Recently, several immune checkpoint inhibitor (ICI) regimens have gained regulatory approval for neoadjuvant, adjuvant, and perioperative treatment, transforming the treatment landscape for patients with resectable non-small cell lung cancer (NSCLC). Based on the KEYNOTE-671 study, the perioperative pembrolizumab regimen has been approved for resectable NSCLC in stages II, IIIA, or IIIB (T3-4N2). Is this now the standard treatment for resectable stage II/III NSCLC, regardless of PD-L1/EGFR/ALK status? Dr. Sheena Bhalla, Dr. David Nelson, and Dr. David Gerber from the Harold C. Simmons Comprehensive Cancer Center share their insights on this topic.

In recent years, new treatment options for resectable NSCLC have emerged. Just five years ago, adjuvant (or neoadjuvant) platinum-based chemotherapy was the only available drug therapy for early-stage NSCLC following surgery. In the years since, targeted therapies, including EGFR and ALK inhibitors, have been approved for patients with surgically resected tumors carrying these driver mutations. Additionally, ICI-based therapies have demonstrated promising results before, after, or around the time of surgery and received regulatory approvals across a broader patient population (see Table). Among these therapies, the perioperative pembrolizumab regimen employed in the KEYNOTE-671 study has stood out due to its robust follow-up, proven efficacy, and ease of implementation.

In the KEYNOTE-671 trial, nearly 800 patients with stage II, IIIA, or IIIB NSCLC were randomly assigned to receive either 4 cycles of neoadjuvant pembrolizumab plus cisplatin chemotherapy or placebo plus cisplatin chemotherapy, followed by surgical resection. After surgery, participants received up to 13 cycles of adjuvant pembrolizumab or placebo within a one-year period. With a median follow-up of more than 36 months, the pembrolizumab group demonstrated significantly improved overall survival (OS) (HR=0.72; P=0.005), event-free survival (EFS) (47 months vs. 18 months), and pathological complete response rate (18% vs. 4%). The KEYNOTE-671 regimen was approved by the FDA in October 2023 without requiring PD-L1 expression or excluding EGFR mutation-positive or ALK-positive cancer patients, making it applicable to a wide range of resectable lung cancer cases. Nonetheless, several key points merit consideration when choosing this therapy for stage II or III NSCLC patients who are candidates for surgery.

Surgical Opportunity

In the KEYNOTE-671 study, about 20% of patients who received neoadjuvant therapy did not proceed to surgery. This rate is consistent with other neoadjuvant and perioperative studies and was mainly due to adverse events, disease progression, or physician decision. Until we can reliably predict which patients may not undergo surgery after neoadjuvant therapy, oncologists and thoracic surgeons must carefully tailor perioperative chemotherapy/immunotherapy decisions for each patient.

Relative Benefit

Although the pembrolizumab group in the KEYNOTE-671 study demonstrated improved EFS across all subgroups, patients with specific tumor characteristics appeared to benefit the most. As is typical with resectable NSCLC treatments, patients in stage III (60% of the trial population) experienced greater EFS improvement (HR=0.54) than those in stage II (HR=0.65). Furthermore, similar to other chemotherapy/immunotherapy trials, PD-L1 expression was associated with higher efficacy (PD-L1≥50%: HR=0.42; PD-L1<1%: HR=0.77). For patients with a high risk of complications, these efficacy differences may impact clinical decision-making.

Availability of Other Treatment Options

Unlike other perioperative chemotherapy/immunotherapy phase III trials, EGFR- and ALK-mutant NSCLC patients met the inclusion criteria for KEYNOTE-671 and were thus included in the regulatory approval. However, molecular testing was not mandatory, and the study could not assess these patient subgroups adequately. Additionally, patients with EGFR/ALK-positive NSCLC benefit substantially from adjuvant targeted therapies (e.g., OS benefit from osimertinib: HR=0.49; DFS benefit from alectinib: HR=0.24; P<0.0001). Advanced-stage EGFR/ALK-positive NSCLC cases often exhibit poor responses to immunotherapy, and combining or administering osimertinib and immune checkpoint inhibitors in close proximity poses a significant risk of pulmonary toxicity.

For EGFR/ALK-positive NSCLC cases, a reasonable treatment strategy may involve early molecular testing and consideration of adjuvant targeted therapy instead of perioperative chemotherapy/immunotherapy.

Clinical and Financial Toxicity

In contrast to traditional chemotherapy and targeted therapy, which have a limited and time-defined toxicity profile, immune-related adverse events can affect nearly any organ system and may occur at any point during immunotherapy, sometimes even after treatment has ended. Indeed, in the KEYNOTE-671 trial, around half of autoimmune toxicities first manifested during the adjuvant treatment stage. Along with the high cost of a year-long adjuvant immunotherapy (estimated at over $90,000), these risks underscore a significant limitation of the KEYNOTE-671 and other perioperative immunotherapy trials for thoracic malignancies: none of these trials examined the independent benefits of the neoadjuvant and adjuvant immunotherapy stages, increasing the risk of overtreatment. As perioperative immunotherapy becomes more widely used, it is our responsibility to address this ongoing critical question for both patients and society.

Conclusion

Perioperative chemotherapy/immunotherapy adds a new option to the treatment strategy for resectable NSCLC. Optimal management for each patient requires multidisciplinary discussions and the careful integration of tumor characteristics and patient preferences. Future clinical trials must aim to address current knowledge gaps by comparing the individual benefits of the neoadjuvant and adjuvant stages in perioperative immunotherapy regimens to minimize the risk of overtreatment.

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