First-Line Immunotherapy in Advanced Squamous Cell Carcinoma of the Anal Canal (SCAC): Evidence Review

Image

Al B. Benson III, MD, FACP, FACCC, FASCO, is a professor of medicine in the Division of Hematology/Oncology at Northwestern University’s Feinberg School of Medicine in Chicago, Illinois. He is also the associate director for Cooperative Groups at the Robert H. Lurie Comprehensive Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center, at Northwestern University. 

Dr Benson reviews the epidemiology and unmet clinical need in advanced squamous cell carcinoma of the anal canal (SCAC) and examines the evolving role of immunotherapy in the first-line setting. He also contextualizes recent regulatory and guideline updates and highlights evidence-based frameworks to support population-level decision-making in rare malignancies.

Welcome to this presentation discussing anal cancer. My name is Al Benson. I'm a GI medical oncologist and professor of medicine at the Robert H. Lurie Comprehensive Cancer Center in the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

There have been two important randomized clinical trials investigating immunotherapy in combination with carboplatin and paclitaxel. One has been published. The other, we're still waiting for the study results. The first is the POD1UM-303 study, also referred to as InterAACT-2, which was a global study comparing paclitaxel, carboplatin, with or without the addition of the immunotherapeutic agent retifanlimab. This study used PFS as its primary endpoint and demonstrated the superiority of the immunotherapy combination, with a median PFS of 9.3 months, compared to 7.4 months for those who received chemotherapy and placebo. The hazard ratio was significant at 0.63.

An interim analysis of overall survival was conducted. However, these data are not mature. The median overall survival at the interim analysis was 29.2 months with the immunotherapy combination, compared with 23 months with placebo. However, I must emphasize that these are not mature data. It did show a trend. Survivorship data are also somewhat confounded by crossover.

As expected, there were certainly toxicities, grade three or higher, which occurred in over 80% of individuals. The serious adverse events were reported in approximately 47% of those individuals who received the retifanlimab arm of the study. There were immune mediated adverse events, which occurred in about 49% in the immunotherapy group, and also 26% were reported in the placebo group, and these included toxicities such as pneumonitis, colitis, hepatitis, and endocrinopathies. The retifanlimab was discontinued due to adverse events in approximately 11% of people who received the combination.

The second trial is a US cooperative group study coordinated by ECOG-ACRIN EA2176. And this had a very, very similar design to the POD1UM study, except the immunotherapeutic agent is nivolumab combined with carboplatin and paclitaxel. And we're very hopeful that these results will be reported soon.

Because of the results from the POD1UM-303, the FDA, upon its review, approved retifanlimab in combination with carboplatin and paclitaxel as a first-line treatment for those with inoperable or metastatic squamous cell carcinoma of the anus. It should also be mentioned that the FDA had previously approved retifanlimab as monotherapy for patients with advanced or metastatic disease who had progressed or who were intolerant to platinum-based chemotherapy. Also, the National Comprehensive Cancer Network, NCCN, has integrated retifanlimab with carboplatin and 5-FU as a preferred first-line regimen for those with metastatic or recurrent squamous cell anal carcinoma. And this is now listed in the anal carcinoma guidelines.

From a regulatory perspective and also from a managed care perspective, rare cancers do present significant challenges. In fact, I think we're seeing increasing challenges because even common diseases now have rare subsets of patients for whom targeted therapies are available. In the case of anal cancer, it was fortunate that we have been able to conduct randomized phase three trials with significant numbers of patients that, certainly in the case of immunotherapy now, have shown statistical significance, at least in terms of progression-free survival and overall response.

So, from a managed care perspective, this is high-quality evidence that should lead to integration in any platform or reimbursement. And given the strength of the evidence in anal carcinoma, for example, that's why the NCCN has included immunotherapy with chemotherapy as a first-line regimen. There are cases, however, where it's not possible to conduct a randomized phase three study because a particular molecular event, for example, may be very, very rare.

And we have cases where, for example, a molecular variant may occur in 1% of the population, yet we have developed drugs that target it. In those cases, we're often dealing with single-arm small studies. However, we can examine endpoints such as response rate and progression-free survival to provide evidence of the agent's activity against a particular molecular variant. And this needs to be taken into consideration, and certainly is by guideline panels, is also considered by regulatory agencies, and should also be considered by managed care professionals.

In summary, anus squamous cell carcinoma is a rare disease that has often been ignored in terms of clinical research, particularly for those individuals with metastatic disease. Fortunately, more recently, there has been global interest in the anal squamous cell carcinoma population. And this research has led to defining a more optimal platform chemotherapy regimen with carboplatin and paclitaxel. Also, through clinical research, we now know that immunotherapy combined with chemotherapy is effective, and we now have a preferred first-line regimen. We are also awaiting clinical trial results from the ECOG-ACRIN 2176 trial, which is evaluating the combination of nivolumab, carboplatin, and paclitaxel as a first-line regimen for those with metastatic disease. Thanks for your attention.