The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 28, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC).
Anti-PD-L1 atezolizumab was granted accelerated approval for first-line treatment of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma in April 2017, based on an objective response rate (ORR) of 23.5% and median duration of response (DOR) of 59.1 months within cohort 1 of the phase 2 IMvigor210 trial. In May 2017, anti-PD-1 pembrolizumab also received accelerated approval in the first-line setting for metastatic urothelial carcinoma based on an ORR of 28.6% and a median DOR not yet reached (median follow up = 7.8 months) in the phase II KEYNOTE-052 trial. Both atezolizumab and pembrolizumab were initially approved irrespective of tumor PD-L1 status, but the indications were subsequently restricted based on signals for decreased overall survival (OS) with checkpoint inhibitor therapy in the PD-L1-negative populations in interim analyses of the confirmatory trials IMvigor130 and KEYNOTE-361, respectively.
Full approvals for both checkpoint inhibitors were contingent on their respective confirmatory trials, yet statistically and clinically significant OS benefit was not observed in the final analysis of KEYNOTE-361 for pembrolizumab and the interim analysis of IMvigor130 for atezolizumab. The treatment landscape has also evolved in recent years with the full regulatory approval of anti-PD-L1 avelumab as maintenance therapy after completion of standard first-line chemotherapy. However, a significant proportion of patients are not eligible for cisplatin treatment or for any platinum-based regimens, making first-line pembrolizumab or atezolizumab the only options for this otherwise unmet clinical need.
On April 28, 2021, the FDA ODAC panel was asked to vote on the appropriateness of maintaining the accelerated approval for pembrolizumab and atezolizumab for this patient population.
Pembrolizumab
The outcome of the vote at the FDA ODAC meeting was 5 to 3 in favor of maintaining the accelerated approval for pembrolizumab for the first-line treatment of advanced/metastatic urothelial carcinoma in cisplatin-ineligible patients with PD-L1-positive tumors and carboplatin-ineligible patients regardless of PD-L1 status.
Sponsor Position:
- Pembrolizumab fills an unmet need for patients who are ineligible or unwilling to receive platinum-based chemotherapy
- There was evidence of activity for pembrolizumab from durable responses in long-term follow-up of registration trial as well as demonstrated benefit in KEYNOTE-045 assessing efficacy in the second-line setting
- ORR and favorable safety profiles that were the basis for accelerated approvals for pembrolizumab in KEYNOTE-052 were recapitulated in KEYNOTE-361
- Crossover from the control arm to subsequent anti-PD-(L)1 therapy in KEYNOTE-361 complicate interpretation of OS and progression-free survival (PFS)
FDA Position:
- OS and PFS benefit are not validated in confirmatory trials KEYNOTE-361
- The addition of avelumab as an option has altered the treatment landscape for patients with urothelial carcinoma
- The proposed alternative trial to confirm benefit in metastatic setting (LEAP-011) may not isolate effects of pembrolizumab due to combination with enfortumab vedotin as a comparator
- Studies in peri-operative settings that include cisplatin-eligible patients (KEYNOTE-866 and KEYNOTE-905) will not be complete within a reasonable timeframe
Public Comment:
- Immunotherapy offers an alternative for many patients who are unable or unwilling to tolerate treatment with platinum-based regimens
Rationale for the vote centered on the significant unmet medical need for ineligible for platinum-based chemotherapy. Although LEAP-011 will only provide single-arm evidence on the efficacy of pembrolizumab monotherapy, the trial was deemed appropriate as a confirmatory study when taken in context of the totality of data from KEYNOTE-052 and KEYNOTE-045.
Atezolizumab
ODAC voted 10 to 1 in favor of maintaining the accelerated approval for atezolizumab as first-line treatment of cisplatin-ineligible patients with advanced/metastatic urothelial carcinoma who are PD-L1-positive or for platinum-ineligible patients with any PD-L1 status.
Sponsor Positions:
- Atezolizumab fills an unmet need for patients who are ineligible or unwilling to receive platinum-based chemotherapy
- Atezolizumab is well-tolerated and displays a favorable safety profile
- Clinically meaningful improvement in ORR and DOR were observed in cisplatin-ineligible patients when compared to historical controls from IMvigor210. Long-term follow up indicates that responses continue to remain durable
- Although the IMvigor211 trial failed to show benefit of atezolizumab in the PD-L1+, previously treated urothelial cancer patients, a signal for increased survival was observed in the ITT population—though this could not be formally assessed for significance due to the pre-specified hierarchical statistical plan
- Confirmatory trial data from IMvigor130 is not yet mature
- Interim analyses of IMvigor130 suggest a statistically significant PFS benefit in patients receiving atezolizumab + chemotherapy versus chemotherapy alone. Data also trend toward improved OS in the PD-L1+ and ITT populations, though these have not yet been verified via statistical analyses
FDA Position:
- OS and PFS benefit was not validated in interim analysis of IMvigor130
- Atezolizumab did not show benefit in the PD-L1-positive group during the second-line setting in IMvigor211, leading to voluntarily withdrawal
- Negative results were also reported with atezolizumab in the adjuvant setting.
- While statistically significant, the 1.9 month improvement in PFS seen in IMvigor130 is not considered clinically meaningful
- Conclusions cannot be drawn from subgroup analyses at this time, due to the prespecified hierarchical statistical design
- Treatment landscape has changed since the 2017 accelerated approval, with demonstrated OS benefit from avelumab maintenance therapy after completing platinum-based chemotherapy
Public Comment:
- Immunotherapy offers an alternative for many patients who are unable or unwilling to tolerate treatment with platinum-based regimens
Justification for maintaining the indication predominantly cited the need to wait for final analysis of IMvigor130 to evaluate potential clinical benefit. Of note, data from the arm evaluating atezolizumab + chemotherapy may not only support the full approval of atezolizumab monotherapy, but also influence the regulatory status of an additional indication for the combination regimen.
