Long-Term Data Refine the Role of Immunotherapy Across Early-Stage NSCLC Settings

Five-year follow-up from the phase 3 CheckMate 816 trial (NCT02998528) demonstrated that neoadjuvant nivolumab (Opdivo) plus chemotherapy continued to improve event-free survival (EFS) and overall survival (OS) vs chemotherapy alone in patients with resectable non–small cell lung cancer (NSCLC), according to a presentation by Heather Wakelee, MD, FASCO, during the 27th Annual International Lung Cancer Congress.¹

“[These] 5-year data from CheckMate 816 are very exciting,” Wakelee, the Winston Chen and Phyllis Huang Professor, deputy director, and division chief of medical oncology at Stanford Cancer Institute in California, said during the presentation. “At 5 years, EFS was improved by 15% and OS by 10%, [which were] statistically significant. Keep in mind that the OS statistically significant benefit was only in the PD-L1–positive patient population; the PD-L1 biomarker remains the only one where we’ve seen consistent results.”

During the presentation, Wakelee reviewed long-term outcomes across the neoadjuvant, adjuvant, and perioperative immune checkpoint inhibitor (ICI) settings in resectable NSCLC, along with emerging biomarker and translational research efforts aimed at refining patient selection.

What did the 5-Year CheckMate 816 data show?

At 5 years, neoadjuvant nivolumab plus chemotherapy (n = 179) showed an EFS rate of 49% vs 34% with chemotherapy alone (n = 179); the median EFS values were 59.6 months and 21.1 months, respectively.² The 5-year OS rates were 65% and 55%, and the median OS values were not reached (NR) and 73.7 months, respectively (HR, 0.72; 95% CI, 0.523-0.0479).

Wakelee underscored that the OS benefit in patients with stage II or III disease was observed only in those with PD-L1–positive tumors, emphasizing PD-L1 expression as a key determinant of long-term benefit with neoadjuvant chemoimmunotherapy in this population.

What has been learned from adjuvant ICI trials?

In the phase 3 IMpower010 trial (NCT02486718), patients with stage II to IIIA NSCLC and PD-L1 expression of at least 1% showed a disease-free survival (DFS; HR, 0.70; 95% CI, 0.55-0.91) and OS (HR, 0.77; 95% CI, 0.56-1.06) benefit with adjuvant atezolizumab (Tecentriq; n = 248) vs best supportive care (n = 228) at more than 60 months of follow-up.¹

In the phase 3 BR.31 trial (NCT02273375), adjuvant durvalumab (Imfinzi) displayed no significant DFS benefit compared with placebo among patients with EGFR- and ALK-negative disease and a PD-L1 level of at least 25% (HR, 0.935; 95% CI, 0.706-1.247; 2-sided P = .642). The 36-month OS rates in the durvalumab (n = 316) and placebo (n = 161) arms were 63.9% (95% CI, 58.2%-69.0%) and 62.4% (95% CI, 54.1%-69.6%), respectively.

In the phase 3 KEYNOTE-091 study (NCT02504372), adjuvant pembrolizumab (Keytruda; n = 590) improved DFS vs placebo (n = 587) in the overall population (HR, 0.76; 95% CI, 0.63-0.91; P = .0014), with median DFS values of 53.6 months and 42.0 months, respectively.

In the phase 3 NADIM ADJUVANT trial (NCT04564157), adjuvant chemotherapy plus non-sequential nivolumab (n = 103) showed a DFS HR of 0.65 (95% CI, 0.40-1.07; P = .085) vs chemotherapy alone (n = 103), with neither arm reaching median DFS at a median follow-up of 34.0 months.

What do perioperative ICI trials indicate, and how does PD-L1 status affect outcomes?

Perioperative ICI regimens combining 4 cycles of chemoimmunotherapy with 1 year of adjuvant ICI have been evaluated across the phase 3 AEGEAN (NCT03800134), KEYNOTE-671 (NCT03425643), and CheckMate 77T (NCT04025879) trials.

In CheckMate 77T, which examined perioperative nivolumab (n = 229) vs placebo (n = 232), the pathologic complete response (pCR) and major pathological response (mPR) rates with pembrolizumab were 25% and 35%, respectively.³ The median EFS in the nivolumab arm was 40.1 months (95% CI, 33.7-NR) compared with 17.0 months (95% CI, 13.6-28.1) in the placebo arm (HR, 0.59; 95% CI, 0.45-0.79).

