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.