OBR Journal

Receive OBR green
OBR green is our dynamic, eco-friendly digital journal featuring all of our original content. Register to begin receiving OBR green today. View the Most Recent Issue»



Archives

  • Links

  • Recent Posts

  • Does Cyramza RAISE the Bar in Second-line CRC, or Do Efficacy and Cost Hold It Back?

    Patients with metastatic colorectal cancer (mCRC) are typically treated at some point with at least one angiogenesis inhibitor. According to Kantar Health’s CancerMPact® Treatment Architecture U.S. data, Avastin® (bevacizumab, Genentech/Roche) is offered to approximately one-half of KRAS wild-type chemotherapy-naïve patients and three-quarters of KRAS mutated chemotherapy-naïve patients in the first-line setting. In the second- or third-line setting, patients might be treated with Avastin, Zaltrap® (ziv-aflibercept, Sanofi) or Stivarga® (regorafenib, Bayer/Onyx). Given data from the 2015 ASCO Gastrointestinal Cancers Symposium, Cyramza® (ramucirumab, Eli Lilly) may soon be added to the list of agents for second- or third-line therapy.

    The use of Cyramza in this setting was examined in the Phase III RAISE trial, which enrolled 1,050 mCRC patients who had progressed during or after first-line Avastin, oxaliplatin and a fluoropyrimidine and randomized them to treatment with FOLFIRI q2w or FOLFIRI plus Cyramza 8 mg/kg q2w.1 Treatment would continue until disease progression or unacceptable toxicity. The trial roughly included similar numbers of KRAS wild-type and mutant patients, and this status was a stratification factor for the trial.

    RAISE met its primary endpoint of improving overall survival (OS) as the addition of Cyramza reduced the risk of death by 16% (median OS: 13.3 months versus 11.7 months, HR 0.84, p=0.0219). Both KRAS wild-type and mutant patients achieved benefit, although neither subgroup analysis was statistically significant. RAISE also met a secondary endpoint of progression-free survival (median PFS: 5.7 months versus 4.5 months, HR 0.79, p=0.0005) but did not significantly improve the response rate (13.4% versus 12.5%, p=0.6336) or disease control rate (74.1% versus 68.8%, p=0.0587). The toxicity profile was not surprising given Cyramza’s current approvals in both relapsed/refractory gastric cancer and non-small cell lung cancer (NSCLC). Common Grade 3 or higher toxicities that were significantly increased with Cyramza included neutropenia (38.4% versus 23.3%), fatigue (11.5% versus 7.8%), hypertension (10.8% versus 2.8%) and thrombocytopenia (3.0% versus 0.8%).

    Given the statistically significant improvement in overall survival, Cyramza should ultimately be approved by the U.S. Food and Drug Administration (FDA) for use in this setting. Although the degree of benefit in RAISE borders on clinically meaningful (1.6-month OS benefit, HR 0.84, p=0.0219), the FDA approved it in December for use in second-line NSCLC based on similar borderline benefit in the REVEL trial2 (1.4-month OS benefit, HR 0.857, p=0.0235). In both of these trials, the magnitude of benefit fell short of the Recommended Targets for Meaningful Clinical Trial Goals that were put forth by an ASCO working group in early 2014 for these two indications.3 Nevertheless, the FDA approved Cyramza in NSCLC and may do the same in mCRC given the demonstrated OS benefit.

    However, earning regulatory approval may be the least of Cyramza’s difficulties for gaining future utilization in mCRC. Once approved, Cyramza will compete in the second-line setting with Avastin and Zaltrap as noted above. Both of these agents have been tested in patients pretreated with Avastin. Second-line Avastin in Avastin pretreated patients was directly examined in the Phase III ML 18147 trial, colloquially referred as TML (for Treatment across Multiple Lines).4 TML evaluated the addition of Avastin to chemotherapy (either oxaliplatin- or irinotecan-based). Zaltrap was approved for second-line use based on data from the Phase III VELOUR study, which evaluated the addition of Zaltrap to FOLFIRI in second-line patients. Subgroup analysis in patients who were treated with first-line Avastin has been published.5 As shown in the table below, all three anti-angiogenic agents show similar underwhelming (>0.80) hazard ratios for OS.

