What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?
To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.
“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.
Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.
Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.
Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.
“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?
“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”
This view, however, remains contested by some oncologists.
Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.
“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”
The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.
“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”
On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”
Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.
“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”
Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.
“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”
Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.
“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”
The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
A version of this article appeared on Medscape.com.