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.

SITC Meeting Report: April 28 FDA ODAC Summary

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. 

SITC Meeting Report: April 27 FDA ODAC Summary

The Society for Immunotherapy of Cancer (SITC) is pleased to present this report on the April 27, 2021, meeting of the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC). 

Anti-PD-L1 atezolizumab initially obtained an accelerated approval in combination with nab-paclitaxel for adult patients with metastatic triple-negative breast cancer (mTNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering greater than 1% of the tumor area) as determined by an FDA-approved test. Accelerated approval in this disease setting was granted in March 2019 based on results of the IMPassion130 trial that demonstrated a median progression-free survival (PFS) of 7.4 months for patients being treated with atezolizumab + nab-paclitaxel versus 4.8 months for those on placebo + nab-paclitaxel. However, the IMPassion131 confirmatory trial did not meet its pre-specified endpoint in overall survival (OS).

On April 27, 2021, FDA ODAC was asked to consider the appropriateness of maintaining the accelerated approval for atezolizumab in this indication. The committee voted 7-2 in favor of maintaining the current approval. Committee members universally agreed that mTNBC remains a disease with a profound unmet medical need and repeating the landmark placebo-controlled trial that led to accelerated approval would likely present an insurmountable logistical obstacle given the current availability of the regimen in almost 90 countries worldwide and increasingly routine use in clinical practice.  

Sponsor Position:

• Statistically significant improvement in PFS and a clinically meaningful benefit in OS was observed in patients with PD-L1+ tumors in the pivotal phase III IMpassion130 trial
• Atezolizumab addition to nab-paclitaxel provided a manageable toxicity profile and did not cause deterioration in healthcare-related quality of life 
• Differences between IMpassion130 and IMpassion131 including chemotherapy backbones (ie, nab-paclitaxel vs paclitaxel), concomitant corticosteroids, and randomization schema complicated OS comparisons between the two data sets
• Interpretation of IMpassion131 may be further complicated by OS in the placebo arm being among the longest ever reported in a mTNBC trial (28 months as opposed to the historical 12-18 months)
• Other possible confirmatory trials are ongoing and are expected to provide results by 2023/2024. These trials include IMpassion132 evaluating atezolizumab + capecitabine or gemcitabine/carboplatin in patients with mTNBC, and IMpassion031 assessing neo-adjuvant atezolizumab + nab-paclitaxel in patients with early-stage TNBC. 

FDA Position:

• The OS results for the biomarker-selected group in IMpassion130 may be due to chance, as the pre-specified hierarchical statistical plan prevented formal testing in the PD-L1+ population
• IMpassion131 did not demonstrate a PFS benefit for patients treated with combination atezolizumab, and data suggest potentially lower OS in the investigational arm 

Public Comments:

• There remains a significant unmet medical need for evidence-supported therapies for mTNBC
• Black women are disproportionately affected by mTNBC, and IMpassion130 only enrolled a small percentage of Black women 
• mTNBC patients desire clear results for FDA approved therapeutics 

Rationale for Continued Approval:

• Unchanged unmet medical need
• It remains possible that negative results in IMpassion131 were an outlier due partly to the uncharacteristic OS in the placebo arm

The sponsor has been in conversation with the FDA to identify appropriate post-market trials to support full approval and further discussed the merits of IMpassion031 and IMpassion132. Clinical benefit has been reported with the addition of atezolizumab to neoadjuvant nab-paclitaxel in IMpassion031, although the utility of pathologic complete response as an appropriate surrogate endpoint for survival remains an unanswered question within the field. Despite IMpassion132 incorporating a different chemotherapy regimen as well enrolling a different patient population, the expected results in 2023 were identified as important to address the question of whether the addition of atezolizumab to chemotherapy offers confirmed clinical benefit to patients with mTNBC.

Letter from the Editor- April

Dear JITC Readers,

It is a pleasure to welcome you to this month’s JITC digest. The original research articles highlighted in this edition are fantastic examples of mechanistic insight interwoven with new strategies for intervention and vice versa—the seamless reverse translational cycle that is central to the immunotherapy field.

 

Novel targets for immunotherapy are characterized by Aiqin Gao and colleagues, who show that blocking ILT4 relieves T cell immunosenescence via ERK-dependent metabolic perturbations, as well as François Anna et al, who take aim at HLA-G with the first chimeric antigen receptor (CAR) T cells against the dual function tumor-specific antigen and immune checkpoint.

 

Esther Redin and colleagues demonstrate that inhibition of the SRC-family kinase YES1 with the approved leukemia drug dasatinib decreases CD4+ Treg conversion and enhances the efficacy of PD-1 blockade in non-small cell lung cancer.

 

Another strategy to augment the anti-tumor effects of PD-1 inhibition is identified by Yoke Seng Lee et al, who establish a link between conventional type 1 dendritic cell counts and responses to immunotherapy in patients with melanoma as well as in a novel humanized mouse model.

Finally, Gino M Dettorre and colleagues validate a readily available index of hyperinflammation incorporating lymphopenia and hypoalbuminemia that predicts outcomes of SARS-CoV-2 infection in patients with cancer—research that hints at interventions to prevent severe disease and nicely complements recently published articles in JITC’s ongoing COVID-19 and Cancer Immunotherapy Review Series.

 

Best regards,

Pedro J. Romero, MD
Editor-in-Chief, Journal for ImmunoTherapy of Cancer

To view the entire April 2021 JITC Digest, please click here.