    Efficacy Comparisons Between Avastin, Zaltrap and Cyramza in 2nd-Line mCRC
      TML (Avastin-Pretreated3) VELOUR (Prior Avastin Subgroup Only4) RAISE (Avastin-Pretreated1)
      Placebo + CT (n=410) Avastin + CT (n=409) HR (p-value) Placebo + FOLFIRI (=187) Zaltrap + FOLFIRI (n=186) HR (p-value) Placebo + FOLFIRI (n=525) Cyramza + FOLFIRI (n=525) HR (p-value)
    Median OS 9.8 11.2 0.81 (p=0.0211) 11.7 12.5 0.862 (NP) 11.7 13.3 0.84 (p=0.0219)
    Median PFS 4.1 5.7 0.68 (p<0.0001) 3.9 6.7 0.661 (NP) 4.5 5.7 0.79 (p=0.0005)
    CT: Chemotherapy; NP: Not provided

     

    Not only is Cyramza attempting to compete with agents that have been approved for this setting since 2012 (Zaltrap) and 2013 (Avastin for use in Avastin-pretreated CRC), but it may be doing so with a pricing problem. One physician in attendance at the ASCO GI presentation directly asked why he should offer Cyramza if it costs “twice as much” as Avastin. Estimated costs of these agents support this claim: Avastin per cycle, assuming the use of the lower dosage of 5 mg/kg q2w, is approximately $2,400. Cyramza is expected to cost $5,900 per cycle of therapy based on the dose used in this trial and its current price for approved indications. This is eerily reminiscent of difficulties for Zaltrap, when several physicians from the Memorial Sloan-Kettering Cancer Center wrote an opinion piece in The New York Times stating they would not provide Zaltrap to their patients since it was more than twice the cost of Avastin; the negative publicity associated with the article forced Sanofi to drop its pricing for Zaltrap.  

    The situation doesn’t improve for Cyramza even if it is considered in later lines of therapy. Not only would Cyramza need to compete with the anti-angiogenic agent Stivarga, which was approved in 2012 by the FDA, but it also will likely need to compete against TAS-102 (Lonsurf® in Japan, Taiho Oncology), a formulation of two antimetabolic agents that met its primary endpoint of OS in the Phase III RECOURSE study.6 The FDA has granted TAS-102 a fast-track designation, and Taiho confirmed that it had already initiated a rolling submission for approval.

    Cyramza faces tough hurdles ahead given the data presented at the ASCO Gastrointestinal Cancers Symposium: activity comparable to other anti-angiogenic agents that are already approved in the same setting, and at a potentially higher cost. With these hurdles, it is hard to imagine Cyramza “RAISEing” the bar in second-line CRC in the near future.

    References: 

    1. Tabernero et al.; Abstract 512, 2015 ASCO Gastrointestinal Cancers Symposium
    2. Perol, et al.; Abstract LBA8006, ASCO 2014
    3. Ellis, et al.; J Clin Oncol, 32(12): 1277-1280, 2014.
    4. Bennouna, et al.; Lancet Oncol, 2013
    5. Tabernero, et al.; Eur J Cancer, 2014
    6. Yoshino, et al.; Abstract O-0022, 2014 ESMO World Congress on Gastrointestinal Cancer.

    By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A, Consultant, Clinical and Scientific Assessment, Kantar Health

    Immunotherapy: Shining a Light on the Gastric Cancer Landscape

    Designated as a “breakthrough therapy” by the FDA for both advanced and unresectable malignant melanoma and advanced non-small cell lung cancer (NSCLC), and approved by the U.S. Food and Drug Administration (FDA) in September 2014 for advanced pretreated metastatic melanoma, the immune checkpoint inhibitor Keytruda® (pembrolizumab, Merck) has also shown promise for several other indications including (but not limited to) head and neck cancer, Hodgkin’s lymphoma and triple-negative breast cancer (TNBC).

    Given Keytruda’s remarkable performance as an antitumor agent in several advanced/metastatic diseases, the therapeutic potential of this promising new drug is now being explored in the context of advanced gastric cancer. In a keynote address on Thursday, Jan. 15 at the 2015 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, an updated cohort analysis of 39 patients with either recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction from the Phase 1b KEYNOTE-012 study1 was presented. For this specific analysis, only patients with distinctive stromal or ≥1% tumor nest cell PD-L1 staining were included. Patients were heavily pretreated; 67% of the patients had received two or more prior therapies. Patients were given 10 mg/kg Keytruda every two weeks for up to 24 months or until complete response, progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR), and secondary endpoints were duration of response, progression-free survival (PFS) and overall survival (OS).

