Update Confirms 5-Year Survival Benefit With Dual Immune Checkpoint Blockade in NSCLC

The benefits to overall survival (OS) with the use of dual immune checkpoint inhibitors over chemotherapy alone were further confirmed based on results of a 5-year survival update for CheckMate 227 (NCT02477826).¹ Findings support the use of nivolumab (Opdivo) and ipilimumab (Yervoy) as a potential firstline approach in advanced non–small cell lung cancer (NSCLC), and were presented at the International Association for the Study of Lung Cancer 2022 North America Conference on Lung Cancer by Jonathan W. Riess, MD, MS.²

Riess, director of thoracic oncology and an associate professor of medicine at UC Davis Health Medical Center in Sacramento, California, noted that recently, 5-year OS data from KEYNOTE-189 (NCT02578680) and KEYNOTE-407 (NCT02775435) had also been presented at the 2022 European Society for Medical Oncology Congress.^3,4

In CheckMate 227, the 5-year rate of OS was 24% in patients who received nivolumab/ ipilimumab and who had PD-L1 expression of at least 1%. The OS was 19% in patients with PD-L1 expression of less than 1%, vs 14% and 7%, respectively, in patients who received chemotherapy. The immunotherapy combination also had a significantly higher duration of response (DOR) of 24.5 months for those with positive PD-L1 expression and 19.4 months for those with negative PD-L1 expression vs 6.7 months and 4.8 months with chemotherapy, respectively.

In part 1a of the trial, which focused on patients with PD-L1 expression of 1% or greater, 1189 patients were randomly assigned on an equal basis to receive either nivolumab plus ipilimumab (n = 396), nivolumab alone (n = 396), or chemotherapy (n = 397). In part 1b, which focused on patients with PD-L1 expression of 1% or less, patients also were randomly assigned equally to receive the immunotherapy combination (n = 187), nivolumab plus chemotherapy (n = 177), or chemotherapy (n = 186).

In the current update, Riess reported that in patients with PD-L1 expression of 1% or greater, median OS was 17.1 months in the nivolumab plus ipilimumab arm, 15.7 months in the nivolumab alone arm, and 14.9 months in the chemotherapy arm. Median progression-free survival (PFS) was 5.1 months, 4.2 months, and 5.6 months, respectively.

“What was impressive was the duration of response for patients, regardless of their PD-L1 status,” Riess said. The median DOR in the arms was 24.5 months (95% CI, 15.5- 33.9), 15.5 months (95% CI, 12.5-20.8), and 6.7 months (95% CI, 5.6-7.6), respectively.

In patients with PD-L1 expression of less than 1%, median OS was 17.4 months in the nivolumab plus ipilimumab arm, 15.2 months in the nivolumab plus chemotherapy arm, and 12.2 months in the chemotherapy arm. Median PFS was 5.1 months, 5.6 months, and 4.7 months, respectively. Similar to that in patients with PD-L1 expression of 1% or greater, the median DOR was 19.4 months (95% CI, 12.4-33.2), 8.3 months (95% CI, 5.9-9.4), and 4.8 months (95% CI, 3.7-5.8).

When reviewing recent 5-year OS updates by histology and PD-L1 expression, Riess said, “Even though [the immunotherapy combination] is not FDA approved for the indication, I am struck by [the effect on] the PD-L1–negative squamous population.”

In CheckMate 227, patients with PD-L1 expression less than 1% and who had squamous cell cancer had a median OS of 16.3 months in the immunotherapy combination arm (n = 46), 11.3 months in the nivolumab plus chemotherapy arm (n = 43), and 8.5 months in the chemotherapy alone arm (n=46). “I think this is an area [that needs] further investigation,” Riess said. “I would also like to see the 1% to 49% subset because I think that’s clinically relevant.”

In patients with high PD-L1 expression, Riess pointed out survival trends from KEYNOTE-024 (NCT02142738) and KEYNOTE-589 (NCT03302234). In KEYNOTE-024, which evaluated pembrolizumab (Keytruda) in patients with high PD-L1 expression, the median 5-year OS was 26.3 months in the treatment arm vs 13.4 months in the control arm. In KEYNOTE-589, which evaluated pembrolizumab plus ipilimumab vs pembrolizumab alone in patients with PD-L1–high expression, the median OS was 21.4 months (95% CI, 16.6- not reported [NR]) in the treatment arm vs 21.9 months (95% CI, 18.0-NR) in the control arm.

“KEYNOTE-589 [results] demonstrated that there’s probably not much benefit to adding a CTLA-4 antibody to pembrolizumab in this population,” Riess said. “These findings support the use of nivolumab and ipilimumab as a potential first-line option in advanced NSCLC,” he concluded.

REFERENCES

1. Hellmann MD, Paz-Ares L, Caro RB, et al. Nivolumab plus ipilimumab in advanced non–small cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

2. Borghaei H, Brahmer JR, Lee JS, et al. First-line nivolumab + ipilimumab in metastatic NSCLC: 5-year survival in CheckMate 227. Presented at: International Association for the Study of Lung Cancer 2022 North American Conference on Lung Cancer; September 23-25, 2022; Chicago, IL. Accessed October 11, 2022. https://bit.ly/3g1GuUA

3. Garassino MC, Gadgeel SM, Speranza G, et al. KEYNOTE-189 5-year update: first-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC. Ann Oncol. 2022;33(suppl 7):S448-S554. doi:10.1016/annonc/annonc1064

4. Novello S, Kowalski DM, Luft A, et al. 5-year update from KEYNOTE-407: pembrolizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2022;33(suppl 7):S448-S554. doi:10.1016/annonc/annonc1064