The current market of neoadjuvant NSCLC comes with major challenges and limited treatment options. Merck’s KEYTRUDA is generally considered the ‘gold standard’ of care in 1L NSCLC when combined with platinum chemotherapy, regardless of PD-1 status. In October 2023, a new way of treating early-stage NSCLC was approved by the FDA, giving hope to many patients. Merck’s KEYTRUDA now can be used before and after surgery, along with chemotherapy, to help shrink tumors and prevent recurrence. This is the first time that a PD-1 inhibitor has been approved for both pre-and post-surgical treatment in resectable NSCLC. 

KEYNOTE-671 is a Phase III trial to estimate the efficacy and safety of pembrolizumab with platinum doublet chemotherapy as neoadjuvant/adjuvant therapy for participants with resectable stage II, IIIA, and resectable IIIB (T3-4N2) NSCLC. As per the interim analysis of KEYNOTE-671 results published in ESMO 2023, an improvement in overall survival (OS) and event-free survival (EFS) was continuous in the pembrolizumab arm. 

The difference in OS between arms has increased over time. The 12 month OS rate was 87.6% in the KEYTRUDA arm and 87.7% in the placebo arm. The 24 month OS rate was 79.0% and 74.7%, respectively. The 36 month OS rate was 71.3% and 64.0%, respectively. The 48 month OS rate was 67.1% and 51.5%, respectively.  The 12 month EFS rate was 73.8% in the KEYTRUDA arm and 60.8% in the placebo arm. The 24 month EFS rate was 61.5% and 41.4%, respectively. The 36 month EFS rate was 54.3% and 35.4%, respectively. The 48 month EFS rate was 48.4% and 26.2%, respectively. 

Approximately 45.2% of the patients experienced treatment-related adverse events (grade ≥ 3) which led to discontinuation of treatment in 20.2%. The occurrence of severe (grade ≥ 3) immune-related adverse events and infusion reactions was notably higher in the group receiving pembrolizumab at 26.0% compared to the placebo group, which was at 9.0%. Tragically, there was one fatal immune-related adverse event in the pembrolizumab group, while no such fatalities were observed in the placebo group. The most frequently encountered immune-related adverse events, seen in both the pembrolizumab and placebo groups, included hypothyroidism (10.9% and 1.5%, respectively), pneumonitis (6.1% and 1.8%), and hyperthyroidism (5.1% and 2.0%).

According to the company neoadjuvant KEYTRUDA + Chemotherapy followed by resection and adjuvant KEYTRUDA provided a statistically significant and clinically important improvement in OS compared with neoadjuvant chemotherapy and resection alone in patients with resectable stage II, IIIA, or IIIB (N2) NSCLC. The OS gains seen in KEYNOTE-671 with the absence of new safety signals establish the perioperative regimen as a new standard of care for resectable early-stage NSCLC.

KOL insights

“Patients with resectable stage II-IIIA (IIIB) randomized to neoadj pembro vs placebo plus chemo followed by adjuvant pembro vs. placebo First trial to demonstrate OS with perioperative Immunotherapy HR 0.72 (0.56-0.93)”-Associate professor, Thoracic Oncology & Phase-I, USA

“Keynote 671 neoadjuvant chemo/IO vs chemo - first neoadjuvant study in over 30 years to show OS. Definitely practice changing! Note over 30% of patients still have ongoing tox… selection of patients key.”-Medical Oncologist, UK

 

Conclusion

The FDA's approval of Merck's KEYTRUDA for neoadjuvant and adjuvant use in early-stage NSCLC marks a groundbreaking advancement in the field. The drug's consistent improvement in overall survival and event-free survival, coupled with its unique application, can establish it as a new standard of care for resectable NSCLC. Prior to KEYTRUDA's approval, BMS's OPDIVO was approved last year as a neoadjuvant treatment for NSCLC in stages 1b to 3a. When OPDIVO was added to chemotherapy prior to surgery in the CheckMate-816 trial, the patient group's event-free survival (EFS) improved by 37%.

The competition for KEYTRUDA in the neoadjuvant setting is rising around the corners as AstraZeneca has also shown positive EFS data for IMFINZI in the perioperative setting from the Phase III AEGEAN trial. However, the analysis is too early to support any regulatory filings for now. However, Roche’s TECENTRIQ, another drug in the same setting, has faced repeated delays in its IMpower-030 trial and is now expected to report results in 2024. The future of the neoadjuvant setting market is full of twists and turns, and it remains to be seen which key player will emerge victorious and which will suffer a setback.  KEYTRUDA is already a global blockbuster, and Merck could see KEYTRUDA sales soar even higher with the new FDA approval. It is worth highlighting that Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies in earlier stages of NSCLC and SCLC include KEYNOTE-671, KEYNOTE-091, KEYNOTE-867, KEYLYNK-012, KEYVIBE-006 and KEYLYNK-013.

 NSCLC accounts for up to 85% of lung cancer. DelveInsight estimates that the total incident population of NSCLC in the 7MM will reach ~590,000 in 2032. Estimates show that the highest incident population of NSCLC is in the United States followed by Japan, Germany, and the UK. PD-L1 expression accounted for up to 50% of the NSCLC cases in the United States. 

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Non-Small Cell Lung Cancer Market Report