In 2021, FDA has so far approved six antibodies against PD-1 or PD ligand 1 (PD-L1) for more than 75 indications. Ipilimumab remains the only FDA approved anti-CTLA-4 antibody, in melanoma indications and, in combination with nivolumab (an anti-PD‑1 antibody), in a number of other indications.

We have learned how to better manage the immune‑related side-effects of immunotherapy with delays in treatment and the use of steroids and other immunosuppressants. But, as always, there is a benefit/risk assessment when treating patients with immunotherapy. This was very evident at the February 9, 2021 Oncologic Drugs Advisory Committee (ODAC) discussion of pembrolizumab, an anti-PD-1 antibody, in high-risk, early-stage triple-negative breast cancer (TNBC). The committee voted unanimously that a regulatory decision on this indication should be deferred. This recommendation to FDA was based on the magnitude of the treatment effect and because event-free survival (EFS) and overall survival (OS) data were not mature. One of the issues raised by FDA reviewers was the higher incidence of immune-related adverse events in the pembrolizumab treatment arms - patient deaths due to immune-related reactions. From FDA’s perspective, these findings shifted the benefit/risk balance in this disease setting for this potentially curative treatment. Is one immune‑related death too many?

Drs. Julia A. Beaver and Richard Pazdur (Oncology Center of Excellence, US-FDA) point out in their recent article “Dangling” Accelerated Approvals in Oncology (N Engl J Med. 2021 May 6;384(18):e68. doi: 10.1056/NEJMp2104846. Epub 2021 Apr 21) that development of drugs in this class has occurred more rapidly than in any other therapeutic area in history. These antibodies are approved for use as single agents, in combination with chemotherapy and radiotherapy, and in combination with each other. The first tumor-agnostic indications were granted to pembrolizumab for microsatellite instability-high or mismatch repair deficient cancer and tumor mutational burden-high (TMB-H) cancer, where the approvals are based on characteristics of the cancer rather than the specific tumor type. As we hear in television commercials on a routine basis, the combination of two specific CTLA-4 and PD‑1 inhibitors can give us “a chance to live longer.”

In the article, the FDA officials note that of the first 76 approvals, 35 were accelerated approvals, and, for 10 of these indications, the required confirmatory trials did not end up confirming clinical benefit. Nine of these approvals had two things in common: (1) they were based on single arm studies and (2) they had low (12%-29%) but durable response rates. Discussions with FDA resulted in the sponsors’ decisions to voluntarily withdraw the applications for four indications. These indications included adults with locally advanced or metastatic urothelial carcinoma and patients with metastatic small-cell lung cancer.

The additional six indications, including locally advanced or metastatic TNBC, urothelial carcinoma, hepatocellular carcinoma (HCC), and esophageal cancer, were discussed at a 3‑day ODAC meeting, April 27-29, 2021. The discussions at this meeting were very interesting and enlightening. One could tell that committee members were struggling with their decisions, especially regarding how a recommendation to rescind an indication may impact patient access. Dr. Pazdur pointed out that if patient access was the main concern, there are mechanisms such as compassionate use that can fill this need. In the end, ODAC voted in favor of keeping the indications for four of the applications and voted against keeping the indications for two.

In the cases where the recommendation was to retain the approval, two thoughts were paramount – availability of the therapy for patients and the ability of subsequent studies to confirm approval. This was the case for atezolizumab when given with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1. The committee voted (7‑2) in favor of maintaining the approval.

On the second day of the meeting, ODAC, in a 5-3 vote, recommended keeping pembrolizumab on the market for its bladder cancer indication (advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy and expressing PD-L1, or not eligible for any platinum-containing chemotherapy, regardless of PD-L1 status). The recommendation to maintain this approval, despite the changing landscape with the approval of avelumab as maintenance therapy after completion of first line chemotherapy, was due to the lack of therapies for patients who are ineligible for platinum-based chemotherapy. The committee also voted 10-1 in favor of atezolizumab for the same indication.

ODAC voted 2-6 against maintaining pembrolizumab’s indication for the treatment of recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1. The recent approval of nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma, was a key consideration in the vote.

Two applications for HCC in patients previously treated with sorafenib were reviewed separately with differing results. While it was recommended to keep pembrolizumab on the market for this indication (8-0), the same indication was not supported for nivolumab (4‑5). Part of the discussion focused on the changing landscape for second-line immunotherapy with the approval of atezolizumab with bevacizumab for the first-line treatment of HCC. The main concern was access to immunotherapy in the 15% to 20% of patients with HCC who cannot be treated with bevacizumab due to bleeding risk. Nivolumab in combination with ipilimumab received accelerated approval in March 2020 for patients with HCC who have been previously treated with sorafenib. The unanimous decision in favor of pembrolizumab was based on the unmet need for second-line immunotherapy options in patients ineligible for bevacizumab treatment. With the approval of the combination of nivolumab with ipilimumab, the need for the single agent nivolumab was questioned and it was unclear whether there was a patient population suitable for single-agent nivolumab therapy.

In May of 2021, additional immunotherapy approvals were granted by FDA: full approval for nivolumab for patients with completely resected esophageal or GEJ cancer with residual pathologic disease who have received neoadjuvant chemoradiotherapy; and accelerated approval to pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or GEJ cancer.

While we have made great strides since the discovery of the first immunotherapy targets and are continually advancing the field clinically and mechanistically, there is still much research to be done. A recent search of using the term immunotherapy yielded a list of over 3000 studies. While we have shown that immunotherapy can induce long-lasting tumor regressions, these striking benefits are only seen in a minority of the patients treated. As we learn more about how these pathways work, and the molecules that we develop to modulate them, the hope is that we may be find ways to increase the number of cancer patients who can benefit from immunotherapy and better identify those who are more likely to benefit.

While we have made great strides since the discovery of the first immunotherapy targets and are continually advancing the field clinically and mechanistically, there is still much research to be done.

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