, ASPIRE is the nearest term hope to launch the drug in that market. In both the U.S. and Europe, the trial design should be sufficient for approval, since Revlimid plus dexamethasone is approved in the second-line setting. Is there a role for triplet therapy in second-line, especially in the new era of triplet therapy in first-line? Perhaps. Currently, U.S. physicians use second-line Kyprolis monotherapy most commonly in patients who received first-line RVD (24%), and only 7% use Rd post-RVD. While there is strong proof that Kyprolis is active in patients who were previously treated with Velcade, the use of Revlimid in two lines back-to-back may be less desirable to U.S. physicians, especially in an era when alternative IMiDs are available. This may limit adoption of KRd in second-line in the U.S. In contrast, European physicians use second-line Rd most commonly in patients who received first-line VTD, so the addition of Kyprolis to this standard regimen sequence might be easily adopted into practice. A key influence in both markets, however, will also be cost of therapy. Revlimid plus low-dose dexamethasone costs approximately $8,000 per month, and adding Kyprolis to that would bring the monthly cost to approximately $14,000. Patients will have to weigh the financial toxicity of this regimen against the efficacy gains, and while the U.S. tends to be more accepting of high-priced regimens, there could be a larger battle brewing in Europe. Last, but certainly not least, is the significant number of new agents with novel mechanisms of action (MOAs) that are currently in development in myeloma. When launched, will these novel MOAs be viewed more favorably than another proteasome-IMiD combination? On the horizon are HDAC inhibitors (the fate of panobinostat (Novartis) currently lies in the hands of the U.S. FDA and European Medicines Agency), anti-CD38 monoclonal antibodies (daratumumab (Genmab/Johnson & Johnson) and SAR650984 (sanofi) both presented encouraging data at ASH 2014; daratumumab has Breakthrough Therapy Status from the U.S. FDA and is already being studied in Phase III), and anti-SLAMF7 monoclonal antibodies (previously known as anti-CS-1; elotuzumab (AbbVie/BMS/Ono) also has Breakthrough Therapy Status and is currently in two Phase III trials), all of which are being studied in combination with a doublet regimen (either VelDex or Rd) in relapsed/refractory multiple myeloma.

    However these various treatment options ultimately compete in the marketplace, patients will certainly be better off. With the KRd regimen demonstrating median PFS in excess of two years in a median third-line setting and overall survival estimated to be in excess of three years, these outcomes are certainly something for us to aspire to.


    1. Kantar Health, CancerMPact® Treatment Architecture, accessed December 8, 2014.
    2. Ludwig H, et al., Abstract LBA28, ESMO 2014.
    3. Stewart AK, et al., Abstract 79, ASH 2014.

    By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health

    Want to develop a new drug? Got $2.56 billion?

    The estimated average pre-tax industry cost per new prescription drug approval now peaks at $2.56 billion—an increase of 145% since 2003. According to a study conducted by the Tufts Center for the Study of Drug Development at Tufts University in Boston, Massachusetts, this cost includes failures and capital costs, with the vast majority of drugs failing at some point during clinical testing.

    This study is one of a series of apples-to-apples comparisons that date back to the 1970s, explained presenter and principal investigator Joseph DiMasi, PhD, in a press conference. In the Tufts study, the term “drug” was used for both drugs and biologics, or both large and small molecules.

    The cost dataset in the study included 106 investigational new drugs and biologics that were first tested in humans anywhere in the world between 1995 and 2007, and came from 10 firms. Clinical period development cost data were collected up to 2013, with 5 compounds still active at the time of data collection. The study broke down annual company biopharmaceutical R&D expenditures between 1990 and 2010 in various ways to estimate pre-human R&D costs.

    Among the 1,442 compounds included, 7% were FDA approved, 80% were abandoned at some point in the development process, and 12.6% were still active in some phase. DiMasi said that, since many compounds fail in testing, phase costs must be weighted by probability of entering the phase to obtain costs per investigational compound. The probabilities of transitioning from one clinical phase to the next were:

    • 59.5% from phase I-II
    • 35.5% from phase II-III
    • 62.0% from phase III-NDA/BLA submission
    • 90.4% from NDA/BLA submission to NDA/BLA approval
    • Overall, 11.8% from phase I to NDA/BLA approval

    Stated another way, DiMasi explained that it takes an average of 8.5 compounds to get to 1 clinical approval.

    The time from synthesis of a compound to its regulatory approval was estimated to be 128 months—roughly 11 years. Pre-human expenditures, meaning R&D before a drug enters clinical testing, were estimated to be 30.8% of costs per approved compound.

    The total out-of-pocket cost per approved new compound was $1,395 billion, while the total capitalized cost was $2.558 billion. Including post-approval costs added $466 million in out-of-pocket costs and $312 million in capitalized costs.

    Capitalized R&D costs were adjusted for inflation and had a compound annual inflation-adjusted growth rate of 8.5% from the 1990s to the early 2010s. The out-of-pocket cost per approved new drug increased at an annual rate of 9.3%, which was higher than the prior studies when annual rates were 7.6% (1980s- 1990s) and 7% (1970s-1980s).

    Most of the estimated increase in R&D costs is due to increases in cash outlays used to conduct clinical development and higher drug failure rates. The direct cash outlay costs in the Tufts study had an 82.5% cost increase for out-of-pocket clinical phase costs when compared to the 2003 study. The overall risk profile, which came from the clinical approval success rate plus the distribution of failures, had costs increased by 47.3% compared to the 2003 study.

    One positive finding was that the cost in time decreased by 4.9% for the pre-human phase, by 3.0% for the regulatory review phase, and by 5.6% for the overall development timeline. This slightly affected the increase in total R&D cost for new drugs.

    by Kathy Boltz, PhD


    Palliative care is finally getting its due, with the kickoff of the Inaugural Palliative Care in Oncology Symposium in Boston, MA, Friday, October 24, 2014. The Symposium is jointly sponsored by four medical societies: American Society of Clinical Oncology (ASCO), American Academy of Hospice and Palliative Medicine (AAHPM), American Society for Radiation Oncology (ASTRO), and the Multinational Association of Supportive Care in Cancer (MASCC).

