By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health
Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial or Stage I bladder tumors. Patients with these superficial tumors can often be cured, but those with muscle-invasive or metastatic disease are cured less often and are treated with surgery, irradiation or a combination of modalities that includes systemic therapy. Platinum doublets are widely utilized as first-line treatment in patients with metastatic disease, but minimal options exist for those failing that treatment. No drugs are approved in relapsed/refractory metastatic bladder cancer in the U.S., and the single compound with European approval, Javlor (vinflunine, Pierre Fabre), produced a meager 8.6% response rate and 3.0-month progression-free survival (PFS) in a Phase III trial.1 Thus any serious contender in this setting is a great cause for excitement. With immunotherapy already such a hot topic, atezolizumab (MPDL3280A, Genentech/Roche) is generating considerable enthusiasm.
Atezolizumab is a human monoclonal IgG1 anti-PD-L1 antibody that inhibits the interaction of the PD-1 receptor with the PD-L1 ligand. In June 2011, a “first-in-human” Phase I (NCT01375842, PCD4989g) trial was initiated to assess atezolizumab in patients with locally advanced or metastatic solid or hematologic malignancies. Preliminary results2,3 from this study in the cohort of patients with advanced bladder cancer were so encouraging that it led to the U.S. Food and Drug Administration (FDA) awarding atezolizumab Breakthrough Therapy status as treatment of relapsed/refractory, PD-L1-positive bladder cancer.
In the Sunday Proffered Papers session on genitourinary cancers at the 2015 European Cancer Congress, a packed auditorium eagerly awaited the results of the Phase II IMvigor 210 trial.4 Data was presented from Cohort 2 of the study, which included 311 patients who were previously treated with platinum-based therapy (Cohort 1 includes platinum-ineligible patients). Atezolizumab was administered at 1200 mg IV every three weeks until loss of clinical benefit. The Ventana PD-L1 (SP142) CDx Assay was used to prospectively stratify participants into three PD-L1-based subgroups based on PD-L1 expression levels in immune cells. IC (tumor-infiltrating immune cell) levels were defined as IC0 for patients with PD-L1 expression in less than 1% of cells (33%, n=103), IC1 for patients with PD-L1 expression in more than 1% but less than 5% of cells (35%, n=108), and IC2/3 for patients with PD-L1 expression in 5% or more of cells (32%, n=100).
The overall response rate (ORR) was 9% in patients with IC0 expression level, 10% in IC1, 27% in IC2/3, and 15% across all patients. PFS was 2.1 months in all PD-L1 cohorts, although beyond the median there appeared to be a greater PFS in the IC2/3 cohort (PFS at six months was approximately 35% for IC2/3 and 20% for IC0/1). Median duration of response was not reached in any subgroup (range 0+ to 43 months). Median overall survival was 7.9 months across all patient cohorts; median OS was 6.7 months in IC0/1 patients and was not reached in IC2/3 patients. The safety profile of atezolizumab was similar to what has been observed in other tumor types, with 15% of patients experiencing a Grade 3/4 adverse event; treatment discontinuations were infrequent (3%), but dose modifications due to adverse events were common (27%).
What is most striking about these data is that these are patients who had been heavily treated. Seventy-eight percent had prior systemic regimen treatment for metastatic disease, and 20% had already completed three or more prior lines of therapy. Compared with the 8.6% ORR, 3.0-month PFS, and 6.9-month OS achieved with Javlor in a second-line population, these results are a huge leap.
With such positive Phase II data, Roche intends to seek regulatory approval, with U.S. and European filings expected to occur in early 2016. Guidance from the company is that they will seek approval in the specific subset of patients with PD-L1-positive disease, although the exact definition of “positivity” intended to be sought is unclear. If they follow their lead from non-small cell lung cancer, the regulatory filing may be limited to patients with IC2/3 PD-L1 expression levels. This would be a wise move, considering that the ORR and PFS were strongest in this patient cohort, although arguably the high unmet need in metastatic bladder cancer could justify the use of atezolizumab in a broad patient population.
In the U.S., accelerated approval of atezolizumab in this indication is highly likely given the lack of any approved therapies for relapsed patients and with the drug having already received Breakthrough Therapy designation in this indication. An accelerated approval will give atezolizumab a significant first-to-market advantage over its closest competitor in the immuno-oncology space, Keytruda® (pembrolizumab, Merck & Co.). Keytruda is currently being studied in a Phase III trial for relapsed/refractory metastatic bladder cancer, with a trial design that is nearly identical to that of atezolizumab’s Phase III trial in this setting, although Merck’s trial started a few months ahead of Roche’s, lending importance to an accelerated market launch. For a disease that until recently has had so few treatment options, the results from the 2015 European Cancer Congress are truly “IMvigor-ating”.