    Keytruda achieved a favorable ORR of 22% by central review and 33% by investigator review. This differs only slightly from that presented at the European Society for Medical Oncology (ESMO) 2014 Congress (30.8% ORR by investigator review).2 Responses were similar between Asian and non-Asian patients. The median time to response was eight weeks, and the median response duration was 24 weeks. The six-month PFS rate was 24%, and the median PFS was 1.9 months. The six-month OS rate was an impressive 69%, and the median OS was not yet reached. Patients had a median follow-up duration of 8.8 months, and 33% remained on therapy as of November 2014. Although the data were very preliminary, a trend toward an association between higher levels of PD-L1 expression and ORR (p=0.102), PFS (p=0.162) and OS (p=0.124) was observed. Only four patients experienced Grade 3 or higher drug-related adverse events: peripheral sensory neuropathy, fatigue, decreased appetite, hypoxia and pneumonitis (2.6% each); one of these adverse events (hypoxia) resulted in patient death.

    To date, the treatment landscape for advanced or relapsed gastric cancer has proven to be relatively bleak. Prior to the approval of the VEGFR-2-targeted therapy Cyramza® (ramucirumab, Eli Lilly), there were no approved targeted agents for the treatment of relapsed gastric cancer, and physicians relied on fluoropyrimidine- or taxane-based chemotherapy. Cyramza was approved in the U.S. and Europe based on results from the REGARD and RAINBOW trials. In REGARD, Cyramza was associated with an OS of 5.2 months versus 3.8 months for placebo (HR 0.776, p=0.0473) in patients previously treated with first-line platinum- or fluoropyrimidine-based therapy. In addition, the six-month OS rates were 41.8% in patients treated with Cyramza versus 31.6% in the placebo group.3 RAINBOW compared paclitaxel ± Cyramza as a second-line therapy; the addition of Cyramza to paclitaxel significantly extended median OS (9.6 months versus 7.4 months, HR 0.81, p=0.017). The six-month and 12-month OS rates for Cyramza plus paclitaxel were 72% and 40%, respectively, compared with 57% and 30% for paclitaxel alone.4

    The results of the KEYNOTE-012 gastric cancer cohort analysis highlight the promising antitumor activity and manageable toxicity of Keytruda in advanced gastric cancer. While there are caveats to comparing trials directly, patients treated with Keytruda monotherapy had a similar six-month OS (69%), as did patients treated with Cyramza + paclitaxel (72%); however, recall that the patients on Keytruda were more heavily pretreated. Building on this signal, Merck has announced plans to initiate a Phase II trial (KEYNOTE-059; NCT02335411) to evaluate Keytruda or Keytruda plus cisplatin and 5-FU in 270 patients with recurrent or metastatic gastric and gastroesophageal junction adenocarcinoma. The primary outcomes will be safety and response. This study will provide some important insights on the activity and safety of Keytruda, including its use in combination with chemotherapy, the importance of PD-L1 as a biomarker, and the role of Keytruda in both first-line and relapsed settings. Findings from KEYNOTE-012 should provide valuable to inform future Phase III trial design.

    However, as with other tumor types, other manufacturers of PD-1 inhibitors have announced plans to compete in this space. A new Phase III trial (NCT02267343) was initiated in October 2014 to compare Opdivo® (nivolumab, ONO-4538/BMS-936558, Bristol-Myers Squibb/Ono Pharmaceuticals) versus placebo in 480 previously treated Japanese patients with unresectable advanced or recurrent gastric and gastroesophageal junction cancer. This trial will not limit patient enrollment by PD-L1 biomarker status. The primary endpoint will be OS, and secondary endpoints will include PFS, ORR and safety. To date, there are no known late-stage trials of Opdivo in Western gastric cancer patients, but it can be assumed that trials may be initiated in the near future. As in melanoma, Opdivo may ultimately have a first-to-market advantage over Keytruda in gastric cancer in Japan, but Keytruda may have a leg up in the Western markets for this indication.

    Along with immunotherapy, other targeted therapies are planning Phase II trials, including Stivarga® (regorafenib, Bayer, NCT01913639) and AMG 337 (Amgen, NCT02016534). Eli Lilly has also announced plans for another Phase III trial for Cyramza (RAINFALL, NCT02314117), which will compare capecitabine plus cisplatin with or without Cyramza in 616 newly diagnosed gastric or gastroesophageal junction cancer patients.

    As with other tumors, the competitive landscape for gastric could dramatically change within the next several years given the data presented. These data are certainly at an early stage, but the high response rates and preliminary OS data justify the excitement associated with the PD-1 inhibitors and add gastric cancer to the growing list of tumors in which immuno-oncology may play a significant role.

    References:

    1. Muro et al., Abstract 3, ASCO GI 2015.
    2. Muro et al, Abstract LBA15, ESMO 2014.
    3. Fuchs et al., Lancet. 2014 Jan 4;383(9911):31-9.
    4. Wilke et al., Lancet Oncol. 2014 Oct;15(11):1224-35.

