Immunotherapy Reshapes Perioperative Strategies for Early NSCLC Without Driver Mutations

Perioperative immunotherapy–based strategies have helped redefine the treatment paradigm for patients with early-stage non–small cell lung cancer (NSCLC) whose tumors do not harbor actionable mutations, and ongoing research could improve neoadjuvant and adjuvant treatment strategies for these patients, according to Roy S. Herbst, MD, PhD.

“In early-stage disease, we want to cure as many patients as possible. The question will be [whether to use] adjuvant vs neoadjuvant therapy, or both,” Herbst explained in an interview with OncLive®.

In the interview, Herbst discussed the evolving treatment landscape for early-stage NSCLC, considerations for the use of neoadjuvant and/or adjuvant therapy in individual patients, and ongoing investigations into perioperative therapies for this patient population.

Herbst is an Ensign Professor of Medicine (Medical Oncology), a professor of pharmacology, and deputy director of the Yale Cancer Center; chief of Hematology/Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital; and assistant dean for Translational research and program director of the Master of Health Science – Clinical Investigation Track at Yale School of Medicine in New Haven, Connecticut.

OncLive: Where do perioperative chemoimmunotherapy treatments play a role in early-stage NSCLC?

Herbst: In the non-mutated stage, we're looking at patients with stage I to III disease whose [tumors] are resectable. Are they candidates for chemoimmunotherapy? There are [multiple] trials now that have shown the benefits of [chemoimmunotherapy in early-stage NSCLC]. That’s one of the things that we're very excited about right now.

What kind of research is needed in future studies to improve treatment strategies for early-stage NSCLC without actionable mutations?

Right now, we're using [perioperative] chemoimmunotherapy in many patients. We're seeing pathologic complete response [pCR] rates of approximately 15% to 20%, and major responses [are observed] in another large percentage of patients. However, not everyone benefits [from perioperative chemoimmunotherapy].

We've already seen an overall survival benefit [with neoadjuvant pembrolizumab [Keytruda] plus chemotherapy, followed by adjuvant pembrolizumab] in the phase 3 KEYNOTE-671 trial [NCT03425643]. We're waiting for results from some other studies in patients who are not candidates for neoadjuvant therapy or those who get surgery first. [For patients who go directly to surgery,] we can consider adjuvant therapy [with pembrolizumab] based on the results of the phase 3 KEYNOTE-091 trial [NCT02504372].

We have both adjuvant and neoadjuvant therapy that we can offer, and the bottom line is that if you [are able to administer] immunotherapy to patients either before or after [surgery], it's worth trying. It's my feeling that it's better to [deliver the therapy in the] neoadjuvant [setting]; however, you need to select patients carefully. You don’t want to delay patients from surgery. If patients don't benefit from neoadjuvant therapy and then become unresectable, that's never good.

What criteria do you look for when selecting treatment for patients within the perioperative setting?

For a patient who’s had surgery and [does not have a driver] mutation, atezolizumab [Tecentriq] is approved [as adjuvant therapy] for PD-L1–positive patients [with stage II to IIIA disease after resection and platinum-based chemotherapy]. [Adjuvant] pembrolizumab is approved without any need for PD-L1 positivity.

The big question comes in the neoadjuvant [setting]. Should we [consider] giving perioperative therapy by continuing with adjuvant therapy after [surgery]? I don't think the answer is quite [clear] on that yet. [Should we consider] another year of [adjuvant] immunotherapy? Are there increased toxicities and costs for patients? We're waiting for data from some trials. There will be some trials coming through the cooperative groups soon that will try to answer these questions.

Right now, I use neoadjuvant therapy [when possible]. If patients have a pCR [following neoadjuvant treatment], I would probably continue them on the immunotherapy [in the adjuvant setting], but some might stop treatment [after surgery]. If patients don't have a pCR, should you keep the immunotherapy going? That's an area where we can think about other agents and other combinations, and that will be something that keeps us busy for years to come.

Are there any notable investigations within the small cell lung cancer (SCLC) space that you’re intrigued by?

Tarlatamab [Imdelltra] is a T-cell engager that’s [garnered a lot of attention]. [It was also recently announced] that atezolizumab plus lurbinectedin inthe maintenance setting [improved survival in patients with extensive-stage SCLC in the phase 3 IMforte trial (NCT05091567)], giving lurbinectedinsome new life. There is a lot [of research] ongoing in SCLC. These are things to keep an eye on in the literature and in meetings in the months to come.