SITC Meeting Report: April 29 FDA ODAC Summary

The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 29, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC).

Gastric and Gastroesophageal Junction Adenocarcinoma

In 2017, anti–PD-1 pembrolizumab was granted an accelerated approval for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (combined positive score [CPS] greater than or equal to 1) as determined by an FDA-approved test, and have failed two or more lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy. Approval was granted based on an observed 13.3% objective response rate (ORR) within Cohort 1 of KEYNOTE-059. However, both KEYNOTE-061 (second-line pembrolizumab vs. paclitaxel) and KEYNOTE-062 (first-line pembrolizumab in combination with 5-fluorouracil and cisplatin vs. chemotherapy alone) have failed to confirm an overall survival (OS) benefit of adding the PD-1 inhibitor to the treatment regimens for patients with PD-L1+ gastric or GEJ adenocarcinoma.

Pembrolizumab

On April 29, 2021, FDA ODAC met to discuss maintaining the indication for third-line pembrolizumab monotherapy for PD-L1+ patients with gastric or GEJ adenocarcinoma in light of currently available clinical trial data as well as the rapidly evolving treatment landscape for this patient population. The committee voted 6-2 to recommend rescinding the current indication.

Sponsor Position:

• Pembrolizumab monotherapy addresses a significant unmet medical need for treatment of heavily pre-treated patients who may not be able to tolerate chemotherapy
• Data provided by KEYNOTE-059 are consistent with data supporting alternative approvals in this patient population with a generally poor prognosis (ex. median OS is 6 months across clinical trials currently supporting treatment approvals)
• Pembrolizumab has an acceptable safety profile and is well tolerated in the third-line, PD-L1+ patient population
• By 2024, four ongoing clinical trials will provide data that may be able to confirm pembrolizumab clinical benefit in this patient population
• KEYNOTE-061 may not serve as appropriate comparisons for approval confirmation, as more recent data suggest earlier lines of gastric and GEJ treatment require chemotherapy addition
• KEYNOTE-590 data revealed an OS benefit of pembrolizumab addition to chemotherapy for the treatment of patients with esophageal or GEJ adenocarcinoma and supported FDA approval for first-line treatment

FDA Position:

• Recent approvals, including first-line PD-1 inhibitor nivolumab + FOLFOX or CAPEOX for patients with gastric and GEJ adenocarcinoma, may address the unmet medical need served by the discussed pembrolizumab indication
• ORR within the PD-L1+ patient population from Cohort 1 of KEYNOTE-059 may have been contaminated through the inclusion of patients with unknown tumor microsatellite instability/tumor mutational burden status
• Ongoing clinical trials by the sponsor evaluate pembrolizumab in combination with chemotherapy and are not assessing monotherapy as described within the current indication
• Given the low ORR demonstrated within KEYNOTE-059, the risk/benefit may not support approval given possibility of immune-related adverse events

Public Comment:

• This treatment addresses and unmet medical need for patients in third-line setting who have not received IO and those who cannot tolerate chemotherapy

Committee members cited currently available clinical trial data as not supporting the risk/benefit ratio of retaining the indication. They also noted that none of the currently ongoing clinical trials would serve to answer whether pembrolizumab monotherapy provides clinical benefit. Lastly, there was discussion on how recent first-line immunotherapy indications would likely become standard of care, and that future patients requiring third-line treatment may not be eligible for checkpoint inhibitor therapy. Given the recommendation to rescind the indication, committee members emphasized the importance of delaying any planned market removal to ensure that patients currently receiving the therapy could enter into an expanded access program or single patient IND to continue treatment. The FDA was in support of these measures and emphasized that they were cognizant of the impact upon patients if the indication were to be ultimately rescinded.

Hepatocellular Carcinoma

Anti PD-1 nivolumab, the first checkpoint inhibitor to be marketed for treatment of patients with hepatocellular carcinoma (HCC) whose disease progresses after treatment with the first-line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) sorafenib, gained accelerated approval in September 2017. Approval was based on the results of one of the treatment arms of the multicenter, open-label, phase I/II trial CheckMate 040, which showed a confirmed ORR in this patient population of 14.3% (95% CI: 9.2, 20.8), with 91% of responders having responses lasting 6 months or longer and 55% having responses lasting 12 months or longer. A second anti-PD-1 agent, pembrolizumab, received accelerated approval for the same indication based on an independent central review-assessed ORR of 17% (95% CI: 11, 26) with 89% of responders having durations of 6 months or longer and 56% having response durations of 12 months or longer in the single-arm, multicenter, phase I/II study KEYNOTE-244.

Advanced HCC is associated with a very poor prognosis and the disease almost always develops against a background of cirrhosis, complicating therapy selection in patients with poor liver function and high burden of comorbidities. Since the initial accelerated approvals of pembrolizumab and nivolumab, the treatment landscape for HCC has changed, with the combination of the anti-PD-L1 atezolizumab plus the anti-VEGF bevacizumab attaining full approval for first-line treatment of HCC based on significant OS and PFS improvements in the multi-center, open-label IMbrave150 trial. However, up to 15% to 20% of patients with HCC cannot be treated with bevacizumab due to bleeding risk. Nivolumab in combination with anti-CTLA-4 ipilimumab also received accelerated approval for patients with HCC who have been previously treated with sorafenib in March 2020. This indication was not under consideration at this meeting.