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

    Colorectal Cancer in the Spotlight at GI Cancers Symposium

    Four studies presented at a media telebriefing prior to the Gastrointestinal Cancers Symposium 2015 highlighted key findings in colorectal cancer. The findings will be presented January 15-17, 2015, in San Francisco.

    The studies were culled from more than 800 abstracts that will be viewed by 3,200 specialists and surgical, medical and radiation specialists from around the world.

    Survival Advantage Shown for Ramucirumab Plus Chemotherapy in Second-Line CRC Treatment

    The phase 3 international RAISE trial (Abstract 512) found that ramucirumab extends survival when given with chemotherapy to metastatic colorectal cancer patients who progress on treatment.

    The RAISE study randomized 1,072 patients who progressed after first-line therapy to treatment with FOLFIRI (leucovorin, fluorouracil, irinotecan) plus ramucirumab or placebo. Response rates were similar between the two arms—13.4% with ramucirumab; 12.5% with placebo—but ramucirumab significantly improved both progression-free and overall survival.

    Median time to disease progression in patients receiving ramucirumab plus FOLFIRI was 5.7 months compared with 4.5 months in the placebo arm (HR=0.79; P=0.0005). Median overall survival was 13.3 months and 11.7 months (HR=0.84; P=0.0219), respectively.

    The regimen was well tolerated, though the addition of ramucirumab increased the incidence of Grade 3-4 neutropenia, fatigue, diarrhea, and hypertension.

    “Though the rate of neutropenia was higher, the rate of febrile neutropenia, the clinically significant toxicity, was similar, 3.6% versus 2.7% in the placebo arm,” said Josep Tabernero, MD, Vall d’Hebron Institute of Oncology in Barcelona, Spain. According to Dr. Tabernero the adverse events were manageable.

    The study validates angiogenesis as an important target in colorectal cancer. Other angiogenesis inhibitors approved in this malignancy include bevacizumab, ziv-aflibercept, and regorafenib.

    Dr. Tabernero pointed out that the study population was representative of patients seen in everyday practice. He cautioned, however, that the findings should not be extrapolated to other regimens used in colorectal cancer. Ramucirumab is currently FDA-approved in gastric and non-small lung cancer.

    Commenting on the study, moderator Smitha S. Krishnamurthi, MD, Associate Professor of Medicine at Case Western Reserve University School of Medicine, Cleveland, acknowledged that improvements in 1 to 2 months in progression-free and overall survival appear modest. However, she said, “We want to offer patients all we can, because these agents [biologics] tend to be well tolerated and they can be combined with chemotherapy.”

    Bevacizumab Works Best Combined with Intensive Chemotherapy

    Updated results from the phase 3 TRIBE study (Abstract 657) conducted in Italy indicate that bevacizumab is more effective in metastatic colorectal cancer when combined with the FOLFOXIRI regimen than FOLFIRI. FOLFOXIRI plus bevacizumab extended overall survival by 4 months and doubled the 5-year survival rate over the control arm, reported Chiara Cremolini, MD, of the Tuscan Tumor Institute in Pisa.

    In the U.S., FOLFOX (leucovorin, fluorouracil, oxaliplatin) and FOLFIRI (leucovorin, fluorouracil, irinotecan) are more commonly used than FOLFOXIRI, which adds oxaliplatin to the FOLFIRI regimen.

    The study evaluated 508 patients randomized to bevacizumab plus either FOLFOXIRI or FOLFIRI for 6 months, after which they received maintenance bevacizumab with 5-FU/leucovorin. After a median follow-up of about 4 years, median overall survival was 29.8 months in the FOLFOXIRI arm versus 25.8 months in the FOLFIRI arm (HR=0.80; P=0.030).

    “Looking at the final part of the shape of the survival curves, we see that the benefit of FOLFOXIRI plus bevacizumab increases over time, and the estimated 5-year survival is 24.9% versus 12.4%, which is double to that of FOLFIRI plus bevacizumab…Based on these results, FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer,” Dr. Cremolini concluded.

    The study found a higher incidence of Grade 3-4 diarrhea, mucositis, neuropathy, and neutropenia, with the FOLFOXIRI regimen, but no increase in febrile neutropenia and or serious adverse events of treatment-related deaths. The incidence of severe neuropathy, which is a concern with oxaliplatin, was only 5%. 

    Dr. Cremolini acknowledged that the regimen, which tends to be more difficult and leads to more dose reductions and delays, “is not a regimen for every patient.” In her opinion, it is probably not suitable for patients older than age 75 or younger patients with poor performance status.