    Themes of the Palliative Care in Oncology Symposium segue from presentations at last week’s ASCO Quality Care Symposium. At that meeting, the focus was on palliative care—an important component of quality care, especially at end of life. Billions of dollars a year are wasted on unnecessary direct care, much of it on end of life care (in fact a 2012 IOM report states that it reaches $210 billion each year).  The field is moving toward greater acceptance and use of palliative care when appropriate.

    The pre-symposium press cast for the Palliative Care Symposium featured four presentations that addressed strategies to improve palliative care and the treatment-related financial burdens of cancer care for patients (referred to by quality care experts as “financial toxicity”).

    Addressing Patients’ Financial Burdens (Abstracts 238 and 161)

    In an analysis of nearly 1600 cancer survivors, a sizeable proportion of cancer patients reported financial and work-related burdens: about half were under age 65; 96% reported some kind of insurance; 27% reported at least one financial difficulty (defined as borrowing money, debt, bankruptcy, worry, and financial sacrifices), and 37% reported having to make at least one work modification (defined as early retirement, changing jobs, turning a promotion down, unpaid or extended leave) due to a cancer diagnosis.

    People younger than age 65 reported 130% more financial difficulties than older survivors; the uninsured had 67% more financial difficulties than the insured; and minority groups reported 42% more financial difficulties than whites. The 14% of patients currently in active treatment made 120% more work modifications than those less than 5 years post-treatment; non-white minorities made 57% more work modifications than whites.

    Lead author Robin Whitney, RN, BSN, a cancer survivor and PhD student at the University of California, Davis, Betty Irene Moore School of Nursing, said: “Many cancer survivors, particularly those who are younger and from underserved populations, experience financial or work-related hardship –even when insured and years out from treatment.” She and her co-authors say the findings of this study are generalizable to the U.S. population and reveal the need for screening and support for financial and work challenges across the survivorship trajectory.

    “We now have more than 12 million cancer survivors,” said press cast moderator Jyoti Patel, MD, representing ASCO, “We need to address their financial hardships. As we deal with the consequences of cancer treatment and therapy, we need to find creative ways to address these burdens.”

    Cancer Patients Make Lifestyle Adjustments

    A related nationwide survey showed that due to treatment-related financial burdens, many insured cancer patients either make adjustments in lifestyle or make a compromise with their medical care. The study included 174 patients currently undergoing treatment for solid tumors—all of them insured and requesting financial assistance through a national copay assistance program.

    Overall, 89% reported at least one lifestyle-altering strategy while 39% reported at least one medical care-altering strategy. Most common medical care-altering strategies were not filling a prescription (28%) and taking less medication than prescribed (23%). Lifestyle-altering coping strategies included spending less money on leisure activities (78%), spending less on food and clothing (57%), borrowing money (54%), and spending savings (50%).Younger age and lower income people were associated with increased care-altering strategies; while younger age, higher education level, and shorter time on chemotherapy were associated with greater likelihood of adopting lifestyle coping strategies compared with their counterparts.

    “We need a better, more open dialog between patients and providers about the financial burdens associated with cancer care costs. People use a range of coping strategies, and we need to engage with patients on their choices and develop screening tools to identify patients who are likely to make potentially harmful decisions about their treatment,” said lead author Ryan Nipp, MD, an oncology fellow at Dana-Farber Cancer Institute in Boston.

    Dr. Patel commented, “As we make strides in understanding the whole patient, it is incumbent upon us to have these discussions about financial burden with them. We need guided efforts to help support these patients, especially those at risk.”

    “Co-Rounding” at Duke (Abstract 3)

    According to a retrospective cohort analysis of a pioneering approach of “co-rounding” at Duke University Medical Center, daily collaboration between medical oncologists and palliative care specialists improved health system-related and patient-related outcomes. “Co-rounding” teams included 1 medical oncologist and 1 palliative care specialist as attending physicians, as well as ancillary healthcare providers. The teams met each day to discuss individual patients.

    This first evaluation of “co-rounding” at Duke took place after one year of the new partnership which functioned in the hospital’s inpatient solid tumor oncology unit. Comparison between 731 patients admitted pre-intervention and 783 admitted in the first year of the intervention showed that “co-rounding” was associated with a significant decrease in length of hospital stay (4.17 days versus 4.51 days, respectively, P=.02); 15% reduction in the risk of 7-day readmission (P<.0001), and a 23% risk reduction for 30-day readmission (P=.048). ICU transfers were decreased by 15% from pre- to post-intervention, and hospice referrals were increased by 17% after “co-rounding” was instituted. Doctors and nurses expressed satisfaction with the new approach.

    “Leveraging the skill sets of both palliative care physicians and medical oncologists has allowed us to better manage symptoms, shorten hospital stays, and prevent readmissions. We’ve also been able to dispel any misconceptions that individuals may have had about the role of palliative care, and we’ve shown that nursing and physician impressions of palliative care, as a whole, are very favorable,” stated lead author Richard Riedel, MD, Duke University Medical Center, Durham, NC.

    “This study shows that integrating palliative care into oncology defines good oncologic care. We see that a novel approach called ‘co-rounding’ has achieved impressive results,” Dr. Patel stated.

    “Smart Phone” System for Home Hospice (Abstract 85)

    Preliminary findings from a randomized study of 319 hospice dyads and 121 nurses (some cared for multiple families) suggest that daily use of “smart technology” with an automated telephone-based remote symptom monitoring and coaching system alleviated patients’ symptoms and caregiver burden during home hospice care in the final weeks of life. The study population was drawn from 12 hospices in four different states. Almost half the patients (n=153) were randomly assigned to the intervention and the other patients (n=166) received usual care, which entailed symptom reporting alone.