By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Len Kusdra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health
Without a doubt, PD-1 and PD-L1 inhibitors have taken the oncology field by storm. With its approval in Japan in July 2014 for unresectable melanoma, Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) was the first PD-1 inhibitor to be approved worldwide and represented the culmination of a longstanding quest to harness the body’s inherent immune system to combat cancer. With the proverbial “cat out of the bag,” the approval also sparked a furious race between Opdivo and its closest competitor, Keytruda® (pembrolizumab, Merck), with the U.S. Food and Drug Administration (FDA) granting Keytruda accelerated approval in relapsed unresectable/advanced melanoma (September 2014) and subsequently approving Opdivo in the same setting (December 2014). All eyes turned to non-small cell lung cancer (NSCLC) in March 2015, when Opdivo became first-in-class in this indication with its approval in second-line squamous histology, and Merck quickly followed suit filing for Keytruda in NSCLC (PDUFA date: October 2, 2015). It seemed initially that these two agents would dominate the field of immuno-oncology; however, agents such as atezolizumab (Roche/Genentech), avelumab (Merck Serono/Pfizer), and durvalumab (MEDI4736, MedImmune/AstraZeneca) have entered the fray, and their entry into late-stage development, particularly in NSCLC, has intensified competition with no signs of abating in the near future. A question (among many) now becomes how will all these agents equilibrate in the market and what factors will guide physicians in their treatment paradigms for NSCLC?
Atezolizumab is Roche/Genentech’s gateway into this hot area. While a slight latecomer, atezolizumab is one of the most advanced immuno-oncology agents, representing a complementary mechanism by being an inhibitor of the PD-L1 ligand. The companies have initiated a broad NSCLC development program for atezolizumab, with three pivotal Phase II trials (FIR, NCT01846416; POPLAR, NCT01903993; and BIRCH, NCT02031458) and one Phase III trial (OAK, NCT02008227) for atezolizumab in second-line NSCLC in an effort to catch up with Opdivo and Keytruda; recently five Phase III trials also were initiated in the first-line setting as well as another Phase III trial in the adjuvant setting. FIR (n=138) and BIRCH (n=667) are single-arm trials of atezolizumab in PD-L1-selected patients in metastatic NSCLC. In both trials, atezolizumab was given at 1200 mg/kg IV every three weeks, and the primary endpoint was objective response rate (ORR). POPLAR (n=287) was a randomized Phase II trial that enrolled all-comers with relapsed metastatic NSCLC, with an accompanied stratification by PD-L1 expression; in this trial, atezolizumab (1200 mg/kg IV every three weeks) was compared with standard-of-care chemotherapy docetaxel (75 mg/m2 IV every three weeks). Roche has consistently guided that these three Phase II trials will form the basis for regulatory applications in the U.S. and Europe.
Interim results for POPLAR and FIR were first reported at the American Society of Clinical Oncology (ASCO) 2015 annual meeting.1,2 Patients in POPLAR who had higher levels of PD-L1 expression in either the tumor (TC1/2/3) or immune cells (IC1/2/3) showed increased overall survival with atezolizumab compared with docetaxel (median not reached versus 9.1 months (HR 0.63, p=0.024)) and the magnitude of overall survival (OS) benefit was greater for patients who more strongly expressed PD-L1 (immunohistochemistry score (IHC) 2/3, HR 0.56; IHC3, HR 0.46); this survival benefit did not significantly differ among patients with TC or IC IHC0. The FIR trial showed that patients expressing a high level of PD-L1 (TC or IC IHC2/3) exhibited an ORR of 29% for first-line patients, 17% for second-line or later patients without brain metastases, and 23% for second-line or later patients with brain metastases. After POPLAR and FIR reported data at ASCO 2015, the last of the Phase II trials, BIRCH, was highly anticipated. In August 2015, Roche announced that BIRCH had met its primary endpoint and induced tumor shrinkage in patients who expressed PD-L1, and that PD-L1 expression correlated with response; the results were presented Sunday at the 2015 European Cancer Congress in Vienna.3
The BIRCH trial evaluated atezolizumab in patients with locally advanced or metastatic NSCLC who expressed high levels of PD-L1 on either TC or IC, as determined by the VENTANA SP142 IHC assay. TC2/3 or IC2/3 was equal to or greater than 5% of PD-L1-positive TCs or ICs, while TC3 or IC3 was equal to or greater than 50% TCs or 10% ICs expressing PD-L1. Patients were stratified into three cohorts: Cohort 1 had received no prior chemotherapy (n=142), Cohort 2 had received one prior platinum chemotherapy (n=271), and Cohort 3 had received at least two prior chemotherapies including one platinum (n=254). Patients were treated until progressive disease or until loss of clinical benefit. The ORR in all three patient cohorts correlated with level of PD-L1 expression: ORR for IHC2/3 versus IHC3 was 19% versus 26% in Cohort 1; 17% versus 24% in Cohort 2; and 17% versus 27% in Cohort 3. Median PFS was 5.5 months, 2.8 months and 2.8 in Cohorts 1, 2, and 3 in patients with TC-IC2/3, while a similar trend was seen in patients with TC-IC3 (Cohort 1 5.5 months, Cohort 2 4.1 months, Cohort 3 4.2 months). OS data is not yet mature; however, six-month OS rates in Cohorts 1, 2, and 3 were 82%, 76% and 71%, respectively, in IHC2/3 patients and 79%, 80%, and 75% in Cohorts 1-3 in the IHC3 population. Adverse events seen with atezolizumab were similar to those seen in other studies, with the most common Grade 3/4 adverse events being rash, pneumonitis, elevated liver transaminases and colitis, all which had a frequency less than 2% each.
