Abstract CT003: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial

Chemotherapy + PD-1/PD-L1 Blockade Should Be the Preferred Option in the Neoadjuvant Therapy of NSCLC

Background: CheckMate 816 (NCT02998528), a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo for resectable NSCLC, met its first primary endpoint with a statistically significant improvement in pathological complete response (pCR) rate (24% vs 2%; odds ratio 13.94 [99% CI, 3.49-55.75; P < 0.0001]). pCR benefit was consistent across key subgroups, including disease stages, histologies, and PD-L1 expression levels. Notably, neoadjuvant NIVO + chemo did not impede feasibility of surgery nor increase incidence of surgical complications or adverse events (AEs) vs chemo alone. We report results from the first prespecified interim analysis of EFS, the other primary endpoint. Methods: Adults with stage IB (≥ 4 cm)-IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ALK alterations were randomized to NIVO 360 mg + chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Primary endpoints were EFS and pCR (both assessed by blinded independent review) in the randomized population. EFS was defined as the length of time from randomization to any disease progression precluding surgery, disease progression or recurrence after surgery, or death due to any cause. An exploratory analysis of EFS by pCR status was conducted. Results: At a median follow-up of 29.5 mo (database lock, October 20, 2021), neoadjuvant NIVO + chemo significantly improved EFS vs chemo in the randomized population (median [95% CI], 31.6 mo [30.2-not reached (NR)] vs 20.8 mo [14.0-26.7]; HR [97.38% CI], 0.63 [0.43-0.91]; P = 0.0052; 2-year EFS rates, 64% vs 45%). EFS results in the subgroups by disease stages, histologies, and PD-L1 expression levels are shown in the Table: In the pooled patient population (NIVO + chemo and chemo arms combined), EFS was improved in patients with pCR compared with those without (median, NR vs 21.1 mo; HR [95% CI], 0.11 [0.04-0.29]). Incidence of grade 3-4 treatment-related (33.5% vs 36.9%) and surgery-related AEs (11.4% vs 14.8%) was similar between the NIVO + chemo and chemo arms, as reported previously. Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo showed a statistically significant and clinically meaningful improvement in EFS vs chemo alone. These results, along with the significant improvement in pCR, support NIVO + chemo as a potential new treatment option for patients with stage IB-IIIA resectable NSCLC. Subgroups Median EFS, mo (95% CI) HR (95% CI) NIVO + chemo Chemo Overall (n = 358) 31.6 (30.2-NR) 20.8 (14.0-26.7) 0.63 (0.43-0.91)a Baseline disease stage IB-II (n = 127) NR (27.8-NR) NR (16.8-NR) 0.87 (0.48-1.56) IIIA (n = 228) 31.6 (26.6-NR) 15.7 (10.8-22.7) 0.54 (0.37-0.80) Tumor histology Squamous (n = 182) 30.6 (20.0-NR) 22.7 (11.5-NR) 0.77 (0.49-1.22) Non-squamous (n = 176) NR (27.8-NR) 19.6 (13.8-26.2) 0.50 (0.32-0.79) PD-L1 expression level < 1% (n = 155) 25.1 (14.6-NR) 18.4 (13.9-26.2) 0.85 (0.54-1.32) ≥ 1% (n = 178) NR (NR-NR) 21.1 (11.5-NR) 0.41 (0.24-0.70) 1-49% (n = 98) NR (27.8-NR) 26.7 (11.5-NR) 0.58 (0.30-1.12) ≥ 50% (n = 80) NR (NR-NR) 19.6 (8.2-NR) 0.24 (0.10-0.61) a97.38% CI reported. Chemo, chemotherapy; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; mo, months; NIVO, nivolumab; NR, not reached; PD-L1, programmed death ligand 1. Citation Format: Nicolas Girard, Jonathan Spicer, Mariano Provencio, Shun Lu, Stephen Broderick, Mark M. Awad, Tetsuya Mitsudomi, Keith Kerr, Julie Brahmer, Scott J. Swanson, Enriqueta Felip, Changli Wang, Gene B. Saylors, Ke-Neng Chen, Fumihiro Tanaka, Moishe Liberman, Cecile Dorange, Javed Mahmood, Junliang Cai, Patrick M. Forde. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer (NSCLC): Event-free survival (EFS) results from the phase 3 CheckMate 816 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT012.