    “This is the first study to evaluate automated collection of patient-reported symptoms and its effect on family caregiver well-being and on coaching families on ways to improve care for their family member,” said lead study author Kathi Mooney, PhD, RN, Utah College of Nursing and the Huntsman Cancer Institute in Salt Lake City.

    “Remote symptom care, working through the caregiver, provides benefits to the dying patient and caregiver,” stated Bob Wong, PhD, a statistician from the same institution who was an author of the study.

    The automated, telephone-based symptom monitoring system used computer-based technology; the caregiver entered daily ratings (0-10, with 10 being the most severe) for 11 common symptoms that the patient could have experienced in the past 24 hours, and then got feedback from the system if any of the symptoms were rated 4 or higher. The feedback included tips for the caregiver about how to relieve patient’s symptoms; for example, coaching on such maneuvers as positioning the patient for greater comfort or improved breathing, and how to improve time together. Caregivers also reported their own difficulties during the past 24 hours, such as fatigue, anxiety, difficulty sleeping and negative mood.

    Over a 91-day period, patients whose caregivers were assigned to the automated system experienced 44% fewer days of moderate or severe fatigue or anxiety compared with patients in the usual care group. Caregivers in the intervention group had no worsening of vitality (as measured by daily functioning and sleep) over that period, while the usual care caregivers had worsened vitality.

    “Caregiving is a 24-hour-a-day, 7-days-a-week job,” Dr. Patel commented. “Most caregivers cannot do it alone. This remote monitoring system proactively supports the caregiver at this difficult time when the patient is near death.”

    By Alice Goodman

    HER2+ Breast Cancer: Immediate Impact of 2014 ESMO Presentations on Clinical Practice


    In an effort to provide you with timely market feedback from ESMO 2014, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPoll™ from the meeting. This report explored presentations in HER2+ Breast Cancer.

    OncoPoll™ Methodology

    • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in breast cancer utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
    • Timing: October 2014. Launched three days after close of ESMO 2014 Congress, held in Madrid, Spain September 26th – 30th, 2014
    • Fielding via <10 minute long interactive internet survey utilizing proven effective methodology via the MDoutlook® survey tool
    • Links to discussed abstracts on the ESMO website were provided within the survey
    • Reponses at data collection: 104 on October 13th
      • 37 US respondents
      • 67 EU/Rest of World (RoW) respondents
      • 28 countries represented
    • No financial incentives provided for participation

    Attendance at 2014 ESMO Congress

    Key Conclusions

    • Nearly a 50/50 split of EU/Rest of world (RoW) respondents* attended the ESMO 2014 Congress
    • US survey respondents were nearly five times less likely to attend ESMO 2014, in comparison to their international counterparts

    * Survey Participants = Medical Oncologists with an identified clinical interest in breast cancer

    Survey Participants’ Metastatic Breast Cancer Patient Flow: Average Over 40 Breast Cancer Cases Each Quarter

    Key Conclusions

    • On average, US oncologists reported seeing more patients in all three subtypes in the last three months, in comparison to their international colleagues
    • US oncologists see nearly 14 HER2+ patients per quarter
      • EU/RoW oncologists see nearly 11 HER2+ patients per quarter
    • Cases of HR+/HER- metastatic breast cancer were more common for both US oncologists (avg. 28/quarter) and EU/RoW oncologists (avg. 26/quarter) than other metastatic breast cancers

    Impact of the Phase III Cleopatra Study: EU/RoW Oncologists Expecting to Increase Usage of Trastuzumab+Pertuzumab in the Next Year for HER2+ Metastatic Breast Cancer Patients

    Key Conclusions

    EU/RoW Clinicians

    • The majority of EU/RoW oncologists (65%) are currently using Trastuzumab combined with chemotherapy alone for their HER2+ metastatic breast cancer (in all lines of therapy). 23% of EU/RoW oncologists are using Trastuzumab+Pertuzumab, and 11% are using Trastuzumab emtansine
    • In the next year, nearly all EU/RoW oncologists expect to completely forego the use of Trastuzumab alone for their metastatic patients (in all lines of therapy)
    • In the next year, 52% of EU/RoW oncologists expect to use Trastuzumab + Pertuzumab. Additionally, 55% of EU/RoW oncologists expect to use Trastuzumab emtansine for their HER2+ metatstatic breast cancer patients (in all lines of therapy)

    US clinicians

    • Currently, US oncologists are utilizing several HER2+ targeted therapies, with 49% using Trastuzumab, 49% using Trastuzumab+Pertuzumab, and 38% using Trastuzumab emtansine for their HER2+ metastatic patients (in all lines of therapy)
    • In the next year, a minimal proportion (10%) of US oncologists will be using Trastuzumab alone
    • In the next year, 64% expect to use Trastuzumab emtansine while only 39% of US oncologists expect to use Trastuzumab + Pertuzumab for their HER2+ metastatic patients (in all lines of therapy)

    Impact of the Phase III Cleopatra Study: US and EU/RoW Oncologists Expect to Use Trastuzumab+Pertuzumab in the First Line for their HER2+ Metastatic Breast Cancer Patients

    Key Conclusion

    • When Trastuzumab+Pertuzumab is used, ~75% of both US and EU/RoW oncologists expect to use it as a first line therapy for their HER2+ metastatic patients

    Impact of the CherLOB Study: The Majority of US and EU/RoW Oncologists Believe the Data Presented in the CherLOB Study is Clinically Important

    Key Conclusions

    • 75% of US oncologists rated the clinical importance of this study highly (either a four or five)
      • Similarly, 61% of EU/RoW oncologists rated this data to be either a four or five
      • Very few (<5%) oncologists rated this study as not having clinical importance

    Impact of the CherLOB Study: US and EU/RoW Oncologists Expect to Increase Testing for the PIK3CA Mutations in HER2+ Breast Cancer Patients

