The Case for Chemotherapy Plus Immunotherapy for Patients With Low or Negative PD-L1

At the Great Debates & Updates in Lung Cancer meeting in New York, New York, Karen Reckamp, MD, Cedars-Sinai Medical Center, Los Angeles, California, debated in favor of using chemotherapy plus immunotherapy for patients with non-small cell lung cancer and PD-L1 expressions of <1% and 1% to 49%.

Transcript:

Hi I’m Karen Reckamp, the Division Director of Medical Oncology and Professor of Medicine at Cedars-Sinai Medical Center in Los Angeles. We're here at the Great Debates & Updates in Lung Cancer in New York, New York.

There’s a large number of patients who do not have high-PD-L1 and in general, though there is an approval for pembrolizumab for patients over 1% PD-L1, for the most part we see less robust responses and less efficacy. Generally, we’re using combinations in this setting and there are a multitude of combinations that have been investigated versus chemotherapy. We have combinations of immunotherapy with chemotherapy and that includes pembrolizumab with chemotherapy, atezolizumab with chemotherapy, and cemiplimab also with chemotherapy.

Then we also have some combinations of PD-L1, PD-1, and CTLA-4 combined immunotherapy, some of those are with chemotherapy and some without. The oldest of the trials is the CheckMate 227 trial, which at the World Conference on Lung Cancer 2023 had a 6-year update, and they’re still seeing benefit for patients with PD-L1 greater than 1%, about 22% overall survival at 6 years, and for those with less than 1%, 16% overall survival. So we do see continued benefit even in the PD-L1 less than 1% cohort of patients.

Then looking at combinations of PD-1, PD-L1, CTLA-4 with chemotherapy, we have the CheckMate 9LA study that utilizes 2 cycles of chemotherapy with nivolumab and ipilimumab, and that's a positive aspect, especially as we think about supply issues with chemotherapy such as the platinums, so then potentially giving 2 cycles of chemotherapy may be a benefit for patients. And we see, again, prolonged overall survival in these patients, and even those patients who may have had increased toxicity from the combination immunotherapy, even those patients went on to have significant benefit. The POSEIDON study with durvalumab and tremelimumab and chemotherapy also showing improved overall survival across all PD-L1 cohorts, including the 1% to 49% and less than 1% and these are all good options for patients.

The one challenge we have is that all of these combinations and single agents have been compared to chemotherapy. We know they're all better than chemotherapy, but we don't know if one is better than another and really cannot do those types of cross-trial comparisons as each of the trials was slightly different. We're left with a lot of good options and the future, hopefully looking at which options may be best. We do have the INSIGNA trial which is looking at sequencing of therapy but not necessarily looking at different combinations versus each other.

Moving on to the second-line setting of therapy, so now most patients are receiving immunotherapy in the frontline, the majority with platinum-based doublet chemotherapy still at this time, and though we see these great long-term responses and overall survival, that's still kind of around 15% to 20% of patients, so there are a large majority that still need other therapies.

In today's world, the approved therapies really are docetaxel and docetaxel-ramucirumab in the US population. They have docetaxel-nintedanib in Europe. But the options are less than stellar and we all want better options for our patients. It is an exciting time, there are a multitude of ways that tumors can develop immunotherapy resistance, and when they develop a resistance, there are multiple potential combinations that may try to overcome those resistance. I think we need better biomarkers to try and overcome the resistance to be more rational about those combinations.

One of the areas where we're working is with angiogenesis, and we have a randomized phase 2 study that showed improvement in overall survival with ramucirumab and pembrolizumab over standard of care in which most people received docetaxel-ramacirumab, and the hazard ratio is 0.69 with 14-month overall survival for the ramucirumab-pembrolizumab arm. Based on that, we're doing a randomized phase 3 trial, the Pragmatica-Lung trial, S2302, and that is randomizing patients to standard of care, which is investigator's choice, versus ramucirumab and pembrolizumab. We are primarily looking at overall survival and very high-grade toxicities. This is a study that increases the ability for participation because we have reduced the eligibility criteria significantly, and it decreases the burden on sites so it improves our ability to conduct the trial with less burden and allows the investigators to treat patients as they would in standard practice. We're hoping this helps to change paradigm of some clinical trials in lung cancer.

There are multiple combinations, you'll be hearing in this whole meeting about [antibody drug conjugate] ADCs. Everybody's excited about other immunotherapy combination therapies such as LAG-3 and then also thinking about more novel therapies, neoantigen vaccines, cellular therapy, CAR T-cell therapy, which are all moving into the solid tumor and lung cancer space. There's a lot to be excited about, and we still have a long ways to go for our patients to treat without oncogenic drivers.

Source:

Reckamp K. Debate: How to handle PD-L1 <1% - chemo + IO. Presented at Great Debates & Updates in Lung Cancer; September 21-23. New York, NY.

Reckamp K. Debate: How to handle PD-L1 1-49% - chemo + IO. Presented at Great Debates & Updates in Lung Cancer; September 21-23. New York, NY.