IO Combos Yield OS Advantage Vs Chemo Alone in Stage IV PD-L1–Negative NSCLC

Hossein Borghaei, MS, DO

As treatments for patients with stage IV non–small cell lung cancer (NSCLC) continue to evolve, patients with PD-L1–negative disease represent a unique cohort and chemotherapy/immunotherapy or immunotherapy doublet regimens appear to be effective, according to Hossein Borghaei, MS, DO.

In a presentation during the 18th Annual New York Lung Cancers Symposium, Borghaei presented data from several trials comparing therapeutic approaches with pembrolizumab (Keytruda), cemiplimab-rwlc (Libtayo), and nivolumab (Opdivo) plus ipilimumab (Yervoy) with or without the addition of chemotherapy vs chemotherapy alone.¹

“PD-L1, as imperfect as it may be, is a good marker for identifying the majority of patients who would benefit from a checkpoint inhibitor,” said Borghaei, chief of the Division of Thoracic Medical Oncology, professor in the Department of Hematology/Oncology, co-director of the Immune Monitoring Facility, and the Gloria and Edmund M. Dunn Chair in Thoracic Oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. “PD-L1–negative tumors could still respond to checkpoint inhibitors but usually in combination with either chemotherapy or a dual checkpoint inhibitor combination.”

Borghaei noted that additional randomized studies are needed to help determine the optimal available treatment and it is still to be determined if there are molecular subtypes that may be more common in this subgroup of patients.

KEYNOTE-189

The phase 3 randomized KEYNOTE-189 trial (NCT02578680) enrolled patients with untreated stage IV nonsquamous NSCLC evaluated the addition of pembrolizumab to chemotherapy vs chemotherapy alone. All the trials discussed by Borghaei enrolled patients without sensitizing EGFR mutations or ALK alterations who had not received prior systemic therapy and had an ECOG performance score of 0 or 1.²

The final overall survival (OS) analysis of KEYNOTE-189 by PD-L1 status revealed that the greatest benefit for those given pembrolizumab plus chemotherapy vs chemotherapy alone was in patients with PD-L1 expression less than 1% (HR, 0.51; 95% CI, 0.36-0.71). Patients treated with pembrolizumab plus chemotherapy (n = 127) achieved a median OS of 17.2 months (95% CI, 13.8-22.8) compared with 10.2 months (95% CI, 7.0-13.5) for those given chemotherapy (n = 63).

In patients with a PD-L1 tumor proportion score (TPS) of 1% to 49%, those given the combination (n = 128) achieved a median OS of 21.8 months (95% CI, 17.7-25.6) vs 12.1 months (95% CI, 8.7-19.4) for patients in the chemotherapy-alone arm (n = 58; HR, 0.66; 95% CI, 0.46-0.96). In the PD-L1 TPS of 50% or greater group, the median OS was 27.7 months (95% CI, 20.4-not reached) vs 10.1 months (95% CI, 7.5-22.0) for those given pembrolizumab (n = 132) vs chemotherapy (n = 70), respectively (HR, 0.59; 95% CI, 0.40-0.86).²

Patients in KEYNOTE-189 were randomly assigned 2:1 to receive pembrolizumab 200 mg or placebo plus pemetrexed 500 mg/m² plus carboplatin area under the curve 5 or cisplatin 75 mg/m² every 3 weeks for 4 cycles followed by pembrolizumab 200 mg every 3 weeks or placebo for up to 31 cycles plus pemetrexed 500 mg/m² every 3 weeks. Patients in the chemotherapy arm could crossover during the induction or maintenance phases to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles if progressive disease occurred.

Moreover, patients were stratified by PD-L1 expression (TPS of less than 1% vs 1% or greater), platinum chemotherapy received (cisplatin vs carboplatin), and smoking history (never vs former/current). Additional enrollment criteria cited that symptomatic brain metastases and pneumonitis requiring systemic steroids were not allowed.

CheckMate-227

The multi-part, phase 3 CheckMate 227 trial (NCT02477826) enrolled patients with stage IV or recurrent NSCLC. Part 1a included those with PD-L1 expression of 1% or greater and randomly assigned patients 1:1:1 to receive nivolumab plus ipilimumab, chemotherapy alone, or nivolumab monotherapy. Part 1b randomly assigned patients 1:1:1 with PD-L1 expression less than 1% to receive nivolumab plus ipilimumab, chemotherapy alone, or nivolumab plus chemotherapy. Baseline characteristics were well balanced.³

Four-year data revealed that those with PD-L1 expression less than 1% in the nivolumab plus ipilimumab arm (n = 187) achieved a median OS of 17.2 months (95% CI, 12.8-22.0) compared with 15.2 months in the nivolumab plus chemotherapy arm (n = 177; 95% CI, 12.3-19.8) and 12.2 months in the chemotherapy alone arm (n = 186; 95% CI, 9.2-14.3). The nivolumab plus ipilimumab vs chemotherapy HR was 0.64 (95% CI, 0.51-0.81); patients with nonsquamous histology experienced a HR of 0.69 (95% CI, 0.53-0.89) and those with squamous achieved a HR of 0.53 (95% CI, 0.34-0.84), respectively.

Five-year OS data for this patient population demonstrated a survival benefit when examining nivolumab plus ipilimumab vs chemotherapy (HR, 0.65; 95% CI, 0.52-0.81) and nivolumab plus chemotherapy vs chemotherapy (HR, 0.80; 95% CI, 0.64-1.00).³

In patients with PD-L1 expression greater than 1%, the median OS was 17.1 months (95% CI, 15.0-20.2) in the nivolumab plus ipilimumab arm (n = 396) compared with 15.7 months in the nivolumab arm (n = 396; 95% CI, 13.3-18.1) and 14.9 months in the chemotherapy-alone arm (n = 397; 95% CI, 12.7-16.7). The HR for nivolumab plus ipilimumab vs chemotherapy was 0.77 (95% CI, 0.66-0.91) and for nivolumab vs chemotherapy, HR was 0.92 (95% CI, 0.79-1.07).