    Key Conclusions

    • In the past year, minimal PIK3CA mutation testing by US and EU/RoW oncologists was occurring for HER2+ breast cancer patients (<10%)
    • Due to the correlation between the PIK3CA mutation and pathological complete response (pCR) in patients with HER2+ early breast cancer being treated with neoadjuvant lapatinib and trastuzumab, both US and EU/RoW oncologists expect to increase testing for PIK3CA mutations in both early and metastatic breast cancer patients
      • 31% of early breast cancer patients being treated by US oncologists will be tested for the PIK3CA mutation in the next year
        • This data had less of an effect on EU/RoW oncologists: 16% of early breast cancer patients will be tested
    • Over 40% of metastatic breast cancer patients being treated by US oncologists will be tested
      • Nearly 1 in 5 of metastatic breast cancer patients being treated by EU/RoW oncologists will be tested for the PIK3CA mutation

    Conclusions: Impact of ESMO 2014 Presentations on Clinical Practices for HER2+ Breast Cancer

    • US oncologists see nearly 14 HER2+ patients per quarter
      • EU/RoW oncologists see nearly 11 HER2+ patients per quarter
    • Trastuzumab is currently the most commonly used HER2 targeted therapy by EU/RoW oncologists (64%)
      • Trastuzumab and Trastuzumab+Pertuzumab are being equally used (~45%) by US oncologists
      • Impact of the Phase III Cleopatra Study:
        • EU/RoW oncologists are expecting to increase their usage of Trastuzumab + Pertuzumab in the next year for their HER2+ metastatic breast cancer patients (52%) (in all lines of therapy)
        • US oncologists are expecting to decrease their usage of Trastuzumab+Pertuzumab for HER2+ metastatic patients (39%) (in all lines of therapy)
          • US oncologists (64%) are expecting increase usage of Trastuzumab emtansine
          • Impact of the CherLOB Study:
            • The majority of US and EU/RoW oncologists believe the data presented in the CherLOB study is clinically important
            • In the past year, minimal PIK3CA mutation testing by US and EU/RoW oncologists was occurring for HER2+ breast cancer patients (<10%)
            • 31% of early breast cancer patients being treated by US oncologists will be tested for the PIK3CA mutation in the next year
              • 16% of early breast cancer patients treated by EU/RoW oncologists will be tested
    • Over 40% of metastatic breast cancer patients being treated by US oncologists will be tested in the next year
      • 19% of metastatic breast cancer patients being treated by EU/RoW oncologists will be tested for the PIK3CA mutation

    For a more detailed analysis report, please click here to download the full report.

    Submitted by Jessica Harnisch, Assoc. Global Medical Analyst; Robert Stephan, Sr. Director Medical Services and Strategy; Justin Boag, Consultant; and Jan Heybroek, President MDoutlook.


    ALEXANDRIA, VA – A pre-meeting presscast gives a bird’s eye view of research that will be presented when ASCO’s 2014 Quality Care Symposium meeting swings into full gear in Boston, Mass., this coming Friday.  Separate studies featured at the presscast focused on the influence of sociodemographic factors on treatment selection and mortality, as well as physician and patient factors associated with improved cancer care.

    Parental Status and Treatment Choice

    A pilot survey of 42 patients indicates that having children influences choice of cancer treatments for patients with advanced cancer (Abstract 65). The majority of parents (64%) in the study indicated that parenthood motivates them to purse life-extending treatment so that they can gain more time with their children. About 15% said that preserving parental functioning was a treatment priority, and 12% cited the importance of receiving treatments close to home rather than travel for a second opinion or have treatment that requires long hospital stays. Interestingly, 24% of respondents did not perceive having children as an influence on their treatment decisions.

    About 50% viewed hospice as a supportive resource, taking the burden off of family, and about 21% were not interested in hospice. Respondents seemed to conflate palliative care with end of life care, suggesting an area where more clarification is needed for patients.

    These findings suggest that physicians should discuss factors related to parental status with their patients when deciding on a course of treatment. “This study provides some insights into parenting considerations for the first time, and should encourage conversations between oncologists and patients about treatment priorities,” said lead author Devon Check, a PhD candidate at the University of Carolina in Chapel Hill, NC.

    This is the first study to ask advanced cancer patients with dependent children directly about the effect of parental status on treatment decision-making.  The researchers are planning a larger study to explore the associations among parental status, parental concerns, and medical decision-making for patients with advanced cancer.

    “This study stresses the need to individualize care according to the patient’s circumstances. It would be great to see other studies of this sort,” said presscast moderator Gregory A. Masters, MD, Chair of ASCO’s Cancer Care Communications Committee.

    Financial Assistance Improves Adherence

    It is well known that adherence to adjuvant hormone therapy improves survival, yet it is suboptimal among women with hormone receptor-positive breast cancer. A large study of more than 23,000 women suggests that Medicare Part D Extra Help program, which provides low-income subsidies for medications, boosts adherence to adjuvant hormonal therapy across the board in racial/ethnic groups and reduces disparities in health care (Abstract 2). These findings suggest that addressing economic barriers to medication access has the potential to reduce disparities in outcomes, especially among racial minority groups.

    “Patients are more likely to take their medications if they can afford them. Our study shows that federal policy interventions that help cover out-of pocket costs may be able to reduce the gap in breast cancer outcome between white patients and racial minorities,” stated lead author Alana Biggers, MD, MPH, Medical College of Milwaukee, Wisc.

    The study population included 23,299 Medicare Part D enrollees with early-stage breast cancer who received hormone therapy within 1 year of surgery. Overall, 27% were enrolled in the Extra Help low-income subsidy program. Women from racial minority groups were more likely to be enrolled in the program; 70% of black women and 56% of Hispanic women received Extra Help, compared with 21% of white women.

    Overall, 3-year adherence rates for hormonal therapy were similar across all races; but in the subgroup not enrolled in the Extra Help program, white women had significantly higher adherence rates (62%) compared with black and Hispanic women (55%). Adherence rates were highest among women receiving the low-income subsidy versus those who did not for all racial groups: 71% for white women versus 62% for white women; 67% versus 55% for black women; 71% versus 55% for Hispanics.

