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.

SITC 2017 Scientific Highlights - Nov. 11

The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights from the Saturday programs (Nov. 11, 2017) of the 32nd Annual Meeting in National Harbor, Md. (Scroll to the bottom of this blog post to view the Glossary).

Dendritic cell acquisition of MHC I controls CD8+ T cell priming

Brandon MacNabb, BS (University of Chicago) presented data supporting the concept of MHC I antigen presentation by Batf3-lineage DCs as a critical component of CD8+-mediated anti-tumor response. Researchers initially generated H2-KbAB (MHC I+) and Kb-/-(MHC I-) C1498.SIY acute myeloid leukemia cell lines and subsequently engrafted C57BL/6 mice to determine the contribution of tumor cell MHC I presentation in CD8+ T cell priming. Initial assessment revealed reduced tumor growth in C1498.SIY KbAB mice compared to C1498.SIY Kb-/- mice. CD8+ T cell proliferation was also increased in KbAB mice compared to Kb-/- mice (p < 0.05). The observed C1498.SIY KbAB-dependent CD8+ proliferation was abolished in Batf3-/- C57BL/6 mice (p < 0.01). IFN-ϒ secretion was also decreased in Batf3-/- KbAB mice, suggesting that Batf3 initiates CD8+ priming. Transfer of autologous T cells from KbAB tumor-bearing mice offered complete protection from tumor growth in tumor-free mice. Conversely, autologous T cells from Kb-/- mice offered no such protection. Interestingly, DCs isolated from the TME and the tumor-draining lymph node in tumor-positive mice had increased KbAB MHC I expression (p < 0.001), suggesting DC acquisition of tumor-derived MHC I. Ex vivo experiments confirmed that migratory KbAB DCs are capable of CD8+ priming. These data reveal the importance of Batf3-lineage DCs and tumor-derived MHC I presentation in CD8+ T cell activation of anti-tumor response, providing insight into potential development of DC-oriented therapies.