By Stephanie Hawthorne, Director, CancerMPact®, Kantar Health
Kantar Health, a leader in global oncology consultancy, continuously monitors drug development in the oncology marketplace to remain abreast of evolving oncology treatment trends. Kantar Health offers a conference surveillance service, Oncology Conference Insight, to enhance competitive intelligence within pharmaceutical and biotech companies and provides analysis on significant information presented at oncology meetings. Kantar Health has identified several pivotal clinical trials that will be presented at the upcoming American Society of Clinical Oncology (ASCO) conference, which have the potential to significantly alter the treatment paradigm in several tumor types. A brief synopsis of those trials and an evaluation of the data expectations are discussed.
Yervoy™ (ipilimumab, Bristol-Myers Squibb) in First-line Metastatic Melanoma
In March 2011, Yervoy became the first FDA-approved drug in more than a decade for patients with metastatic melanoma, and was the first to demonstrate an overall survival (OS) benefit in this patient population. In addition, BMS also announced that a second Phase 3 trial, this time comparing chemotherapy with or without Yervoy in chemotherapy-naïve melanoma patients, also met its primary endpoint of significantly improving OS. During the Plenary session at ASCO, this data will be presented and it will be interesting to note the level of OS benefit by a few different measures. An improvement in median OS in excess of 4 months would be considered a clinically meaningful level of activity.
Equally important for evaluation will be long-term survival differences between the 2 arms. In the second-line study, a significant percentage (approximately 20%) of the Yervoy treated patients remained alive for 3 or more years – there was a noticeable flattening of the Kaplan-Meier curve for the Yervoy arms highlighting this population of long-term survivors. Will something similar be observed in the first-line study, and if so how large of a population will achieve this survival benefit?
Another important outcome that needs to be evaluated is the safety profile of Yervoy plus chemotherapy. Yervoy monotherapy results in a high rate of immune-related adverse events, and while most of these events are reversible, they must be managed with systemic corticosteroids early on and require close medical follow up. It will be interesting to see how significantly these toxicities are exacerbated with the higher dose of Yervoy used in the first-line study, as well as the tolerability during the prolonged maintenance administration. Abstract LBA5, Sunday June 5, 3:30pm Plenary
Vemurafenib (RG7204, PLX4032, Plexxikon/Daiichi Sankyo/Roche) in B-RAF Mutant Melanoma
ASCO 2011 could be the year for skin cancer. In addition to the results for Yervoy, results from the Phase 3 BRIM3 study of RG7204, Roche’s and Daiichi Sankyo’s B-RAF inhibitor, will also be presented. This trial enrolled 675 previously-untreated advanced/metastatic melanoma patients who have a V600 mutant B-RAF gene. In this trial, patients were randomized to receive either RG7204 monotherapy or dacarbazine, and in January 2011, Roche announced that the primary endpoint of improving OS was met, as well as a significant improvement in progression free survival (PFS).
Roche initially planned to seek accelerated approval for RG7204 based on the Phase 2 BRIM2 study data (which will also be presented at ASCO). Astonishingly, BRIM3 progressed so rapidly (trial initiation to primary endpoint of OS met in just 13 months!) that accelerated approval may no longer be necessary. The rapid enrollment of this trial speaks to the enthusiasm among the oncology community for a personalized therapy to treat this sub-population of melanoma patients (B-RAF mutations occur in approximately 60% of melanomas), and the speed at which the endpoints were reached speaks to the aggressiveness of this disease and the high unmet needs of these patients. Having significantly improved OS leaves little doubt that regulatory approval will be granted; nevertheless, the data is highly anticipated.
The survival and progression data will also provide a glimpse at the next melanoma revolution – options for patients who fail a B-RAF inhibitor. We know from earlier studies that resistance to B-RAF inhibition does occur, which creates an opportunity for alternative agents (e.g., MEK inhibitors), or combination approaches to prolong initial benefit (e.g., could RG7204 be combined with Yervoy?) The BRIM studies won’t answer these questions, but could provide a good idea of the rate at which these melanoma patients develop resistance to RG7204. BRIM3, Abstract LBA4, Sunday June 5 Plenary, 3:15pm; BRIM2, Abstract 8509, Saturday June 4, 4:00pm
Update: Roche/Genentech just announced on May 10 that new drug applications in the U.S. and Europe were filed for vemurafenib (RG7204, PLX4032) as a treatment for patients with BRAF V600 mutation-positive metastatic melanoma. The companies said that the submissions are based on positive results from BRIM2 and BRIM3. Comprehensive data from BRIM3 will be presented at ASCO’s plenary session in addition to updated BRIM2 data.