Roche has guided that it plans to file for regulatory approval in the U.S. and EU in 2016; in light of the Breakthrough Status granted by the FDA, combined results from FIR, POPLAR, and BIRCH should support an accelerated approval of atezolizumab in patients with PD-L1-positive, relapsed metastatic NSCLC. A question that stands out is how Roche will differentiate atezolizumab from its competitors and how will physicians adopt atezolizumab in their clinical practice. In terms of entry into market, Opdivo is ahead of atezolizumab, allowing Opdivo to establish itself in clinical practice. While cross-trial comparisons should always be made with caution, the survival curves in Opdivo’s CheckMate-017 and CheckMate-057 trials in second-line NSCLC and atezolizumab’s POPLAR trial in second-line NSCLC indicate very similar levels of efficacy between Opdivo and atezolizumab, so similar that the BIRCH trial discussant, Dr. Luiz Paz-Ares, stated that the trials “confirmed each other.” Given the similar level of benefit, it is unlikely atezolizumab will compete with Opdivo based on efficacy alone. Additionally, Keytruda is expected to receive FDA approval in relapsed NSCLC very shortly, thus putting atezolizumab third to market in the U.S.
One point of differentiation is in patient selection. The data showing increased response in patients with higher PD-L1 supports a regulatory filing in PD-L1-positive patients for atezolizumab, which is also supported by its FDA Breakthrough Therapy designation in this patient type; Opdivo is unlikely to have such a biomarker-restricted label, and whether or not Keytruda’s label will include a biomarker restriction is an area of hot debate. If atezolizumab becomes the first of these drugs to be approved with a PD-L1-positive biomarker limitation in its label, this could prove advantageous. Physicians may shift their preference toward atezolizumab if the efficacy is more pronounced in this patient population or if payers strictly enforce PD-L1 biomarker testing and subsequently choice of PD-1 or PD-L1 inhibitor. The loss of a fraction of patients who are PD-L1-negative if a restricted label is granted may be counterbalanced by the gain of greater market share among patients who are PD-L1-positive than might have been obtained by competing against two other drugs in an all-comers population.
Many questions remain (largely around implementation of the PD-L1 diagnostic), and physicians will soon find themselves with many arguably similar therapeutic choices for their relapsed NSCLC patients. Until more definitive data becomes available to better guide immuno-oncology treatment decisions, physicians may be left analyzing individual “trees” before the forest that is the clinical paradigm for immuno-oncology products can be fully understood.
By: Arnold DuBell, Ph.D., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
Sutent® (sunitinib, Pfizer) and Votrient® (pazopanib, Novartis) are currently considered the standards of care for first-line therapy in renal cell carcinoma (RCC). However, neither drug (nor any other agents currently approved) has been able to show an overall survival (OS) benefit in clinical trials; they were approved by regulatory agencies based on a significant improvement in progression-free survival (PFS). Since 2005, seven agents have been approved, including Sutent and Votrient, on the basis of PFS alone.
Moreover, the presence of two established agents with strong utilization in the first-line setting contributes to the need for agents that can be utilized following relapse. Two agents are currently approved for use in this setting – Afinitor® (everolimus, Novartis), based on significant improvements in PFS compared with placebo, and Inlyta® (axitinib, Pfizer), based on significant improvement in PFS compared with Nexavar® (sorafenib, Bayer/Amgen). Given the lack of proven OS benefits for any of these agents, an opportunity exists for an agent that can establish a significant benefit for this endpoint. It is in this framework that two trials presented in the Presidential Symposium Saturday at the 2015 European Cancer Congress finally show the possibility of improving OS. The trials were CheckMate-025, which evaluated Opdivo® (nivolumab, Bristol-Myers Squibb/Ono), and METEOR, which evaluated Cometriq® (cabozantinib, Exelixis).
