Pembrolizumab (Keytruda) gains FDA Approval for patients in stage IB-IIIA of lung cancer (NSCLC), regardless of PD-L1 expression

Merck announced the FDA approval of pembrolizumab (Keytruda) as adjuvant treatment following surgical resection and platinum-based chemo for patients with stage IB-IIIA NSCLC, regardless of PD-L1 expression, based on pivotal results from P3 KEYNOTE-091/PEARLS (NCT02504372).

Highlights and Implications

• IO use in earlier phases may impact regimen choice in later settings. Additionally, the movement of IO into neoadjuvant & adjuvant settings will need to be taken into consideration for any future trial designs for therapies in this segment

• Based on this approval, pembro is the first all-comer adjuvant IO option that does not require TPS ≥ 1% PD-L1 expression. In addition, this is the first IO therapy for stage IB NSCLC. This is a broader indication to adjuvant atezolizumab which is restricted to stage II-IIIA and PD-L1 TPS ≥1% (FDA approved in Oct. 2021 based on Roche’s P3 IMpower010 trial).

• With two adj. IO therapies now approved, with overlapping indications, it is unclear how patients will be selected for each treatment

• Although PD-L1 expression subgroup analyses have been presented for both adj. pembro (ESMO 2022 Abs. 930MO) and adj. atezo (WCLC 2022, Abs. PL03.09), cross-comparison between this data is challenging as the powering, sample sizes, and patient populations are different for the two trials and subsequent subgroup analyses

• The role of PD-L1 expression for prediction of clinical benefit remains unclear in the adjuvant treatment setting, although the distinctions in adj. pembro and atezo labels will likely lead to more PD-L1 testing in early-stage NSCLC
• The resectable NSCLC landscape is quickly evolving, and the interplay between neoadjuvant, perioperative, and adjuvant therapies may add complexity to physician decision making
• Neoadjuvant nivolumab was recently approved based on P3 CheckMate-816, and it remains unclear how and if neoadjuvant IO and adjuvant IO can be sequenced
• Multiple perioperative IO P3 studies are expected to readout through 2023 which will continue to add to the available regimens to physicians

• Pembrolizumab in this indication is currently under review by the EMA with estimate for a Q2-3 2023 EU approval

Additional Background Information

• Interim data from KEYNOTE-091 was presented at the ESMO Plenary Session in March 2022
• Adjuvant pembrolizumab (after platinum-based chemotherapy following surgical resection) demonstrated significant clinical benefit over placebo, regardless of PD-L1 expression
  • mDFS, mos: 58.7 vs 34.9
  • DFS rate, %: 27 (HR=0.73)
  • mDoR, mos: 11.7
  • Exploratory subgroup analysis of pts who did not receive adjuvant chemotherapy (N=167), DFS HR=1.25
  • Company noted that OS data is not yet matured with only 42% of pre-specified OS events in the overall population.
• Adj. pembro vs placebo, (N=1,177)

• DFS data by PD-L1 stratification for KEYNOTE-091 was presented at ESMO 2022 (Abs. 930MO)