Neoadjuvant Chemoimmunotherapy Anchors an Expanding Treatment Paradigm in Resectable NSCLC

Treatment of resectable non–small cell lung cancer (NSCLC) has moved from a simple choice of surgery with or without chemotherapy to a crowded field of neoadjuvant, perioperative, adjuvant, and biomarker-directed strategies, according to Patrick Forde, MD, MBBCh. ¹

"In the context of immunotherapy, we're still trying to decide: should some patients have upfront surgery for stage II and III, or should everybody get neoadjuvant chemoimmunotherapy and then consider surgery afterwards?" Forde said during a presentation at the 44th Annual Chemotherapy Foundation Symposium, an event held by Physicians’ Education Resource, LCC.¹

Forde is the Patrick Prendergast Professor of Clinical Immuno-Oncology at Trinity St. James's Cancer Institute, Trinity College Dublin, in Ireland.

He centered his presentation around the overall survival (OS) data for preoperative immunotherapy, the unsettled role of adjuvant immunotherapy, and targeted options for oncogene-driven disease.

How do neoadjuvant and perioperative approaches compare?

Four global phase 3 trials have shown an event-free survival (EFS) benefit with preoperative chemoimmunotherapy, and 2 have also demonstrated an OS benefit: the neoadjuvant-only phase 3 CheckMate 816 trial (NCT02998528) of nivolumab (Opdivo) plus chemotherapy for 3 cycles, and the perioperative phase 3 KEYNOTE-671 trial (NCT03425643) of pembrolizumab (Keytruda) delivered for a total of 17 cycles before and after surgery.^1-3

In the absence of head-to-head data for these regimens, Forde acknowledged that cross-trial comparison is unavoidable.

"We don't have randomized data to compare neoadjuvant and perioperative,” jhe said. "These data look remarkably similar.”

The 5-year OS rates were 65% vs 55% with nivolumab plus chemotherapy vs chemotherapy alone in CheckMate 816, and 64.6% vs 53.6% with pembrolizumab vs placebo in KEYNOTE-671.^2,3 Forde noted one caveat: 65% of patients in the KEYNOTE-671 control arm received anti–PD-(L)1 therapy at relapse vs 51% in CheckMate 816, which may have narrowed the survival curves in the pembrolizumab trial.¹

In exploratory KEYNOTE-671 analyses, EFS benefit was seen regardless of tumor mutational burden (TMB; TMB-low HR, 0.63; 95% CI, 0.47-0.86; TMB-high HR, 0.49; 95% CI, 0.32-0.73) and was similar in KRAS-mutant and wild-type subgroups.⁴

"In the perioperative setting, KRAS status shouldn't direct what we do in terms of selection of immunotherapy," Forde said.

What role does pathologic complete response play?

Although biomarkers to guide immunotherapy selection in early-stage disease remain an area of active investigation, Forde pointed to one measure that is already informing prognosis after preoperative treatment.

"In the neoadjuvant [or] perioperative setting, we do have an emerging biomarker, and that's actually pathological complete response [pCR]," Forde said.

In CheckMate 816, pCR rates were 24% with nivolumab plus chemotherapy vs 2.2% with chemotherapy, and among patients in the nivolumab arm who achieved a pCR, 3 deaths occurred, none due to disease, compared with 44 disease-related deaths (33.1%) among those without a pCR.¹ In KEYNOTE-671, 8 of 72 patients (11%) with a pCR had died at 5 years, and lung cancer–specific survival was 93%.

"If you want to give a rough number to a patient, 93% to 100% of patients who have a pCR from the 2 most reported trials are likely to be alive at 5 years," he said.

Does adjuvant immunotherapy add benefit?

Landmark analyses from the phase 3 CheckMate 77T (NCT04025879), KEYNOTE-671, and AEGEAN (NCT03800134) trials suggest patients who received adjuvant immunotherapy fared better, but those patients may simply have been fitter after surgery, Forde cautioned.

"We can't tell whether the benefit is coming mainly or all from the neoadjuvant component, or whether the adjuvant component is really adding something," he said.

Two phase 3 trials aim to address the question from opposite directions: ADOPT-lung (NCT06284317) is evaluating whether further adjuvant durvalumab (Imfinzi) adds benefit for patients without a pCR, and INSIGHT (NCT06498635) is enrolling only patients with a pCR. Readouts are not expected until between 2032 and 2035, he noted.

Data for adjuvant-only immunotherapy are more conflicting. The phase 3 BR31 (NCT02273375) and ANVIL (NCT02595944) trials were negative, whereas the phase 3 IMpower010 (NCT02486718) and PEARLS/KEYNOTE-091 (NCT02504372) trials each showed a disease-free survival (DFS) benefit.

In the final analysis of PEARLS, DFS favored pembrolizumab (HR, 0.85; 95% CI, 0.73-0.98), but 6-year OS rates were 68.5% vs 66.4% (HR, 0.98; 95% CI, 0.81-1.18).⁵ In IMpower010, adjuvant atezolizumab (Tecentriq) did not improve OS in the intention-to-treat population (HR, 0.97; 95% CI, 0.78-1.22) but showed an exploratory OS benefit in patients with PD-L1 expression of at least 50% (HR, 0.44; 95% CI, 0.26-0.74).⁶ Postoperative minimal residual disease testing in IMpower010, "doesn't appear to predict benefit from adjuvant immunotherapy," Forde added.