“A pooled analysis of these studies [examining nivolumab and ipilimumab] were published in Annals of Oncology. It's a pooled analysis so there's some statistical trickery that goes into the interpretation of this data, but when you don't have randomized studies, you run the risk of doing these kinds of trials and trying to make a clinical decision based on retrospective data and statistical assessment,” Borghaei said.¹

EMPOWER-Lung 3 and CheckMate 9LA Updates

Additionally, 2-year follow-up data from part 2 of the phase 3 EMPOWER-Lung 3 study (NCT03409614) demonstrated a survival benefit with the combination of cemiplimab plus chemotherapy vs chemotherapy alone in those with PD-L1 expression of less than 1% (HR, 0.73; 95% CI, 0.50-1.08), 1% to 49% (HR, 0.48; 95% CI, 0.34-0.68), and 50% or greater (HR, 0.48; 95% CI, 0.32-0.72).⁴

In the phase 3 CheckMate 9LA trial (NCT03215706) patients with stage IV or recurrent NSCLC who had not received prior systemic therapy and had PD-L1 expression of less than 1% experienced a survival benefit when treated with nivolumab, ipilimumab, and chemotherapy vs chemotherapy alone.⁵

The median OS in the investigative arm (n = 135) was 17.7 months vs 9.8 months for those in the control arm (n = 129; HR, 0.67; 95% CI, 0.51-0.88). The median overall response rate was 31.1% in the nivolumab/ipilimumab/chemotherapy arm vs 20.2% in the chemotherapy-alone arm and median duration of response was 17.5 months vs 4.3 months, respectively. Patients experienced a median progression-free survival of 5.8 months vs 4.9 months (HR, 0.68; 95% CI, 0.51-0.89), respectively.

Patients enrolled in CheckMate 9LA were stratified based on PD-L1 status (less than 1% vs 1% or greater), sex, and histology. They received nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks plus chemotherapy every 3 weeks for 2 cycles or chemotherapy every 3 weeks for 4 cycles with optional pemetrexed maintenance for those with nonsquamous histology. Treatment was given until disease progression, unacceptable toxicity, or for 2 years with the immunotherapy agents.

Real-World Data: Flatiron Analysis

Borghaei also presented real-world data examining OS outcomes for patients with squamous and nonsquamous histology treated with immunotherapy monotherapy and immunotherapy plus chemotherapy.⁶

Those with nonsquamous histology and PD-L1 expression of less than 1% (n = 102), 1% to 49% (n = 239), and 50% or greater (n = 1582) treated with immunotherapy alone experienced median OS rates of 13.4 months, 9.1 months, and 15.3 months, respectively. Patients with squamous histology and PD-L1 expression of less than 1% (n = 52), 1% to 49% (n = 157), and 50% or greater (n = 536) treated with immunotherapy alone experienced median OS rates of 11.0 months, 12.1 months, and 11.9 months, respectively.

Further, patients treated with a combination of immunotherapy and chemotherapy with nonsquamous histology and PD-L1 expression of less than 1% (n = 1064), 1% to 49% (n = 967), and 50% or greater (n = 679) experienced median OS rates of 10.2 months, 11.8 months, and 19.1 months, respectively. Patients treated with the combination who had squamous NSCLC and PD-L1 expression of less than 1% (n = 209), 1% to 49% (n = 252), and 50% or greater (n = 120) experienced median OS rates of 8.7 months, 10.2 months, and 12.3 months, respectively.

Editor’s Note: Dr Borghaei cites receiving research support from Millennium, Merck/Celgene, and BMS/Lilly. He is on the Advisory Board or Consults for BMS, Lilly, Genentech, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTEO, Jazz, Janssen, Da Volterra, Puma, BerGenBio, Bayer, Iobiotech, and Grid Therapeutics. He is also on the Scientific Advisory Board for Sonnetbio (Stock Options), Rgenix (Stock Options), and Nucleai (Stock options) and on the Data and Safety Monitoring Board for University of Pennsylvania, CAR T Program, Takeda, and Incyte.

References

1. Borghaei, H. Stage IV NSCLC: coming up zero: what do you do? Presented at: NY Lung Cancers Symposium. November 11, 2023; New York, NY.
2. Rodríguez-Abreu D, Powell SF, Hochmair MJ, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021;32(7):881-895. doi:10.1016/j.annonc.2021.04.008
3. Ramalingam SS, Ciuleanu TE, Pluzanski A, et al. Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1. J Clin Oncol. 2020;38(suppl 15):9500-9500. doi:10.1200/JCO.2020.38.15_suppl.9500
4. Makharadze T, Gogishvili M, Melkadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in advanced NSCLC: 2-year follow-up from the phase 3 EMPOWER-Lung 3 part 2 trial. J Thorac Oncol. 2023;18(6):755-768. doi:10.1016/j.jtho.2023.03.008
5. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(suppl 15):9000. doi:10.1200/JCO.2021.39.15_suppl.9000
6. Waterhouse D, Lam J, Betts KA, et al. Real-world progression-free survival in first-line advanced non-small cell lung cancer treated with immunotherapy-based regimens using a US dataset. Data Brief. 2021;37:107195. doi:10.1016/j.dib.2021.107195.