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

Adjuvant chemotherapy for surgically resected non–small cell lung cancer

Early and locally advanced non-small-cell lung cancer: an update of the ESMO Clinical Practice Guidelines focusing on diagnosis, staging, systemic and local therapy

LBA8511 Background: Several studies have shown an association of pathological response, a common efficacy endpoint in neoadjuvant therapy trials, with survival for chemo in various cancers including resectable NSCLC. However, the association between pathological complete response (pCR) and survival as well as the degree of pathological regression that may be predictive of EFS for neoadjuvant immunotherapy has not been rigorously studied. CheckMate 816 (NCT02998528), a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC, met both of its primary endpoints with a statistically significant and clinically meaningful improvement in EFS and pCR. Here, we report a post hoc analysis from CheckMate 816, characterizing the association between pathological regression and EFS. Methods: Adults with resectable NSCLC were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo alone Q3W for 3 cycles. Primary endpoints were EFS and pCR (0% residual viable tumor [RVT] in the primary tumor [PT] and lymph nodes [LN] based on immune-related pathological response criteria), both assessed by blinded independent review. Major pathological response (MPR; ≤10% RVT in the PT and LN) was a secondary endpoint. In this post hoc analysis, EFS was assessed based on depth of pathological regression (measured by %RVT) in the PT only. Also, a time-dependent receiver operating characteristic curve analysis assessed the predictive ability of %RVT (PT only) for EFS outcome at 2 years, using area under the curve (AUC) to summarize the overall diagnostic accuracy (0.5 = random chance; 1 = perfect accuracy). Results: Baseline characteristics in patients (pts) with pathologically evaluable samples were well balanced between the NIVO + chemo and chemo arms, similar to the overall population. In both treatment arms, EFS (minimum follow-up, 21 months) was improved in pts with vs without pCR or MPR (Table). %RVT appeared to be predictive of EFS at 2 years for NIVO + chemo (AUC = 0.74) but an association was not clear for chemo (AUC = 0.54). 2-year EFS rates for NIVO + chemo were 90%, 60%, 57%, and 39% for pts with 0–5%, >5–30%, >30–80%, and >80% RVT, respectively. Conclusions: In CheckMate 816, pathological response (pCR and MPR) in the PT was associated with improved EFS with neoadjuvant NIVO + chemo. Additionally, depth of pathological regression appeared to be predictive of improved EFS. Clinical trial information: NCT02998528. [Table: see text]

SY13-03: Neoadjuvant immunotherapy for operable non-small cell lung cancer: Lessons learned and current challenges

Background: Programmed death-1 (PD-1) blocking antibodies improve survival in patients with advanced non-small-cell lung cancer (NSCLC) but have not been tested in resectable NSCLC, where little progress has been made over the last decade. Methods: Adults with untreated surgically resectable stage I-IIIA NSCLC received two doses of nivolumab (anti-PD-1) preoperatively. The primary endpoints of the study were safety and feasibility. Tumor pathologic response, PD-L1 expression, mutation burden and mutation-associated neoantigen-specific T-cell responses were evaluated. Results: Neoadjuvant nivolumab was had an acceptable side effect profile without surgical delays, and 20 of 21 tumors were completely resected. Major pathologic response occurred in 45% (9/20) of resected tumors. Responses occurred in both PD-L1 positive and negative tumors. Pathologic response significantly correlated with pre-treatment tumor somatic mutation burden. T-cell clones shared between the tumor and peripheral blood increased systemically upon anti-PD-1 treatment in 8 of 9 patients analyzed. Mutation-associated neoantigen-specific T-cell clones, from a primary tumor that underwent pathologic complete response, rapidly expanded in peripheral blood at 2-4 weeks post-treatment, some of these clones were not detected before anti-PD-1. Conclusions: Neoadjuvant nivolumab was associated with few side effects, did not delay surgery, and induced major pathologic responses in 45% of resected tumors. Tumor mutation burden is predictive of pathologic response to anti-PD-1. Anti-PD-1 can induce expansion of mutation-associated neoantigen-specific T-cell clones in peripheral blood. [P.M.F., J.E.C., and K.N.S. contributed equally to this work.] Citation Format: Patrick M. Forde, Jamie E. Chaft, Kellie N. Smith, Valsamo Anagnostou, Tricia R. Cottrell, Matthew D. Hellmann, Marianna Zahurak, Stephen C. Yang, David R. Jones, Stephen Broderick, Richard J. Battafarano, Moises J. Velez, Natasha Rekhtman, Zachary Olah, Jarushka Naidoo, Kristen A. Marrone, Franco Verde, Haidan Guo, Jiajia Zhang, Justina X. Caushi, Hok Yee Chan, John-William Sidhom, Robert B. Scharpf, James White, Edward Gabrielson, Hao Wang, Gary L. Rosner, Valerie Rusch, Jedd D. Wolchok, Taha Merghoub, Janis M. Taube, Victor E. Velculescu, Suzanne L. Topalian, Julie R. Brahmer, Drew M. Pardoll. Neoadjuvant PD-1 blockade in resectable lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT079.

