Stage as the Sole “Biomarker” for Adjuvant Pembrolizumab in Resected Stage IB to IIIA NSCLC without Considerations for PD-L1 Expression Level, ALK/EGFR Mutational Status, and Prior Adjuvant Chemotherapy per FDA Approval Indications of PEARLS/Keynote-091?

Figures & data

Table 1 Comparison of IMpower-010 and Keynote-091 Trial Characteristics and Approval Indication

Trial Name	IMpower-010	Keynote-091
# of patients	Total: 1,005 ITT: 507 (atezolizumab), 498 (Best Supportive care)	Total: 1,177 ITT: 590 (pembrolizumab), 587 (placebo) PD-L1 ≥50%: 168 (pembrolizumab), 165 (placebo)
Efficacy population	II–IIIA population PD-L1 ≥1% (by SP263 IHC) II–IIIA population IB-IIIA population (ITT) Hierarchical testing	ITT
Primary endpoint	DFS assessed by investigator in the subpopulation of patients in the stage II–IIIA population with PD-L1 ≥1% (by SP263 IHC), in all patients in the stage II–IIIA population and in the stage IB–IIIA population (ITT)	1. DFS assessed by investigator in ITT 2. DFS assessed by investigator in PD-L1 ≥50% population
Secondary endpoints	OS in the ITT population DFS in the patients in the stage II–IIIA population with PD-L1 ≥50% 3-year and 5-year DFS rates in patients in the stage II–IIIA population with PD-L1 ≥1%, in all patients in the stage II–IIIA population, and in the ITT population	DFS in PD-L1 ≥1% OS in ITT OS in PD-L1 ≥50% OS in PD-L1 ≥1% Lung cancer specific survival Adverse events
Statistical calculation of sample size	The trial had 90% power for the primary analysis of DFS in the stage II–IIIA population with tumors expressing PD-L1 on 1% or more of tumor cells, with a hazard ratio (HR) for disease recurrence or death of 0.65 (corresponding to median DFS durations of 52 months in the atezolizumab group and 34 months in the best supportive care group). The trial had 76% power for the primary analysis of DFS in the ITT population, with an HR for disease recurrence or death of 0.78 (corresponding to median DFS durations of 48.7 months in the atezolizumab group and 38 months in the best supportive care group). Full details of the statistical analysis plan are provided in the protocol (appendix, pp 277–286).	86% power at an α level of 0.0125 to detect a hazard ratio (HR) for DFS of 0.75 in the overall population (corresponding to median DFS of 56 months in the pembrolizumab group and 42 months in the placebo group) and approximately 90% power at an α level of 0.0125 to detect an HR for DFS of 0.55 in the PD-L1 TPS of 50% or greater population (corresponding to median DFS of 76.4 months in the pembrolizumab group and 42 months in the placebo group).
Subgroup analysis	Category with 10 patients or more was analyzed	Univariate analysis by treatment arm with the exception of PD-L1 expression Only subgroup with at least 50 patients per category (combined pembro + placebo) were analyzed
Adjuvant chemotherapy	Cisplatin-based (with either navelbine, docetaxel, pemetrexed, or gemcitabine) chemotherapy required	Recommended for Stage II–IIIA but NOT required. If adjuvant chemotherapy given, n< 4 cycles
Stratification factors	Sex (female vs male), Tumour histology (squamous vs non-squamous), Stage (IB vs stage II vs stage IIIA), PD-L1 expression status (tumor cell [TC] 2/3 and any tumor-infiltrating immune cells [IC] vs TC0/1 and IC2/3 vs TC0/1 and IC0/1 by SP142 IHC (BUT efficacy analyzed by SP263 IHC)	Disease stage (IB vs II vs IIIA), Adjuvant chemotherapy (yes vs no), PD-L1 tumor proportion score (TPS; percentage of tumor cells with membranous PD-L1 staining; <1% vs 1–49% vs ≥50%), Geographical region (Asia vs eastern Europe vs western Europe vs the rest of the world)