Avastin® (bevacizumab, Genentech/Roche) in Platinum-sensitive Ovarian Cancer
The Phase 3 OCEANS trial, sponsored by Genentech, compares platinum-based chemotherapy with or without Avastin in patients with advanced ovarian cancer who have failed one prior line of therapy but remain sensitive to platinum-based chemotherapy. Genentech announced in February 2011 that this trial met its primary endpoint of significantly improving PFS. With a presentation of the second-line OCEANS data as a Late-Breaking Abstract at ASCO, we will be critically evaluating the magnitude of the PFS benefit. Currently, platinum-sensitive ovarian cancer patients achieve PFS of nearly 12 months; a clinically meaningful PFS benefit with the addition of Avastin, particularly in the symptomatic patient population, should be in the range of 4 to 6 additional months. Any less than this level of benefit risks a tempered enthusiasm among the oncology community, as evidenced by the National Comprehensive Cancer Network (NCCN) guideline committee not recommending Avastin for use in combination with first-line chemotherapy or utilized as maintenance due to a significant but small magnitude of benefit in two Phase 3 trials. However, Avastin is on the NCCN compendium as an option for platinum-resistant, recurrent ovarian cancer which supports significant off-label utilization – 33% of platinum-resistant second-line patients and 25% of third-line patients receive an Avastin-containing regimen (CancerMPact® Treatment Architecture U.S. 2010 Ovarian cancer data).
A meaningful PFS benefit in the OCEANS data could positively sway perception of the variable first-line data results (previously published), and along with that first-line data could support FDA and EMA approval in a broad ovarian cancer patient population. Abstract LBA5007, Saturday June 4, 4:15pm
Tarceva® (erlotinib, Astellas/Roche) in First-line, EGFR Mutant Non-Small Cell Lung Cancer (NSCLC)
The last couple of years have led to an appreciation that the EGFR tyrosine kinase inhibitors are exquisitely active in NSCLC patients who harbor EGFR mutations. Iressa™ (gefitinib, AstraZeneca) is approved in Europe specifically for the treatment of EGFR mutant NSCLC, in any line of therapy, and is currently utilized in nearly one-half of EGFR mutant patients in the first-line setting (CancerMPact® Treatment Architecture Western Europe 2010 NSCLC data).
Tarceva, another EGFR inhibitor, is approved in the U.S. and Europe for use in refractory NSCLC regardless of EGFR status. The similar mechanism of action of Tarceva and Iressa has led to assumptions within the oncology community that Tarceva is also superior to chemotherapy in the first-line setting in selected patients, resulting in significant off-label utilization of Tarceva in first-line EGFR mutant NSCLC in the U.S. (50% of patients according to CancerMPact® Treatment Architecture U.S. 2010 NSCLC data).
At ASCO we will see the results of the EURTAC trial, which will be the first Phase 3 trial to compare Tarceva versus chemotherapy as first-line treatment for EGFR mutants in a Western patient population. Roche announced in January 2011 that this trial met the primary endpoint of prolonging PFS. With significant off-label utilization already occurring in the U.S., these results and a formal approval in this indication could provide a minor increase in utilization in the U.S. In Europe, the results of EURTAC and EMA approval will set the stage for a strong battle between Tarceva and Iressa, one which we will eagerly follow in our continuous monitoring of treatment patterns globally.
Results from the Chinese OPTIMAL study showed a PFS of 13.1 months with Tarceva, which appears superior to the 9-10 months PFS achieved with Iressa in the IPASS, NEJ002, and WJTOG 3405 studies in Asian and Japanese patients. If the EURTAC trial also shows a PFS exceeding one year, Tarceva will be well-positioned to challenge Iressa in the European market. EURTAC, Abstract 7503, Sunday June 5, 9:30am
Erbitux® (cetuximab, Eli Lilly, Bristol-Myers Squibb, Merck KGaA) in Locally-advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Erbitux is currently approved for the treatment of locally-advanced head and neck cancer when used in combination with radiotherapy, based on the results of a Phase 3 study in which the combination of Erbitux plus concurrent radiotherapy significantly improved 3-year OS compared with radiotherapy alone. However, because most physicians believe that platinum-based chemoradiotherapy is the standard of care for these patients, adoption of Erbitux plus radiotherapy has been minimal (14% according to CancerMPact® Treatment Architecture U.S. 2010 Head and Neck cancer data).