    “This interesting study shows that using low-income subsidies can help us understand how these programs support adherence and improve overall survival. Adherence is linked to better care,” Dr. Masters commented.

    Tumor Board Participation Improves Outcomes in Certain Cancers

    Oncologist participation in weekly tumor board meetings appears to improve survival for patients with stage IV small-cell lung cancer and stage IV colorectal cancers, according to a population-based observational study of almost 5000 patients with lung or colorectal cancer and 1600 oncologists (Abstract 179). Oncologist participation in tumor board meetings also boosted the chances of patient enrollment in clinical trials and increased the likelihood of patients with early-stage non-small cell lung cancer (NSCLC) receiving guideline-based curative surgery.

    “These findings are exploratory and will be the basis of future study. Patients with these tumors may want to ask their doctors if their cases will be discussed by a tumor board that includes multidisciplinary experts,” said lead author Kenneth L. Kehl, MD, a fellow in cancer medicine at the University of Texas MD Anderson Cancer Center in Houston.

    The study revealed different patterns of oncologist participation in multidisciplinary tumor boards. About 54% participated weekly, 26% participated monthly, 8% participated quarterly.

    Dr. Kehl cautioned that this was not a randomized trial, so one should not leap to the conclusion that tumor board participation directly improves survival. The study identifies associations rather than direct effects.

    “This study supports our belief that multidisciplinary communication improves outcomes and enrollment in clinical trials. Tumor boards are one educational tool that can improve care for cancer patients and the effect is difficult to measure,” Dr. Masters noted.

    Sociodemographic Disparities Affect Death Rates

    Being married, having insurance, being white, female gender, younger age, higher education level, higher income level, insurance coverage, and earlier stage of cancer all appear to reduce the likelihood of dying 1 month after cancer-related surgery (Abstract 282) These findings come from a study of more than 1.1 million patients in the SEER database undergoing surgery for the most common or most fatal cancers; among these, 53,498 (4.8%) died within 1 month of surgery.

    Previous research suggests that 1-month mortality following surgery is associated with hospital and surgeon volume. Minority race, uninsured status, and low-income level are known factors associated with less likelihood of receiving care at a high-volume, high performance hospital.

    A limitation of the study is that SEER does not include data on comorbidity or place of care.

    “Our results suggest that there is a lot we can do for all patients to improve outcomes. We can start by identifying and supporting improvements for under performing hospitals as well as proactively offering social support services to patients at high risk of poorer outcomes,” said lead author Brandon A. Mahal, a fourth-year medical student at Harvard Medical School and research fellow at Dana-Farber Cancer Institute in Boston.

    “This study highlights special risk groups and emphasizes the need for strong psychosocial support to improve their outcomes,” Dr. Masters said.


    At the presscast, Deborah A. Mayer, PhD, University of North Carolina, Chapel Hill,  informed listeners about the availability of ASCO’s new streamlined template for a care plan for cancer survivors. This 2-year effort makes the care plan easier to implement and will hopefully transition care from oncologists to primary care physicians for the growing number of cancer survivors who benefit from advances in treatment.  The template is available on the ASCO website.

    By Alice Goodman

    The showdown between PD-1 targeted therapeutics spans several tumor types

    By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health, Tatiana Spicakova, Consultant, Clinical & Scientific Assessment, Kantar Health, Greg Wolfe, Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

    The role of Programmed Death-1 (PD-1) pathway in suppression of antitumor immunity has become one of the hottest topics in oncology over the past couple of years. PD-1 is a key immune checkpoint receptor expressed on activated T-cells, and binding of PD-1 to its ligand (PD-L1) results in the suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from the attack by tumor-specific T-cells. A number of immune checkpoint inhibitors are in late-stage clinical development; these agents work by blocking the interaction between PD-1 and PD-L1, thereby activating the immune system against cancer cells.

    PD-1 Pathway Inhibitors in Phase III Development

    Drug Manufacturer Antibody Target Development Stage Ongoing pivotal trials
    Keytruda Merck Humanized IgG4 PD-1 Approved in Yervoy-treated melanoma (U.S.); Phase III Melanoma, NSCLC, Head and Neck
    Opdivo BMS Human IgG4 PD-1 Filed in Yervoy-treated melanoma (US/EU)

    Filed in squamous 3rd line NSCLC (US/EU); Phase III

    Melanoma, NSCLC, RCC, Head and Neck
    MPDL3280A Roche Human IgG1 PD-L1 Phase III Bladder, NSCLC
    MEDI-4736 AstraZeneca Human IgG1 PD-L1 Phase III NSCLC

    For these novel immune checkpoint inhibitors, the fight to capture the lead in high-profile tumor types such as melanoma and non-small cell lung cancer (NSCLC) is becoming increasingly fierce. But their clinical development does not end there and, in fact, continues to expand into other indications, such as renal cell carcinoma (RCC), urothelial cancer, head and neck cancer, gastrointestinal cancer and hematological malignancies. Data continued to report promising activity across different tumor types at the annual 2014 European Society for Medical Oncology (ESMO), as summarized below.

    Opdivo improves response rate versus chemotherapy in Yervoy-treated melanoma in a Phase III randomized trial – is its efficacy superior to the already approved Keytruda?

    (Weber, Abstract LBA3)

    Past oncology meetings have highlighted the promise of Opdivo™ (nivolumab, Bristol-Myers Squibb) in melanoma. Opdivo demonstrated impressive early clinical data that suggested improved overall response rate (ORR) with fewer toxicities when compared with historical data for Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 immune checkpoint inhibitor. At ASCO 2014, another anti-PD-1 monoclonal antibody, Keytruda® (pembrolizumab, Merck), took center stage with impressive Phase II data that ultimately led to its approval in the U.S. in September 2014 as therapy for Yervoy-treated melanoma patients.