Randomization	1:1	1:1
Cross-over	Not allowed	Not allowed
Treatment arms	Atezolizumab vs Best Supportive Care	Pembrolizumab x 18 infusions vs Placebo (triple blinded)
	Results
Patient characteristics	Never-smoker (22.1%) SqCC (34.4%) PD-L1 <1% (44.2%) Randomized after adjuvant chemotherapy African-American (0.60%)	Never-smokers (13%) SqCC (35.3%) PD-L1 <1% (39%) 86% received adjuvant chemotherapy African-American (0.25%)
Median Follow-up	32.8 months (IQR = 27.6–39.0) in stage II–IIIA with PD-L1 ≥1% (SP263) 32.2 months (IQR = 27.4–38.3) in the stage II–IIIA population 32.2 months (27.5–38.4) in the ITT population.	35.6 months (IQR = 27.1–45.5).
Primary results	Stage II–IIIA with PD-L1 ≥1%: NE (95% CI = 36.1 to NE) vs 35.3 months (95% CI = 29.0 to NE) HR = 0.66; 95% CI = 0.50–0.88; p = 0.0039 All patient in stage II–IIIA: 42.3 months (95% CI = 36.0 to NE) vs 35.3 months (95% CI = 30.4 to 46.4), 0.79; 0.64–0.96; p = 0.020 ITT: NE (95% CI = 36.1 to NE) vs 37.2 months (95% CI = 31.6 to NE) 0.81; 0.67–0.99; p = 0.040	ITT: 53.6 months (95% CI = 39.2 to not reached) (36% event) vs 42.0 months (31.3 to not reached) (44% event) HR = 0.76 [95% CI = 0.63–0.91], p = 0.0014 PD-L1 expression ≥50%: NR (95% CI = 44.3 to not reached) (32% event) vs NR (95% CI = 35.8 to not reached); (38% event) HR = 0.82 [95% CI = 0.57–1.18]; p = 0.14
Secondary results	OS data not mature: HR was 1.07 (95% CI = 0.80–1.42) in the ITT population, 0.99 (0.73–1.33) in all patients in the stage II–IIIA population, and 0.77 (0.51–1.17) in the stage II–IIIA population with PD-L1 ≥1%	In the overall population, 98 (17%) of 590 participants in the pembrolizumab group and 111 (19%) of 587 participants in the placebo group had died as of data cutoff. Median overall survival (and 95% CI) was not reached in either group (HR = 0.87 [95% CI = 0.67–1.15], p = 0.17; Figure 3).
Subgroups with positive results	Age <65 yo: 0.67 (0.46–0.96) Male: 0.69 (0.48–0.99), Female: 0.61 (0.38–0.97) White: 0.63 (0.45–0.89) Europe and Middle East: 0.64 (0.45–0.93) PS = 0: 0.57 (0.40–0.83) Previous smoker: 0·54 (0·37–0·78) Non-SqCC: 0.60 (0.42–0.84) Stage IIIA: 0.62 (0.42–0.90) N1: 0.59 (0.36–0.97), N2: 0.66 (0.44–0.99) Lobectomy: 0.63 (0.45–0.87) Cisplatin + Vinorelbine: 0.55 (0.33–0.92) EGFR unknown: 0.61 (0.38–0.91) No ALK: 0.64 (0.44–0.93)	Age <65 yo: 0.73 (0.56–0.96) PS = 0: 0.78 (0.62–0.99) Current smoker: 0.42 (0.23–0.77) Stage II: 0.70 (0.55–0.91) Adjuvant chemotherapy: 0.73 (0.60–0.89) Non-SqCC: 0.67 (0.54–0.83) PD-L1: 1–49%: 0.67 (0.48–0.92) EGFR+: 0.44 (0.23–0.84)
FDA approval date	October 15, 2021	January 26, 2023
FDA approval indication	Stage II–IIIA PD-L1 ≥1% by VENTANA PD-L1 (SP263) EGFR mutation, ALK fusion NOT excluded	Stage IB (T2a. >4 cm) - IIIA Regardless of PD-L1 expression level EGFR mutation, ALK fusion NOT excluded

Abbreviation: ITT, intention-to-treat.

Table 2 Indications of the 12 Immunotherapy Regimens Approved by the FDA in US Circa February 2023

	Chemotherapy Regimens
PD-L1 level	<1%–100%	<1%–100%	<1%–100%	>1%	>50%
Histologies	All histologies	Non-SqCC only	SqCC only	All histologies	All histologies
# trials	3	3	1	2	3
	CM-9LA (Chemo + IO + IO)	IMpower150 (chemo + anti-angiogenesis + IO)	KN-407 (chemo + IO)	KN-042 (IO alone) PD-1 mAb approved: 22C3	KN-024 (IO alone) PD-1 mAb approved: 22C3
	POSEIDEN (Chemo + IO + IO)	IMpower130 (chemo + IO)		CM-227 (IO + IO) PD-1 mAb approved: 28–8:	-IMpower110 (IO alone) PD-L1 mAb approved: SP142
	EMPOWER-Lung03 Chemo + IO (ROS1 fusion excluded)	KN-189 (chemo + IO)			EMPOWER-Lung01 (IO alone) (ROS1 fusion excluded) PD-1 mAb approved: 22C3

Abbreviations: CM, checkmate; KN, Keynote.