In a 5-year update of KEYNOTE-671, perioperative pembrolizumab (n = 397) improved EFS over placebo (n = 400) in the overall population (HR, 0.58; 95% CI, 0.48-0.69).⁴ The median EFS values were 57.1 months (95% CI, 38.0-NR) and 18.4 months (95% CI, 14.8-22.1), respectively. The pCR and mPR rates were 18% and 30%, respectively, in the pembrolizumab arm.

Data from AEGEAN demonstrated that perioperative durvalumab (n = 366) produced pCR and mPR rates of 17% and 33%, respectively.⁵ At a median follow-up of 11.7 months (range, 0.0-46.1), the median EFS in the durvalumab arm was NR (95% CI, 31.9-NR) compared with 25.9 months (95% CI, 18.9-NR) in the placebo arm (n = 374; HR, 0.68; 95% CI, 0.53-0.88; log-rank P = .003902).

What does the NEOVADE study suggest for EGFR-mutant resectable NSCLC?

The phase 2 NEOVADE trial (NCT06300424) evaluated neoadjuvant almonertinib, a third-generation EGFR TKI, followed by adebrelimab plus chemotherapy, in patients with resectable stage II to IIIB EGFR-mutant NSCLC (n = 32).⁶ The primary end point was mPR rate.

Data from the study revealed that efficacy differed by EGFR mutation subtype. Among patients with EGFR exon 19 deletions, the objective response rate (ORR) after TKI alone was 62.5% (n = 10 of 16), with an mPR rate of 31.3% and pCR rate of 6.3%. Among patients with EGFR L858R or other mutations, ORR after TKI alone was 31.3% (n = 5 of 16), improving to 56.3% (n = 9 of 16).

What are the key unanswered questions going forward?

Wakelee outlined several open questions for the field, including the contribution of the adjuvant ICI component following neoadjuvant treatment, particularly its effect on pCR. She also noted that which patients require surgery at all, especially among those achieving pCR, remains undetermined and that better predictive tools for identifying who will or will not benefit from ICI are needed. The optimal duration of ICI or adjuvant targeted therapy, including greater use of circulating tumor DNA (ctDNA) analysis, is also being elucidated.

Waklee highlighted that the ongoing phase 3 ADOPT-lung trial (NCT06284317) is evaluating the benefit of adding adjuvant durvalumab after neoadjuvant chemotherapy plus durvalumab in patients with stage IIB to IIIB (N2) resectable NSCLC.⁷ On the translational side, she noted that PD-L1 expression remains the best-validated biomarker of response to date, with molecular characteristics, radiomics, and ctDNA offering earlier but still-developing predictive value, and cited emerging therapeutic strategies including novel ICIs, antibody-drug conjugates, vaccines, and cellular therapies as areas of ongoing investigation.

References

1. Wakelee H. Immunotherapy in early-stage NSCLC (including long-term results and emerging approaches). Presented at: 27th Annual International Lung Cancer Congress; July 24-25, 2026; Huntington Beach, CA.
2. Forde PM, Spicer JD, Provencio M, et al. Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. N Engl J Med. 2025;393(8):741-752. doi:10.1056/NEJMoa2502931
3. Cascone T, Awad MM, Spicer JD, et al. CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Ann Oncol. 2023;34(suppl 2):S1295. doi:10.1016/j.annonc.2023.10.050
4. Wakelee H, Spicer J, Gao S, et al. Perioperative pembrolizumab in early-stage non-small- cell lung cancer (NSCLC): 5-year follow-up from KEYNOTE- 671. Ann Oncol. 2025;36(suppl 2):S1607-S1608. doi:10.1016/j.annonc.2025.09.079
5. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non-small-cell lung cancer. N Engl J Med. 2023;389(18):1672-1684. doi:10.1056/NEJMoa2304875
6. Lin JT, Zhang C, Yan LX, et al. Neoadjuvant almonertinib followed by chemo-immunotherapy in II-IIIb EGFR-mutant NSCLC: a single arm, phase II study (NEOVADE). J Clin Oncol. 2026;44(suppl 16):8509. doi:10.1200/JCO.2026.44.16_suppl.8509
7. Schmid S, Dimopoulou G, van Schil PE, et al. ETOP 25-23 ADOPT-lung: An international, multicentre, open-label randomised phase III trial to evaluate the benefit of adding adjuvant durvalumab after neoadjuvant chemotherapy plus durvalumab in patients with stage IIB-IIIB (N2) resectable NSCLC. J Thorac Oncol. 2025;20(suppl 1):S118-S119. doi:10.1016/S1556-0864(25)00369-7