    Recognizing the urgency of getting to market as soon as possible, BMS submitted U.S./EU regulatory applications for Opdivo for Yervoy-treated melanoma, with expected U.S. approval in March 2015. Once Opdivo becomes approved, physicians will look to efficacy and safety data to drive their decision when choosing between the two agents. At ESMO, highly anticipated data from a randomized Phase III study (Opdivo versus chemotherapy of choice) were presented for 405 previously treated (including Yervoy) unresectable Stage III/IV melanoma patients.

    The ORR was 32% for Opdivo versus 11% for chemotherapy, with benefit observed across all subgroups, including PD-L1 negative patients. Grade 3/4 toxicities were reported in 9% of patients in the Opdivo arm versus 31% in the chemotherapy arm, with no new safety signals reported. Unfortunately, the progression-free survival (PFS) and overall survival (OS) data were not yet available at the time of analysis, but duration of response among responding patients suggests prolonged benefit (3.6 months in the chemotherapy arm versus median not reached in the Opdivo arm but with 95% of responders still benefiting at six months). So how does Opdivo compare to Keytruda in this patient population? As shown below, the activity appears very similar between the drugs, and no dramatic differences exist in their safety profiles.

    Efficacy in Previously-Treated Metastatic Melanoma

    Drug ORR CR mPFS
    Opdivo (n=120) 32% 3% ND
    Chemotherapy (47) 11% 0% ND
    Keytruda (n=197)1 28% 2% 5.6 mos

    1Ribas, Abstract LBA9000, ASCO 2014

    While response rate is a valid and informative endpoint about the drug’s efficacy, PFS and OS data ultimately might help decide which of the two will become the winner. This is especially important for Opdivo’s trial, in which OS was the co-primary endpoint. Will the improved response rates translate into a statistically significant OS benefit that supports the regulatory applications? The expected answer is yes, although due to immature data we now continue to wait with bated breath for this data. While Keytruda already demonstrated that PD-1 inhibitor works in Yervoy-treated melanoma patients, the results from the Opdivo trial were significant in that it presented, for the first time, data from a randomized Phase III study. Commercially, Keytruda will have a six-month time-to-market advantage over Opdivo and will likely amass a strong foothold in the Yervoy-pretreated setting by the time Opdivo launches. Will having overall survival data from a randomized study (assuming it is available by the time of launch) sway physicians to forgo Keytruda in favor of Opdivo, or will physicians interpret a positive survival benefit for Opdivo to be a surrogate for similar expectations with Keytruda?

    Is Keytruda leading the PD-1 pack in NSCLC?

    (Garon, Abstract LBA43)

    Safety and efficacy data for Keytruda were reported for previously treated and treatment-naive NSCLC patients enrolled in Phase I study expansion cohorts. In 262 patients, treatment-related adverse events included (any grade; Grade 3/4) fatigue (20%; <1%), pruritus (9%; 0%) and pneumonitis (4%, 2%). In 236 evaluable patients, the ORR was 21% (26% in treatment-naïve and 20% in previously treated patients).  Curiously, current/former smokers appeared to achieve a better response compared to never smokers (27% vs 9%), although the underlying reasons for this observation remain unknown. Median PFS and OS also appeared better for treatment-naïve versus previously treated patients (mPFS: 27 weeks vs. 10 weeks; mOS: not reached vs. 8.2 months).

    The study evaluated whether the expression of PD-L1 biomarker correlates with outcomes. Strong PD-L1 expression was defined as 50% or higher membrane staining in tumor cells and weak expression as 1-49%. The ORR correlated with the level of PD-L1 expression (37% for strong positive, 17% for weak positive and 10% for negative). PFS was also longer for patients with strong versus weak PD-L1 expression (HR 0.52), as was OS (HR 0.59). While the efficacy certainly appears better for PD-L1 positive patients, it is not a black-and-white scenario, and many unresolved issues remain. Namely, differences exist in how the PD-L1 biomarker is measured in the different assays that the various manufactures are developing (what antibody is used), how tissue is collected (old, frozen tissue versus fresh biopsy), where it is measured (tumor cells versus tumor-infiltrating immune cells) and which cutoff threshold is used (1% versus 5% versus others). More importantly, a subset of PD-L1 negative patients still derive a benefit from these inhibitors, yet many of the pivotal trials in NSCLC are conducted in PD-L1 positive tumors. How will that affect the real-world patients, and will the biomarker-negative patients be denied treatment if the drugs receive PD-L1 positive labels (especially outside of the U.S., where payers tend to impose stricter rules)? Keytruda is exclusively targeting PD-L1 positive patients in its pivotal NSCLC trials, while BMS chose to target both PD-L1 positive patients as well as all-comers (including squamous and non-squamous histologies). If those trials are positive, perhaps the inclusion of these patients will enable BMS to have a competitive marketing edge over Keytruda.

    While the data presented for Keytruda was certainly very encouraging, how does it compare with the other key competitors that are also vying to win the NSCLC space? At a first glance, it appears that the agents have similar levels of activity in terms of response rates and survival. But the data are still premature, and the efficacy and safety could start differentiating as more patients are enrolled and longer follow-up becomes available. For now, there is no clear winner in NSCLC, and it has yet to be determined whether targeting the receptor versus ligand may prove to be a more efficacious or safer strategy.

    Drug NSCLC ORR



    (1st line)

    NSCLC ORR (pretreated) mPFS mOS
    MPDL3280A1 23% (n=53) ND 23% (n=53) ND ND
    MEDI-47362 16% (n=58) ND 16% (n=58) ND ND
    Opdivo3 17% (n=129) 30% (n=20) 17% (n=129) 2.3 mos 9.9 mos
    Keytruda4 21% (n=236) 26% (n=42) 20% (n=194) 2.5 mos 8.2 mos

    1Soria, 1322P, ESMO 2014

    2Brahmer, Abstract 8021, ASCO 2014

    3Gettinger, Abstract 8024, ASCO 2014

    4Garon, LBA43, ESMO 2014

    In terms of approval timelines in NSCLC, BMS has an advantage over the other agents as it already submitted a regulatory application in the EU and a rolling submission in the U.S. for Opdivo as a third-line therapy in squamous NSCLC. The submissions were based on data from a Phase II study, and the drug could be approved in both regions next year.

