Neoadjuvant, Adjuvant, or Both? The Debate in NSCLC Rages On

MADRID — Should patients with resectable non–small cell lung cancer (NSCLC) receive adjuvant therapy, neoadjuvant therapy, or both experts asked during a special session at the European Society for Medical Oncology (ESMO) Congress 2023 on October 21.

Though immunotherapy is beneficial in resectable NSCLC, “we actually don’t know how much of the effect [is due to] the adjuvant and how much to the neoadjuvant therapy,” Silke Gillessen, MD, head of the Department of Medical Oncology, Università della Svizzera Italiana in Lugano, Switzerland, told Medscape Medical News.

Opening the session, Enriqueta Felip, MD, PhD, argued in favor of adjuvant therapy alone in resectable NSCLC.

Adjuvant immunotherapy after adjuvant chemotherapy is already considered standard of care for patients with resected NSCLC who don’t harbor EGFR and ALK mutations, explained Felip, head of the Lung Cancer Unit at Vall d’Hebron University Hospital in Barcelona, Spain.

One major benefit to providing adjuvant therapy is that curative surgery won’t be delayed. Neoadjuvant therapy, on the other hand, leads about 15% of patients to forgo surgery, and about 30% who have both neoadjuvant therapy and surgery end up not receiving their planned adjuvant immunotherapy.

Another benefit: Emerging evidence suggests that the adjuvant only option can improve disease-free and overall survival in select patients.

In the IMpower010 trial, for instance, adjuvant atezolizumab led to a marked improvement in disease-free survival compared with best supportive care in patients with stage II-IIIA NSCLC. Patients with programmed death–ligand 1 expression of 50% or higher also demonstrated an overall survival benefit (hazard ratio [HR], 0.42).

In the KEYNOTE-091 trial, adjuvant pembrolizumab significantly improved disease-free survival in all comers vs placebo in patients with stage IB, II, or IIIA NSCLC who had surgery (HR, 0.76).

Providing adjuvant-only immunotherapy also allows for biomarker testing in resected specimens, Felip said, which may impact the choice of systemic therapy.

Next, Rafal Dziadziuszko, MD, PhD, argued in favor of neoadjuvant therapy alone in the setting of resectable NSCLC.

The advantages of providing treatment before surgery include initiating systemic treatment at an earlier point when most relapses are distant, possibly reducing the risk for tumor cell seeding during surgery as well as potentially leading to less invasive surgery by shrinking the tumors.

Dziadziuszko, from the Medical University of Gdansk in Poland, highlighted data from the Checkmate 816 trial, which showed that neoadjuvant nivolumab plus chemotherapy vs chemotherapy alone increased the chance of having a pathologic complete response by nearly 14-fold in patients with IB-IIIA resectable NSCLC. Patients in the combination arm also demonstrated marked improvements in event-free survival, 31.6 months vs 20.8 months, and overall survival.

The NADIM II trial, which coupled nivolumab and chemotherapy in stage III disease, found that neoadjuvant chemoimmunotherapy led to a pathogic complete response as well as a 52% improvement in progression-free survival and a 60% improvement in overall survival compared with chemotherapy alone.

Despite these findings, several important questions remain, said Dziadziuszko. How many cycles of neoadjuvant immunochemotherapy should a patient receive before surgery? Will neoadjuvant therapy lead to treatment-related adverse events that preclude surgery? And for those who don’t have a strong response to neoadjuvant therapy, who should also receive adjuvant immunotherapy and for how long?

The latter question represents the “elephant in the room,” session chair Tony S.K. Mok, MD, chairman, Department of Clinical Oncology, The Chinese University of Hong Kong.

With a paucity of overall survival data to provide a definitive answer, oncologists still face the age-old concern of “giving too much therapy in those who don’t need it” and “giving not enough therapy for those who need more,” said Mok.

Federico Cappuzzo, MD, PhD, argued that the key to patient selection for adjuvant therapy after neoadjuvant therapy and surgery lies in who has a pathologic complete response.

The current data suggest that patients receiving neoadjuvant therapy who achieve a pathologic complete response likely do not need adjuvant therapy whereas those who don’t achieve a complete response should receive adjuvant therapy, explained Cappuzzo, director of the Department of Oncology and Hematology, AUSL della Romagna, Ravenna, Italy.

But, Mok asked, what about patients who achieve a major pathologic response in which the percentage of residual viable tumor is 10% or less or achieve less than a major pathologic response?

Mok suggested that measurable residual disease, which is indicative of recurrence, could potentially be used to determine the treatment pathway after neoadjuvant therapy and signal who may benefit from adjuvant therapy. However, he noted, studies evaluating the benefit of adjuvant therapy in this population would need to be done.

For patients who don’t respond well to neoadjuvant therapy and may benefit from adjuvant therapy, the question also becomes: “Do we give more of that same therapy?” asked Zofia Piotrowska, MD, a lung cancer medical oncologist at Massachusetts General Hospital Cancer Center, Boston, who was not involved in the debate.

“I think we really need to rethink that paradigm and try to develop new therapies that may work more effectively for those patients, to improve their outcomes,” Piotrowska said.

ESMO Congress 2023: Session: Adjuvant or neoadjuvant immunotherapy or both in localised NSCLC. Presented October 21, 2023.

Mok declared relationships with a range of companies, including AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ Pharmaceuticals Roche, Merck Sharp & Dohme, and HutchMed. Felip declared relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol- Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffman–La Roche, Genentech, GlaxoSmithKline, Novartis, and others. Dziadziuszko declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, and others. Cappuzzo declared relationships with Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, and others.

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