Review of the HCC indications for nivolumab and pembrolizumab monotherapies was motivated by the low response rates in their respective registration studies as well as failure to verify clinical benefit in the designated confirmatory studies CheckMate 459, which did not meet efficacy thresholds for OS benefit in the first-line setting, and KEYNOTE-240, which did not achieve pre-specified statistically significant OS improvement in the identical to the registration trial post-sorafenib setting.

Pembrolizumab

On April 29, 2021, FDA ODAC voted 8 to 0 in favor of maintaining the accelerated approval of pembrolizumab for patients with HCC who have previously been treated with sorafenib. The unanimous decision was based on the substantial unmet need for second-line immunotherapy options in the population ineligible for bevacizumab treatment as well as the panel’s opinion that KEYNOTE-240 demonstrated clinically meaningful benefit despite not meeting pre-specified significance thresholds in OS.

Sponsor Position:

• Pembrolizumab monotherapy represents an important option for the significant proportion of patients with HCC who cannot receive first-line bevacizumab and whose disease progresses after sorafenib
• The incremental benefit of second-line pembrolizumab is analogous to the approved second-line TKIs, and the toxicities associated with pembrolizumab monotherapy are largely manageable
• Durable responses seen with pembrolizumab monotherapy are clinically meaningful

FDA Position:

• ORR with pembrolizumab monotherapy was low in the registration trial KEYNOTE-244 and the confirmatory trial KEYNOTE-240
• Recognizing that the bevacizumab-ineligible population represents a significant unmet need, patients at high risk for bleeding with bevacizumab were not included in KEYNOTE-244 and KEYNOTE-240

Public Comment:

• HCC is associated with very poor prognosis and significant unmet need, especially for the patients with poor underlying liver function or who cannot receive first-line atezolizumab + bevacizumab due to bleeding risk
• Removing options for second-line therapies is not in the best interest of patients with HCC

Alternative confirmatory trials for pembrolizumab have completed accrual and results are anticipated soon. Specifically, the final analysis of KEYNOTE-394, which is evaluating benefit in the post-sorafenib setting in an East Asian population is expected as early as June or July of 2021, and the results of the LEAP-002 trial comparing first-line pembrolizumab in combination with the VEGF-TKI lenvatinib to lenvatinib monotherapy will be available in 2023.

Nivolumab

In a 4 to 5 vote, ODAC recommended rescinding the indication for nivolumab for the treatment of patients with HCC and prior sorafenib therapy. There was unanimous agreement from committee members that voting was difficult due to the many factors, including the earlier vote to maintain the indication for pembrolizumab monotherapy. Those in favor of continued accelerated approval for nivolumab in this patient population highlighted the unmet need for second-line options. Rationale against continuing the indication centered on the lack of OS benefit in CheckMate 459 and the inadequacy of the proposed alternative studies to generate satisfactory evidence for efficacy in the second-line setting. Discussion also narrowed in on whether data exist to recommend nivolumab monotherapy over an ipilimumab + nivolumab combination regimen, including debate over whether the group of patients deemed unfit for the dual checkpoint inhibitor combination represent a new indication that was not formally defined nor evaluated in trials to date.

Sponsor Position:

• Nivolumab fills an unmet medical need for the patients who cannot receive bevacizumab in the first-line and whose disease progresses after TKI therapy
• Nivolumab monotherapy is well-tolerated in patients with HCC and associated with fewer toxicities than the ipilimumab-containing combination regimen
• Exploratory analyses in CheckMate 459 favor benefit for healthcare-related quality of life with nivolumab
• Delayed benefit was seen at longer follow-up in CheckMate 459, possibly due to subsequent systemic therapy use in sorafenib arm, including immunotherapy

FDA Position:

• Availability of first-line atezolizumab + bevacizumab (in addition to other second-line options, including combination ipilimumab + nivolumab) has changed the HCC treatment landscape
• Statistically significant OS benefit with nivolumab monotherapy was not shown in the designated confirmatory trial, CheckMate 459
• Alternative confirmatory trials CheckMate 9DX (adjuvant nivolumab) and CheckMate 9DW (first-line ipilimumab + nivolumab) will not provide evidence for benefit with second-line monotherapy
• Data are lacking on efficacy of the monotherapy in the population of patients who cannot tolerate first-line bevacizumab as well as those deemed ineligible for other second-line therapies, such as ipilimumab + nivolumab

Public Comment:

• Nivolumab monotherapy is an important option for many HCC patients, especially given the increased potential for toxicity with ipilimumab-containing combinations
• The safety and adverse event profile of nivolumab is favorable compared to other available second-line therapies for HCC

The FDA is not required to implement the recommendations of ODAC. Committee members also noted that nivolumab is widely available for other FDA-approved indications and that off-label use remains a possibility for the patients with second-line HCC. If the indication were to be ultimately rescinded, expanded access programs and single patient INDs also remain possibilities to allow for continued access.