    Keytruda shows promising activity in gastric and urothelial cancers

    Like BMS, Merck is also pursuing an aggressive development strategy for Keytruda that spans multiple tumor types. Promising preliminary results were reported at ESMO for the gastric cancer (Muro, Abstract LBA15) and urothelial cancer (Plimack, Abstract LBA23) cohorts from the KEYNOTE-012 Phase Ib study. In the gastric cancer presentation, 162 patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) were screened to identify 65 (40%) patients with PD-L1 positive tumors, who were then treated with 10 mg/kg Keytruda every two weeks. Keytruda showed an acceptable safety profile in 39 evaluable patients, although there was one incidence each of Grade 4 pneumonitis and Grade 5 (fatal) hypoxia. Keytruda achieved 30.8% ORR (no complete responses) and reduction in tumor size in 41% of patients. Efficacy was similar in Asian and non-Asian patients, and responses were durable. Based on these results, initiation of a Phase II trial in advanced gastric cancer is expected in in the first quarter of 2015.

    In the urothelial cancer cohort, 95 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder or urethra were screened to identify 61 (64.2%) patients with PD-L1 positive tumors. Thirty-three patients with PD-L1 positive tumors were treated with 10 mg/kg Keytruda every two weeks. Grade 3 or higher adverse events were observed in four patients and included AST increase, dehydration, neuromyopathy, macropapular rash, pruritic rash, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy (n=1 for each, some patients had multiple Grade ≥3 adverse events). The ORR was 24.1% (including three complete responses), and a reduction in tumor size was observed in 64% of patients. Six of the seven responses were ongoing, and median duration of response was not reached at a median follow-up of 11 months. These promising results served as the impetus for the Phase III KEYNOTE-045 trial scheduled to begin by the end of 2014.

    MPDL3280A shows promising activity in monotherapy activity in bladder, and activity in RCC in combination with Avastin, but will it succeed in CRC?

    Roche/Genentech was awarded breakthrough therapy status for its MPDL3280A in urothelial bladder cancer (UBC) in May 2014. Unlike Opdivo and Keytruda, this antibody targets the ligand (PD-L1) rather than receptor, but it is too early to tell whether this strategy will translate into better efficacy and/or a better safety profile.  Perhaps recognizing the increasing crowdedness and being too late to the melanoma market, Roche’s clinical development strategy has focused on other tumor types, including NSCLC and RCC as well as the less commercially attractive (in the eyes of big pharma) urothelial/bladder space. Its first potential approved indication is likely to be bladder, in which they could file for an accelerated approval based on data from the ongoing Phase II study, thus potentially beating Keytruda to the market in the urothelial space. It would certainly give physicians the chance to become familiar with the agent in the real-world setting so that by the time the agent is approved (if successful) in larger indications, it may ease the adoption process by clinicians; being approved on the market could also aid in off-label utilization following positive Phase III data in other tumor types, bypassing a delay for supplemental regulatory approval. In terms of its activity in metastatic RCC as monotherapy, data were presented from a Phase I expansion cohort that included 69 patients (McDermott, Abstract 809O). MPDL3280A was very well-tolerated in these patients with Grade 3 or higher fatigue reported in two patients; all other adverse events were Grade 1/2.  In 62 evaluable patients,  the ORR was 20% in patients with PD-L1 expression of IHC1+/2+/3+ (including one complete and six partial responses) and 10% in patients who were PD-L1 negative (IHC0).

    While the inhibitors have been primarily tested as monotherapy, the next wave of trials will examine their efficacy in combination with other regimens, such as chemotherapy, targeted therapy and other immune modulators. Not surprisingly, Roche has already begun the clinical development of MPDL3280A in combination with Avastin® (bevacizumab) and reported preliminary data from a Phase Ib study (Lieu, Abstract 1049O). The study had two arms: Arm A (n=35) evaluated MPDL3280A IV every three weeks plus Avastin 15mg/kg IV every three weeks; Arm B (n=36) evaluated MPDL3280A IV every two weeks plus Avastin 10mg/kg every two weeks and FOLFOX. Dose expansion cohorts in Arm A included patients with colorectal cancer (CRC) and other solid tumors, including breast, melanoma, NSCLC and RCC; Arm B included oxaliplatin-naïve CRC (with or without liver lesions) as well as other solid tumors, including RCC and breast cancer. In Arm A, the combination with Avastin achieved 40% ORR in the first-line RCC cohort (n=10) and 8% ORR in CRC patients. In Arm B, the combination with Avastin plus chemotherapy achieved 36% ORR in CRC.

    Avastin plus chemotherapy has been a blockbuster regimen in the treatment of CRC, so it is not surprising that Roche is pushing the combination with its PD-L1 inhibitor. Notably, initial data from Opdivo’s Phase I trial did not show activity in CRC (or prostate cancer), so CRC has not been on the forefront of pivotal studies for other PD-1 inhibitors. While the 36% ORR is certainly encouraging, one must question how much of it was contributed by Avastin plus chemotherapy alone. The response rate appears similar to that observed in pivotal trials for Avastin plus chemotherapy, so the early readout seemed perhaps a bit underwhelming.