    Dr. Krishnamurthi indicated that in the U.S, the “uptake was not high, when the data first came out, because we are already combining chemotherapy with bevacizumab,” however, with more evidence of efficacy and safety, she predicted, “I think we will see more use of FOLFOXIRI with bevacizumab.”

    High Vitamin D Associated with Improved Survival

    Newly diagnosed colorectal cancer patients with high vitamin D levels prior to treatment live longer than those with the lowest levels, according to a prospective analysis of data from a phase 3 study (Abstract 507).

    The study adds to a growing body of evidence that vitamin D has an anti-tumor effect. Randomized studies are now underway to confirm the benefit of vitamin D supplementation before and after a cancer diagnosis, said Kimmie Ng, MD, MPD, of Dana-Farber Cancer Institute and Harvard Medical School, Boston.

    “The ultimate goal is to translate this research into an effective intervention for patients,” she said.

    Dr. Ng and colleagues measured the serum levels of vitamin D (25-hydroxyvitamin D) in 1,043 patients enrolling in CALGB 80405, the phase 3 trial evaluating three different first-line treatments for advanced colorectal cancer. Patients’ vitamin D levels ranged from a mean low of 8 ng/mL to a mean high of 27.5 ng/mL. The average for all patients was 17.2 ng/mL, which is below the recommended healthy range of 20 to 30 ng/mL. Few patients report taking vitamin D supplements.

    Divided into quintiles according to their baseline level, and being adjusted for other prognostic factors for survival as well as healthy behaviors, patients with the highest levels of vitamin D had a median overall survival of 32.6 months, compared with 24.5 months for those in the lowest quintile (HR=0.67; P=0.002).

    Higher vitamin D levels were also associated with longer time to disease progression, 12.2 months vs. 10.1 months (HR=0.80; P=0.02). The benefit was seen across the three treatment arms and did not differ by KRAS status, nor was benefit ameliorated when other prognostic factors were adjusted for.

    Despite the encouraging results, Dr. Ng said it is premature to recommend vitamin D as a treatment for colorectal cancer. She noted that the findings do not indicate that raising a low baseline vitamin D level will improve outcomes, only that baseline levels were associated with different outcomes.

    “Watch and Wait” is Acceptable for Some Rectal Cancer Patients

    Some rectal cancer patients who achieve a complete response to neoadjuvant chemoradiation may not need surgery, according to a retrospective review of data on 145 patients with stage I-III rectal cancer.

    Philip Paty, MD, of Memorial Sloan Kettering Cancer Center, New York, said the results should “encourage more doctors to consider a ‘watch and wait’ approach in patients with clinical complete response as an alternative to immediate rectal surgery, at least for some patients.”

    Avoidance of surgery would allow patients to preserve rectal function, which is very important to patients, he explained. “Most patients who qualify for this approach are very interested in it,” he said.

    The study was a retrospective look at 73 patients who achieved a clinical complete response after neoadjuvant chemoradiation and were treated with a non-operative management approach (with frequent monitoring, every 3 months for the first 1.5 years). Their outcomes were compared with those of 72 patients who achieved a pathologic complete response (pCR) and underwent resection.

    Of the 73 patients who were observed, 74% achieved a durable and sustained clinical response and no surgical intervention was required.  Nineteen patients (19%), however, had local regrowth of tumor, and all had successful salvage surgery.

    Altogether, 98% of patients achieved local control (one patient had a recurrence after resection of the tumor regrowth), and 77% had rectal preservation. The disease-specific and overall survival rates were similar between the two groups, suggesting that the nonoperative approach for these patients did not compromise outcomes.

    “We set the bar very high, and found that nonoperative management appears to compare favorably,” said Dr. Paty.

    He acknowledged that “practicing ‘watch and wait’ can be difficult for surgeons” but this approach is being increasingly accepted.

    “Centers are adopting it, and many leaders in clinical trials of rectal cancer recognize that this option is not only reasonable, but perhaps it is necessary to inform patients that it is an option,” he said.

    Complete responses are typically observed in up to 50% of patients with stage I disease and 30% to 40% with stage II-III tumors, making these patients candidates for nonoperative management.

    Dr. Krishnamurthi indicated she would feel better about observing these patients once the investigators can report longer follow-up.

    By Sandra Hanner

    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.

    References: 

    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.

    References: 

    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.

    References: 

    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.

    References:

    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

    INAUGURAL PALLIATIVE CARE SYMPOSIUM READY TO GO

    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

    Introduction

    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.