CheckMate-025 was the first of these two studies to be presented.1 This trial compared Opdivo (3 mg/kg every two weeks) to daily oral Afinitor (10 mg) in 821 advanced or metastatic clear-cell RCC patients who had been treated with one or two prior anti-angiogenic therapies. The trial was stopped early by the data-monitoring committee in July 2015 as the statistical boundary for declaring OS superiority of Opdivo had been reached. Opdivo reduced the risk of death by 27% (median OS: 25.0 months versus 19.6 months, HR 0.73, p=0.0018). Most subgroups favored Opdivo, although the arms for elderly patients (75 years or older), patients with favorable MSKCC risk status, or patients who had received two prior therapies (confidence interval overlapped the mark for non-significance)showed no apparent difference ,. Tumor PD-L1 positivity, defined as PD-L1 membrane expression in 1% or more of cells stained using the Dako immunohistochemical kit, was not predictive of activity. The objective response rate was improved (25% versus 5%, OR 5.98, p<0.0001), but the duration of response (12.0 months in both arms) and PFS (4.6 months versus 4.4 months, HR 0.88, p=0.1135) were not improved.
Opdivo was better tolerated than Afinitor, with fewer treatment-related Grade 3/4 adverse events than Afinitor (19% versus 37%). The more common toxicities of any grade for Opdivo included fatigue (33%), nausea (14%), pruritus (14%), diarrhea (12%), and decreased appetite (12%). The improved efficacy and tolerability were reflected in an improved score in quality of life as measured by the FKSI-DRS questionnaire (p<0.05).
METEOR was presented next in the session.2 METEOR compared oral daily Cometriq (60 mg) with oral daily Afinitor (10 mg) in 658 advanced clear-cell RCC patients who have progressed on a prior VEGFR tyrosine kinase inhibitor (TKI) within six months of enrollment. Despite that inclusion criterion, there was no limit to the number of prior therapies as 29% of patients on the Cometriq arm received two or more prior VEGFR TKI treatments. Other therapies were also allowed but had been less frequently offered to the enrolled patients.
METEOR achieved its primary endpoint, which was PFS, with a 3.6-month improvement (HR 0.58, p<0.001). Subgroup analysis suggested that Cometriq improved PFS in most patients, but PFS may not have been significantly improved in those with two or more prior therapies or a poor MSKCC risk status. The response rate was also improved (21% versus 5%, p<0.001). OS was not yet reached but trended to significance with Cometriq (HR 0.67, p=0.005). The medians could not be estimated due to frequent early censoring, and the interim boundary for significance was set at p=0.00019). As the Kaplan-Meier curves were clearly separated from one another and these data are immature, it is expected that a significant OS benefit ultimately will be reached.
Cometriq had some toxicities but was generally well-tolerated. Grade 3 or 4 adverse events were higher in the Cometriq arm (68% versus 58%) and were reflected in a higher percentage of dose reductions (60% versus 25%). Select Grade 3/4 toxicities of note, compared with Afinitor, included hypertension (15% versus 3%), diarrhea (11% versus 2%) and palmar-plantar erythrodysesthesia (8% versus less than 1%); anemia (5% versus 16%) and hyperglycemia (less than 1% versus 5%) were improved in the Cometriq arm.
If METEOR does not reach its threshold for statistical significance, the decision for physicians will be easy: Choose Opdivo for its improvement in OS. If the OS benefit in METEOR becomes statistically significant (and the Kaplan-Meier curves strongly suggest that it will do so), then physicians will have a more difficult decision to make. The high excitement level for immuno-oncology agents in general, coupled with its seemingly more favorable tolerability, may lead physicians to opt first for Opdivo. On the other hand, Cometriq does have its own advantages, perhaps most notably the ability to delay progression (by 3.6 months at the median in the METEOR trial).
|mOS, mos.||25.0||19.6||0.73||Median not available||0.67|
|Total Grade 3/4 AEs (%)||19||37||68||58|
Making two assumptions – that the METEOR trial ultimately shows a significant OS benefit and that regulatory agencies will approve the two drugs within a few months of each other – these two agents will have a hefty competition for market share in second-line RCC. The toxicity profile for Opdivo may favor its use in many patients, although Cometriq might end up being the agent of choice for select patients, such as those who are older than 75 years of age, where Opdivo appears less effective. In a way, this is a good problem, at least for oncologists and their patients. It’s always better to question which of several good agents to choose from rather than having few options or none at all.