Kantar Health’s data does suggest some off-label use of Erbitux in combination with platinum-based chemoradiotherapy, although use is limited to less than 10% of patients. Comparing across clinical trials, Erbitux plus radiotherapy produces similar locoregional control as cisplatin-based chemoradiotherapy, but cisplatin-based chemoradiotherapy results in fewer distant metastatic recurrences. The pivotal study that will evaluate the benefit of adding Erbitux to chemoradiotherapy is the Radiation Therapy Oncology Group (RTOG) 0522 study, which will be presented at ASCO. This trial randomizes locally-advanced patients to definitive therapy of cisplatin plus radiotherapy with or without Erbitux.
The outcomes of the trial have not previously been announced; the community is anxiously expecting positive results, looking for a 25% reduction in the risk of progression, measured as 3-year PFS (the primary endpoint). Also of interest will be the rates of locoregional control, OS if available, and the toxicity profile. Erbitux plus radiation alone causes a significant amount of severe oral mucositis, as does cisplatin-based chemoradiotherapy. Will the combination of both agents exacerbate oral mucositis, and will it impact patient compliance and efficacy outcomes? RTOG-0522, Abstract 5500, Monday June 6, 3:00pm
Axitinib (AG-13736, Pfizer) in Second-line Renal Cell Carcinoma (RCC)
Renal cell carcinoma treatment is dominated by targeted therapy. Already, 3 VEGFR tyrosine kinase inhibitors are approved: Nexavar® (sorafenib, Onyx/Bayer), Sutent® (sunitinib, Pfizer), and Votrient™ (pazopanib, GlaxoSmithKline)—and 3 others are in Phase 3 development—axitinib, AV-951 (AVEO/Astellas), and TKI-258 (Novartis). Of those, axitinib is the furthest in development. In November 2010, Pfizer announced that the Phase 3 AXIS trial met its primary endpoint of significantly extending PFS with axitinib compared with Nexavar. The magnitude of the benefit was not disclosed and this is something that we will be looking for at ASCO.
Another analysis of keen interest is the degree of benefit with axitinib based on prior treatment received (i.e., another TKI, an mTOR inhibitor, or cytokine therapy). The study design does not specify (or exclude) any systemic therapies from prior treatment, and given the geographic reach of the trial the patient population will likely be heterogeneous. Pfizer is hoping that approval of axitinib could establish them as an RCC powerhouse, with Sutent [and Torisel® (temsirolimus, Pfizer)] as first-line options and axitinib (and Torisel) for patients in the second-line setting, relegating their competitors [Nexavar, Afinitor® (everolimus, Novartis), and Avastin (Roche)] to third-line or later. Success in this endeavor will require an exploratory analysis clearly showing efficacy of axitinib in Sutent-pretreated patients, given Sutent’s dominance in the first-line setting.
Finally, the safety profile of axitinib will be important to note. In Phase 2, axitinib demonstrated a less-than-mild toxicity profile, with rates of grade 3/4 diarrhea, hand-foot syndrome, fatigue, and hypertension all seemingly more frequent than has been previously reported with Nexavar in RCC. We wonder how the safety profiles of these 2 agents will look in the direct comparison offered by the AXIS trial, and whether the degree of PFS benefit outweighs the anticipated poorer tolerability with axitinib. AXIS, Abstracts 4503 and 4504, Monday June 6, 8:00am
MK-8669 (ridaforolimus, ARIAD/Merck) and Votrient (pazopanib, GlaxoSmithKline) in Sarcoma
Treatment options for patients with sarcoma have remained relatively unchanged over the past decade, at least in the U.S. [Yondelis® (trabectedin, PharmaMar/Johnson & Johnson) and Mepact® (mifamurtide, Takeda) have been approved in Europe], and treatment relies heavily on anthracyclines. In patients refractory to anthracycline, few options exist. Two approaches that have been recently studied to address this issue are the development of agents in a newly-emerging maintenance setting to delay progression, and the development of agents for use in anthracycline-refractory disease. MK-8669 has led the way in development in the maintenance setting in patients with sarcoma, both soft tissue and bone disease. The Phase 3 SUCCEED trial compares MK-8669 versus placebo in patients who have achieved a response or stable disease following first- or second-line chemotherapy.
In a press release in January 2011, Merck/Ariad announced that this trial met the primary endpoint of improving PFS compared with placebo. The release stated that independent review resulted in a statistically significant 3.1 week prolongation of PFS (17.1 weeks vs 14.6 weeks, HR 0.72, P=0.0001). While these details are known, a question that continues to be asked is whether physicians will view this benefit as clinically meaningful. Many physicians are beginning to question the relevance of minor benefits in PFS, and the concept of maintenance is at the forefront of these discussions. We look forward to discussions among the oncology community regarding the SUCCEED data in order to gauge enthusiasm and likelihood of adoption upon launch.