8501 Background: Non-small cell lung cancer (NSCLC) is incurable in most patients with locally advanced stage IIIA disease. Previous results indicate that the use of neoadjuvant chemoimmunotherapy could increase the percentage of cured patients being a promising therapeutic option that has to be tested in randomized clinical trials. Methods: NADIM II (NCT03838159) is an open-label, randomized, two-arm, phase II, multi-center clinical trial. Patients with resectable clinical stage IIIA (per AJCC 7th ed) NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to receive Nivolumab (NIVO) 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery, or Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) followed by surgery. Patients with R0 resection confirmed by pathological evaluation initiated adjuvant administration of NIVO within the 3rd to 8th week (+7 days) from surgery and for 6 months. The primary endpoint was pathological complete response (pCR) by blinded independent pathological review (BIPR) in the intent-to-treat population (ITT). pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; patients who did not undergo surgery were classified as non-responders. Major pathological response (MPR; ≤ 10% viable tumor) per BIPR, overall response rate (ORR), toxicity profile, and potential predictive biomarkers are secondary endpoints. Results: Between February 8, 2019, and November 11, 2021, 90 patients were enrolled, of whom 87 patients were valid. Neoadjuvant NIVO + chemo significantly increased the pCR rate compared to chemo in the ITT (36.2% vs 6.8%; Relative Risk (RR) 5.25 [99% CI 1.32-20.87]; P = 0.0071). NIVO + chemo also improved MPR rates vs chemo in the ITT (52 % vs 14 %), as well as ORR (74 % vs 48%). Definitive surgery occurred for 91% of pts treated with NIVO + chemo and 69% with chemo; surgery was cancelled rarely due to AEs (1 pts/experimental arm) and due to disease progression in 1 and 4 pts in the experimental and control arm respectively. Grade 3-4-related AEs were reported in 24 % vs 10% in the NIVO + chemo vs chemo arms, respectively. In the ITT experimental arm, patients with pCR had higher PD-L1 TPS (median 70%, IQR 5-90%) compared to non-responders (median 0%, IQR 0-37.5%, P = 0.0035). AUC to predict pCR was 0.734 (95% CI 0.59-0.88; P = 0.005). The pCR rate rises across increasing categories of PD-L1 TPS ( < 1% 14.3%; 1-49% 41.7%; ≥50% 61.1%; P = 0.008). Conclusions: This study confirms the superiority of the chemo-immuno combination in patients with resectable stage IIIA NSCLC in terms of pCR, as well as the feasibility of surgery, with a moderate increase in grade 3-4 toxicity. Thus, this treatment should become the standard of care in these patients. Clinical trial information: NCT03838159.

8503 Background: CheckMate 816 (NCT02998528) is a randomized phase 3 study of neoadjuvant NIVO + chemo vs chemo in resectable NSCLC. The study met its first primary endpoint, demonstrating significantly improved pathological complete response (pCR) with neoadjuvant NIVO + chemo. Here we report key surgical outcomes from the study. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized to NIVO 360 mg + platinum-doublet chemo Q3W or chemo Q3W for 3 cycles (n = 179 each). Definitive surgery was to be performed within 6 weeks of treatment. Primary endpoints are pCR (defined as 0% viable tumor cells in lung and lymph nodes) and event-free survival; both are evaluated by blinded independent review. Feasibility of surgery and surgery-related adverse events (AEs) are exploratory endpoints. Results: Baseline characteristics were comparable between arms; 64% of patients (pts) were stage IIIA. Definitive surgery rates were 83% with NIVO + chemo (n = 149) vs 75% with chemo (n = 135). Reasons for cancelled surgery were disease progression (12 and 17 pts, respectively), AEs (2 pts/arm), or other scenarios (14 and 19 pts, respectively; including pt refusal, unresectability, poor lung function). Minimally invasive surgery rates were 30% and 22%, and conversion from minimally invasive to open surgery rates were 11% and 16% for NIVO + chemo and chemo, respectively. Lobectomy was performed in 77% vs 61% of pts, and pneumonectomy in 17% and 25% for NIVO + chemo vs chemo, respectively. AEs were responsible for delays of surgery in 6 pts in the NIVO + chemo arm and 9 pts in the chemo arm. An R0 resection was achieved in 83% vs 78% of pts and median residual viable tumor (RVT) cells in the primary tumor bed were 10% vs 74% for NIVO + chemo vs chemo. There was no increase in median (Q1, Q3) duration of surgery and length of hospitalization between NIVO + chemo vs chemo (184 [130, 252] vs 217 [150, 283] min; and 10.0 [7, 14] vs 10.0 [7, 14] days, respectively). Any-grade and grade 3–4 surgery-related AEs were reported in 41% vs 47% and 11% vs 15% of the NIVO + chemo vs chemo arms, respectively. Grade 5 surgery-related AEs were reported in 2 vs 0 pts in the NIVO + chemo vs chemo arms; 0 vs 3 pts died due to treatment-related AEs, respectively. Conclusions: In CheckMate 816, neoadjuvant NIVO + chemo did not impede the feasibility and timing of surgery, nor the extent or completeness of resection vs chemo alone; treatment was tolerable and did not increase surgical complications. NIVO + chemo led to increased depth of pathological response. The surgical outcome data from CheckMate 816 along with significant improvement in pCR support NIVO + chemo as a potential neoadjuvant option for patients with stage IB to IIIA resectable NSCLC. Clinical trial information: NCT02998528.