Can neoadjuvant chemoimmunotherapy expand to borderline resectable disease?

The phase 2 MDT-BRIDGE trial (NCT05925530) enrolled patients (n = 142) with resectable or borderline resectable stage IIB to IIIB NSCLC, as determined by a multidisciplinary tumor board, who received neoadjuvant durvalumab plus chemotherapy before reassessment for surgery or chemoradiotherapy.⁷ The resection rate was 81.5% (95% CI, 72.1%-88.9%) among patients resectable at baseline and 62.0% (95% CI, 47.2%-75.3%) among those deemed borderline resectable.⁷ Notably, 96.2% of resected patients had R0 resections. Early outcomes were favorable in both the surgical and chemoradiotherapy groups.

"They don't appear to be losing anything by getting that chemoimmunotherapy upfront, at least in this controlled environment," Forde said. He noted that the vast majority of patients were enrolled in Europe, where tumor boards are often mandated, and that the data may be less applicable to tumors invading major vessels.

Where does targeted therapy fit in early-stage disease?

In the phase 3 ADAURA trial (NCT02511106), adjuvant osimertinib (Tagrisso) continued to show an OS benefit vs placebo in patients with stage II to IIIA EGFR-mutant NSCLC, with respective 8-year OS rates of 74% vs 58% (HR, 0.53; 95% CI, 0.38-0.75).⁸

"You're still starting to see patients dropping off that blue curve, so perhaps is 3 years enough? I think we don't know," Forde said.

In the phase 2 LORIN trial (NCT05740943), 12 weeks of neoadjuvant lorlatinib (Lorbrena) in patients with ALK-positive stage III NSCLC (n = 43) produced an objective response rate of 84% and a 1-year EFS rate of 97.1% (95% CI, 91.5%-100%).⁹

"This is a potential option, I would say, for a patient with a locally advanced ALK-positive tumor," he said.

In the phase 3 LIBRETTO-432 trial (NCT04819100), adjuvant selpercatinib (Retevmo) significantly improved EFS vs placebo in patients with stage II to IIIA RET fusion–positive NSCLC (HR, 0.172; 95% CI, 0.058-0.509; P = .0003), with 24-month EFS rates of 91.5% vs 61.1%.¹⁰ Forde noted, however, that "there is probably more toxicities to be monitored with selpercatinib than some of the other TKIs."

What is the current standard for early-stage NSCLC?

Forde concluded that adjuvant EGFR- and ALK-directed therapy, and possibly RET-directed therapy, are now standard, and that neoadjuvant or perioperative chemoimmunotherapy is preferred over upfront surgery for resectable stage II to III disease.

Unmet needs include defining the contribution of adjuvant immunotherapy, escalation strategies for patients without a pCR, and biomarkers beyond PD-L1. The role of neoadjuvant chemoimmunotherapy is also expanding, with studies exploring it in unresectable stage III disease.

Despite the open questions, Forde emphasized that outcomes for patients with resected disease are improving.

"Across disease stages, we're seeing an improvement of survival," Forde said. "Some perhaps from the adjuvant treatment, but also from the use of immunotherapy at the time of relapse."

References

1. Forde PM. Updates in perioperative therapy: IO and targeted therapy. Presented at: 44th Annual Chemotherapy Foundation Symposium; November 11-13, 2026; New York, NY.
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. Spicer JD, Garassino MC, Wakelee H, et al. Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone in patients with early-stage non-small-cell lung cancer (KEYNOTE-671): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;404(10459):1240-1252. doi:10.1016/S0140-6736(24)01756-2
4. Garassino MC. Association of biomarkers with efficacy in the phase 3 KEYNOTE-671 study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) in early-stage non–small-cell lung cancer (NSCLC). Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 2519O.
5. O’Brien ME, Paz-Ares L, Marreaud S, et al. Final analysis of adjuvant pembrolizumab in resected early-stage non–small-cell lung cancer: phase 3 PEARLS/KEYNOTE-091 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 2511O.
6. Felip E, Altorki N, Zhou C, et al. Five-year survival outcomes with atezolizumab after chemotherapy in resected stage IB-IIIA non-small cell lung cancer (IMpower010): an open-label, randomized, phase III trial. J Clin Oncol. 2025;43(21):2343-2349. doi:10.1200/JCO-24-01681
7. Reck M, Nadal E, Gay CM, et al. Neoadjuvant durvalumab plus chemotherapy in resectable or borderline resectable non-small-cell lung cancer: the phase 2 MDT-BRIDGE trial. Nat Med. Published online October 26, 2026. doi:10.1038/s41591-026-04742-7
8. Wu YL, Majem M, John T, et al. Adjuvant osimertinib in resected EGFR-mutated stage IB-IIIA NSCLC: exploratory 8-year overall survival landmark update from the ADAURA trial. J Thorac Oncol. Published online September 13, 2026. doi:10.1016/j.jtho.2026.104179
9. Zhang C, Hu Y, Jiang BY, et al. Neoadjuvant lorlatinib in stage III NSCLC harboring ALK fusion: a phase 2 multicenter study (LORIN). J Clin Oncol. 2026;44(suppl 16):8002. doi:10.1200/JCO.2026.44.16_suppl.8002
10. Wu YL, Hochmair M, Yang Y, et al. Selpercatinib in early-stage RET fusion–positive non–small-cell lung cancer. N Engl J Med. 2026;395(7):660-670. doi:10.1056/NEJMoa2602628