In anthracycline-refractory disease, Votrient is the most advanced in development. The Phase 3 PALETTE study compares Votrient versus placebo. This trial has a relatively low bar to success, with comparison only to placebo and response rate as the primary endpoint. In the absence of approved options for these patients (in the U.S., although notably Yondelis is approved in this indication in Europe), this design may be able to support regulatory approval, but market success may hinge more on the outcomes of the secondary endpoints, PFS, and OS. We were initially surprised to find it as a Late Breaking Abstract at ASCO given the company’s silence, until the company announced that the trial was positive in its first quarter results. Unlike the renal cell market where Votrient was first approved, GSK will find much less competition in the sarcoma market. We’ll be tuning in at ASCO to discover the strength of Votrient’s results in patients with anthracycline-refractory soft tissue sarcoma. SUCCEED, Abstract 10005, Monday June 6, 4:30pm; PALETTE, Abstract LBA10002, Monday June 6, 3:30pm
Amrubicin® (Celgene) in Second-line Small Cell Lung Cancer (SCLC)
Like sarcoma, options for refractory SCLC remain limited, and outcomes dire. Topotecan is the only approved agent for relapsed SCLC, with typical outcomes of 3 months time to progression and 6 months OS in patients with platinum-sensitive disease. Amrubicin is being compared with topotecan in a randomized Phase 3 trial as second-line therapy for platinum-sensitive or -refractory SCLC patients. With OS as the primary endpoint and few therapeutic options for these patients, there is little doubt that regulatory approval will be granted if the trial meets its primary endpoint. Like Votrient in sarcoma, however, the company has been relatively silent regarding the outcomes of this study, leaving us unsure about its success. Beyond survival outcomes in the overall population, we are also hoping to see analysis of survival and PFS outcomes by platinum-sensitivity. The degree of activity in platinum-sensitive versus platinum-resistant patients will be highly influential on adoption and eventual market success. Abstract 7000, Tuesday June 7, 8:00am
Xgeva™ (denosumab, Amgen) in Non-metastatic Castrate-resistant Prostate Cancer
Xgeva is approved in the U.S. for the prevention of skeletal-related events in patients with bone metastases from solid tumors. As part of an extensive development program, Amgen is also hoping to launch Xgeva for the prevention of bone metastasis. In men with non-metastatic androgen-independent prostate cancer, Amgen conducted a Phase 3 trial comparing Xgeva with placebo. In December 2010, the company announced that this trial met the primary endpoint of significantly improving bone metastasis-free survival, offering a 4.2 month benefit over placebo (HR 0.85; P=0.03). They also announced that the secondary endpoint of time to first occurrence of bone metastasis was met, although OS was not different between the 2 arms. The lack of a survival benefit could have an impact, as physicians may struggle to weigh the benefits of delaying metastasis if there is no impact on survival outcomes. We are hoping to see some analysis that can speak to the impact of Xgeva on metastasis-related morbidity, as a way of demonstrating that the benefit with Xgeva can have a clinically meaningful impact on patient outcomes. The results of this study will be presented as a late-breaking abstract at the American Urological Association (AUA) meeting on May 17; currently, the ASCO meeting planner does not list these results as being presented, but there is potential for a late addition to the schedule reprising the data from AUA.
|Kantar Health’s Top Presentations of Interest, ASCO 2011|
|Agent||Indication||Abstract||Date and Time|
|Yervoy||Melanoma, first-line||LBA5||Sunday, 3:30pm|
|Vemurafenib||Melanoma, first-line, B-RAF mutants
Melanoma, second+ line, B-RAF mutants
|Avastin||Ovarian cancer, 2nd-line, platinum-sensitive||LBA5007||Saturday, 4:15pm|
|Tarceva||NSCLC, first-line, EGFR mutant||7503||Sunday, 9:30am|
|Erbitux||SCCHN, locally-advanced||5500||Monday, 3:00pm|
|MK-8669||Sarcoma, maintenance||10005||Monday, 4:30pm|
|Votrient||Sarcoma, soft tissue, refractory||LBA10002||Monday, 3:30pm|
|Amrubicin||SCLC, second-line||7000||Tuesday, 8:00am|
In addition to the above pivotal results, we will also see the presentation of several recent high-profile failed pivotal studies, as outlined in the table below. These studies are often valuable for understanding the future clinical potential of these agents (a study that just barely misses significance may not reflect as negatively on additional ongoing trials as would a study that demonstrated a complete lack of efficacy) and other agents in development for the same indication (does failure of one PARP inhibitor signal the downfall of all PARP inhibitors, or are there nuances in the data that suggest the failure may be product-, not class-specific).