Consensus on adjuvant therapy for completely resected non-small cell lung cancer until 2002 was as follows. (1) There was no significant impact of postoperative adjuvant chemotherapy based on meta-analysis and previous clinical trials. (2) Confirmatory studies are necessary in large-scale prospective clinical trials. However, recent mega trials have introduced epoch-making changes for postoperative adjuvant chemotherapy in clinical practice since ASCO 2003. The effectiveness of UFT in N0 patients was confirmed. Patients with completely resected stage I non-small cell lung cancer, especially T2N0 adenocarcinoma, will benefit from adjuvant chemotherapy with UFT. The results of the International Adjuvant Lung Trial (IALT) have confirmed the meta-analysis in 1995. Also, both the JBR10 and Cancer and Leukemia Group B (CALGB) 9633 studies have also confirmed positive IALT results of the benefit for postoperative platinum-based chemotherapy in completely resected non-small cell lung cancer. Adjuvant chemotherapy for pathological stage IB to II, completely resected non-small cell lung cancer is standard care based on clinical trials. UFT showed the strongest evidence for IB in Japan. Platinum doublet chemotherapy with third-generation anticancer agents is also recommended. Adjuvant chemotherapy should be offered as standard care to patients after completely resected early stage non-small cell lung cancer. However, there is no evidence of the feasibility and efficacy for adjuvant chemotherapy with the platinum-based regimen in Japan. Careful management should be necessary in such treatment.

BackgroundTumor and nodal downstaging following neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC) are important markers of therapeutic response associated with favorable prognosis. We studied the impact of four...

Peri-operative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small cell lung cancer: final analysis of the randomized RATIONALE-315 trial.

ED08.04 Perspectives of Targeted Therapies and Immunotherapy in Completely Resected NSCLC

Although neoadjuvant chemoimmunotherapy has emerged as a promising approach for resectable non-small cell lung cancer (NSCLC), comparative real-world data on different PD-1 inhibitors are limited. This study compared the clinical efficacy, pathological response, survival, and safety of four PD-1 inhibitors-pembrolizumab, tislelizumab, camrelizumab, and sintilimab-in patients with Stage II-IIIa NSCLC. We retrospectively reviewed 199 patients with resectable Stage II-IIIa NSCLC treated with neoadjuvant PD-1 inhibitors plus platinum-based chemotherapy from January 2018 to December 2024. After excluding 50 non-surgical cases, 149 patients were included. Outcomes compared included pathological response (pathological complete response, pCR; major pathological response, MPR), recurrence, disease-free survival (DFS), overall survival (OS), and adverse events. pCR and MPR rates were 52.2% and 58.0% (pembrolizumab), 67.6% and 75.7% (tislelizumab), 71.4% and 71.4% (camrelizumab), and 47.2% and 61.1% (sintilimab), respectively. Differences in pCR/MPR were not statistically significant. However, OS differed significantly across groups (p < 0.05), favoring pembrolizumab and tislelizumab. No significant differences were observed in progression-free survival (PFS) or recurrence among patients with pCR. Grade ≥ 3 treatment-related adverse events occurred in 27.0%-42.9% of patients, lowest in the tislelizumab group. All treatment regimens elicited substantial pathological responses and exhibited acceptable safety profiles. Pembrolizumab and tislelizumab were associated with better OS and lower toxicity, supporting their preferential use in neoadjuvant therapy for resectable NSCLC.