    But the response rate may not be the best endpoint to evaluate the efficacy of the combination regimen as immunotherapy does not always follow the standard response kinetics and can be associated with delayed responses. So it is still possible that longer follow-up might show improved survival, but will it produce truly stellar results as we have seen so far for the combination of two checkpoint inhibitors in melanoma (Sznol, Abstract LBA9003, ASCO 2014)? In the absence of randomized data, it is difficult to say whether this combination will pan out in CRC. The data in RCC, on the other hand, appear much more promising for the Avastin combination, although the number of patients was small. Avastin has shown efficacy as monotherapy in frontline RCC by achieving approximately 13% ORR, so the reported 40% ORR when combined with PD-L1 inhibitor provides encouraging evidence that the improved efficacy is driven by the addition of MPDL3280A. The activity of the combination regimen certainly appears higher compared to MPDL3280A alone, as discussed above, and might be the strategy going forward, although no such plans have been announced yet. It certainly would help Avastin garner greater utilization in RCC, where it is approved but not a key competitor. However, MPDL3280A plus Avastin will find itself competing with Opdivo, which is currently being studied in combination with Yervoy as first-line therapy for RCC in a head-to-head trial versus Sutent® (sunitinib, Pfizer).

    The amount of data presented at ESMO on the role of immune checkpoint inhibitors was impressive and quite overwhelming. It has become very clear that PD-1 targeted drugs are considered a major breakthrough in oncology with the promise to make a meaningful impact in the lives of patients with various malignancies. To date, data has focused on their activity in solid tumors, but we expect to see the first sets of data for these agents in hemtatologic malignancies at the upcoming American Society of Hematology (ASH) conference. It is the beginning of exciting times in oncology and we can all sit back and enjoy the fight for the PD-1 space spanning multiple tumors.

    CLEOPATRA: Overall survival data makes Perjeta the unmistakable queen in first-line HER2+ metastatic breast cancer

    By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

    The introduction of Herceptin® (trastuzumab, Roche/Genentech) over a decade ago turned HER2+ metastatic breast cancer (MBC) from what was once a patient population with poor prognosis to one with a vastly improved outlook and led the way for an influx of targeted therapies for this population. Now, the armamentarium against HER2+ MBC has expanded and includes several HER2-targeted agents: Tykerb® (lapatinib, GSK), Perjeta® (pertuzumab, Roche/Genentech) and Kadcyla® (ado-trastuzumab, Roche/Genentech). Updated overall survival (OS) data from the CLEOPATRA (NCT00567190) trial were presented at the Presidential Symposium at ESMO on September 28, 20141, and the results will serve to further solidify Roche as the dominant player in HER2-targeted treatment in MBC, if there was any doubt before now. The CLEOPATRA trial was designed to test whether the combination of Herceptin, Perjeta and docetaxel improved outcomes in first-line HER2+ MBC patients. The study randomized 808 patients to receive Hercpetin plus docetaxel plus either placebo or Perjeta. The primary endpoint was progression-free survival (PFS), and secondary endpoints included OS, PFS as assessed by the investigator, overall response rate and safety.

    The initially published results2 in 2012 showed an improvement in PFS from 12.4 months in the control group to 18.5 months in the Perjeta group (HR=0.62; 95% confidence interval (CI), 0.51-0.75; P<0.001). The objective response rate was 69.3% in the control group and 80.2% in the Perjeta group (95% CI, 4.2-17.5; P = 0.001). These significant positive results led to FDA approval in 2012 and European approval in 2013 for Perjeta in combination with Herceptin and docetaxel as first-line treatment in HER2+ MBC. At the time, however, the data was not yet mature to determine OS, and many were left wondering whether the impressive improvement in the primary endpoint of PFS would translate into an equally significant improvement in OS.

    Final results of CLEOPATRA did not disappoint. With a median follow-up of 50 months (range 0-70 months), addition of Perjeta to Herceptin plus docetaxel provided a 15.7-month improvement in OS compared with patients who received Herceptin, docetaxel and placebo (mOS: 56.5 months in the Perjeta arm vs. 40.8 months in the placebo arm; HR=0.68, 95% CI 0.56-0.84, p=0.0002). Updated PFS data were similar to what was published in 2012, with a slight increase in PFS in the Perjeta arm (18.7 months vs. 12.4 months, HR=0.68, p<0.0001). The toxicity profiles between the arms were similar and manageable, with the Perjeta arm experiencing a higher rate of Grade 3 febrile neutropenia (13.7% vs. 7.6%) and diarrhea (9.3% vs. 5.1%). The significant improvement in OS now solidifies Perjeta plus Herceptin and docetaxel as the new standard care in first-line MBC patients.

    So what is next? According to Kantar Health’s CancerMPact® Treatment Architecture, Perjeta has already benefited from a significant penetration into the first line setting, with use in one-third of U.S. patients in the year after its launch.3 The question that arises is, can we improve even further on these results, and can we do it by eliminating chemotherapy altogether? One intriguing piece of data presented  was the duration of study treatment: While the number of cycles of docetaxel remained the same at eight cycles (range: 1-42 cycles for the placebo arm and 1-52 cycles for the Perjeta arm), the duration of study treatment was extended with the addition of Perjeta from 11.4 months (range: 0.1-66.3 months) in the placebo arm to 17.4 months (range: 0.1-67.7 months) in the Perjeta arm, raising the possibility of prolonged Perjeta and Herceptin combination even after ending the docetaxel portion of the study treatment. The possibility of removing chemotherapy and replacing it with targeted therapy alone has been the Holy Grail in the oncology field ever since Herceptin revolutionized the way MBC is treated. In that vein, the MARIANNE (NCT01120184) study is looking to do just that by examining whether Perjeta and Kadcyla are more efficacious than Herceptin plus Perjeta and a taxane (paclitaxel or docetaxel). In essence, Kadcyla would provide both the targeted therapy and the microtubule-disrupting activity provided by taxanes. Results from this study would certainly provide further impetus for a paradigm shift of complete elimination of chemotherapy in first-line MBC. Results from MARIANNE are expected before the end of this year. Until then, the results from the CLEOPATRA trial provide great hope for patients in a disease that had few options over a decade ago and opens the door for the development of novel and more potent combination therapies in what was once an intractable disease. These are exciting times indeed.


    1. Swain et al. Abstract 350O ESMO 2014
    2. Baselga et al. NEJM 2012
    3. Kantar Health, CancerMPact, Treatment Architecture United States, accessed September 28, 2014