Perhaps the biggest surprise failure at ASCO 2011 is that of iniparib (sanofi-aventis/BiPar) in triple-negative breast cancer. Iniparib inhibits PARP, which is essential for DNA single-strand breaks, such as those caused by alkylating agents. It is hypothesized that inhibition of PARP can overwhelm cancer cells with lethal DNA damage and may be particularly effective when used in combination with DNA-damaging agents or in cells with impaired DNA repair function, such as those tumors with BRCA1 or BRCA2 mutations. While hereditary BRCA-mutant breast cancer is rare, triple-negative breast cancers have BRCA-like qualities, suggesting that these tumors may also prove sensitive to PARP inhibition.
Phase 2 studies with iniparib supported this hypothesis, prompting BiPar and sanofi-aventis to initiate a Phase 3 trial of chemotherapy with or without iniparib in patients with triple-negative breast cancer. The initial excitement generated by the Phase 2 results was deflated on January 24, 2011 when the companies announced that the trial did not meet either of its primary endpoints (PFS and OS). The press release did not contain any data so we are left to speculate on possible reasons for the failure of the Phase 3 trial. Possible explanations for differences in the outcome of the seemingly positive randomized Phase 2 and Phase 3 studies include an imbalance of prognostic factors such as the number and site of metastases favoring the iniparib arm in the Phase 2 and differences in the percentage of first-line patients in the 2 trials.
This last explanation becomes more intriguing given that the company reported that results of a pre-specified analysis in patients treated in the second- and third-line settings showed improvements in both OS and PFS. How large is the population in this analysis, and what is the degree of significance? Also of interest will be biomarker analysis, if presented. Testing for BRCA mutations and PARP expression levels was not mandated in this study, so a subset analysis may not be possible, but we wonder if there is a patient subset that derives substantial benefit from iniparib. This data could help clarify concerns that iniparib may not be a good PARP inhibitor and clarify its true mechanism of action. The answers to all of these questions could make or break iniparib’s chance at redeeming itself in this and other indications.
Kantar Health anxiously awaits evaluation of these data and other failed studies in order to understand their true impact on the drugs’ development and the oncology market. The table below summarizes those recently failed trials which will be presented at ASCO 2011.
|Negative Phase 3 Presentations of Interest, ASCO 2011|
|Iniparib||BiPar/Sanofi Aventis||Breast cancer, triple negative||Abstract 1007|
|AS1413||Antisoma||Secondary AML||Abstract 6520|
|Dacogen||Eisai/Janssen||AML, First-line, Elderly||Abstract 6504|
|Clolar||Genzyme||AML, Relapsed/refractory, Elderly||Abstract 6503|
|Motesanib||Amgen||NSCLC, First-line, Non-squamous||Abstract LBA7512|
Following the 2011 ASCO meeting, Kantar Health will publish an article in Oncology Business Review to provide a synopsis of some of the most interesting next-generation agents and therapeutic approaches in development.
About Kantar Health’s Oncology Conference Insight
Oncology Conference Insight is client-directed oncology conference coverage which analyzes the most important clinical presentations, satellite symposia, poster sessions and floor exhibits at significant oncology meetings including (but not limited to): American Association of Cancer Research (AACR), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), European Multidisciplinary Cancer Congress, American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer (AACR-NCI-EORTC), Japanese Society of Medical Oncology (JSMO), and San Antonio Breast Cancer Symposium (SABCS). For additional information on conference coverage, to request a fact sheet or to speak with someone on our team, please email Stephanie.Houser@kantarhealth.com.
About CancerMPact® Treatment Architecture
Treatment Architecture assesses the current clinical management of cancer patients by site and stage for all treatment modalities – including surgical, radiologic, chemotherapeutic, and untreated populations. Treatment Architecture also provides the benchmarks from clinical data to highlight the factors contributing to standard of care designations. Drug utilization is captured for all treatment settings and lines of therapy, and by patient type in tumors where biomarkers have segmented the drug market.
About Kantar Health (www.kantarhealth.com)
Kantar Health are experts in pharmaceutical and biotechnology consulting and market research, offering unique, proven solutions for marketing insights, brand marketing, business development and health economics/outcomes professionals. We combine scientific and business expertise to ensure evidence-based and commercially focused solutions for both emerging and established markets and spanning the product life cycle.