Molecular Correlates May Be Key in Unleashing the Full Potential of Immunotherapy in NSCLC

Ashish Saxena, MD, PhD

The integration of targeted therapy and checkpoint inhibitors into the adjuvant and perioperative treatment of patients with resectable non–small cell lung cancer (NSCLC) has proven effective as evidenced by the recent string of regulatory approvals, but deeper understanding of the tumor microenvironments primed for durable responses are needed, explained Ashish Saxena, MD, PhD.

In research published in Nature Communications, Saxena and coauthors evaluated survival outcomes with the use of neoadjuvant durvalumab (Imfinzi) plus stereotactic body radiation therapy (SBRT) vs durvalumab alone in patients with stage I to III NSCLC. Exploratory results from the phase 2 trial (NCT02904954) showed that the 3-year disease-free survival (DFS) rate was 63% (95% CI, 46.0%-80.4%) with durvalumab monotherapy (n = 26) vs 67% (95% CI, 49.6%-83.4%) with durvalumab and SBRT (n = 26).

In a post-hoc analysis, investigators evaluated the relationship between peripheral blood immunophenotype and clinical outcome. The results showed that patients who had achieved major pathologic response after neoadjuvant therapy had significantly higher levels of CD103-expressing T-cell populations before treatment. Moreover, the frequency of PD-1–positive T cells, as well as the frequency of CD103-positive CD4 and CD8 T cells 3 months after surgery was higher in patients without progression regardless of treatment arm, suggesting that this population of T cells may represent a predictive biomarker of response for neoadjuvant therapy.

“It’s an exciting time for lung cancer treatment. Immunotherapy has become almost like a backbone of treatment as we’re using these agents almost throughout [the paradigm] with the exception of several of the molecular targeted patient populations,” Ashish Saxena, MD, PhD, assistant professor of medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork-Presbyterian Hospital in New York, said in an interview with OncLive^®. “It’s becoming more complicated but a lot better for patients in that they have a much wider array of drugs and treatments that are available to them.”

In the interview, Saxena discussed the movement of targeted and immune therapies in NSCLC treatment and the importance of staying up to date on their use in clinical practice.

OncLive: Where have we seen the biggest shifts in the use of targeted and immune therapies in NSCLC?

Saxena: We’ve seen a lot of information and a lot of exciting developments with targeted therapies in EGFR-mutated lung cancers, neoadjuvant and adjuvant [uses of] immunotherapies, and the antibody-drug conjugates [ADCs]. We’re seeing the use of EGFR-targeted treatments and immunotherapies in multiple disease stages. With immunotherapy, we’re now basically using [these agents] almost throughout the different stages of NSCLC, in the stage IV setting but also in earlier stages after chemotherapy and radiation but now also perioperatively, and then before and after surgery with some of the more recent studies. That’s sort of continuing into 2024, where the perioperative use of chemoimmunotherapy may become more of a standard of care, although we’re not sure whether that’s better than doing what was previously more of the standard of doing chemoimmunotherapy only before surgery.

For the EGFR-mutated lung cancers, we again are using [EGFR inhibitors] in the adjuvant setting after surgery. There was recently a press release that the LAURA study [NCT03521154], which looked at adjuvant or consolidation of osimertinib [Tagrisso] after chemotherapy and radiation, was also positive. We’re looking forward to seeing the full results of that [study]. That may be another area for EGFR-mutated patients that will offer more treatment options.

Newer drugs that are exciting are amivantamab-vmjw [Rybrevant] for EGFR-mutated lung cancers, both with exon 20 insertion mutations, as well as more classical mutations being used in the stage IV setting—either up-front now with chemotherapy in EGFR exon 20 insertion mutations or with the results of the MARIPOSA trials also in the classical EGFR mutation patients.

In terms of the ADCs, multiple agents are showing efficacy right now maybe in later lines of therapy for stage IV disease, but hopefully going forward, we’ll see them more combined with up-front therapies for stage IV disease.

What work needs to be done to determine what the added benefit of that adjuvant portion of perioperative immunotherapy is?

A good clinical trial that’s designed to ask that question [is one] where we compare patients who get neoadjuvant chemoimmunotherapy, which now has become standard for those who can get checkpoint inhibitor immunotherapy, with those who [also] get adjuvant immunotherapy to see whether there’s a difference in end points like DFS and overall survival. Likely it’s going to depend on the patient, so it’s probably not going to be something that [provides] the same benefit for all patients.

The biomarker analysis is important, and we may hopefully have some way of treating these patients where we see how they respond to the neoadjuvant therapy and that may guide us into whether further immunotherapy is needed. That may be [done] with analysis of the tissue at surgery, or maybe blood-based biomarkers like circulating tumor DNA or others, either before treatment starts or after [patients] undergo surgery; that might help stratify the patients.

You published data looking at molecular correlates with neoadjuvant durvalumab and radiation in patients with stage I to III disease. Could you discuss this research in the context of potential new approaches?

We did a study comparing patients who were treated on a clinical trial with neoadjuvant durvalumab [Imfinzi] alone or with the combination of nonablative radiation, so this was 8 Gy of radiation for three fractions. We found that we had a higher pathologic response rate, complete response rate, and major pathologic response rate by adding the radiation. This is another promising area of treatment, combining radiation and immunotherapy. We looked at the tissues and the signatures of the immune cells that were there to see which patients might be responding better to the combination of radiation and immunotherapy.

What should remain top of mind as the field continues to advance?

It’s becoming a lot more complicated in terms of the treatments that we can give, which is a good thing for the patients because we have more options. [We’re] trying to keep up with all the changes [and] they’re [happening] quickly in lung cancer; it’s sometimes difficult to keep up to date with [everything]. Molecular testing for pretty much all patients at this point with NSCLC is important because particularly with EGFR-mutated lung cancers, when you find [that mutation], you can [utilize] EGFR-targeted therapies at different stages and in different lines. [We also need to] know the different drugs that are now available [for this population], other than just osimertinib. Also, with the immunotherapies, similarly, we are using them throughout different stages of disease, and [we need to make] sure that [they are] built into the algorithm that physicians are treating their patients with.

Reference

Altorki NK, Walsh ZH, Melms JC, et al. Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial. Nat Commun. 2023;14(1):8435. doi:10.1038/s41467-023-44195-x