Perioperative Nivolumab and Chemotherapy in Stage III Non–Small-Cell Lung Cancer

Author(s): Mariano Provencio, M.D., Ph.D., Ernest Nadal, M.D., Ph.D., José L. González-Larriba, M.D., Ph.D., Alex Martínez-Martí, M.D., Reyes Bernabé, M.D., Joaquim Bosch-Barrera, M.D., Joaquín Casal-Rubio, M.D., Virginia Calvo, M.D., Ph.D., Amelia Insa, M.D., Santiago Ponce, M.D., Ph.D., Noemí Reguart, M.D., Ph.D., Javier de Castro, M.D., Ph.D., Joaquín Mosquera, M.D., Ph.D., Manuel Cobo, M.D., Ph.D., Andrés Aguilar, M.D., Guillermo López Vivanco, M.D., Carlos Camps, M.D., Ph.D., Rafael López-Castro, M.D., Teresa Morán, M.D., Isidoro Barneto, M.D., Delvys Rodríguez-Abreu, M.D., Ph.D., Roberto Serna-Blasco, M.Sc., Raquel Benítez, Ph.D., Carlos Aguado de la Rosa, M.D., Ramón Palmero, M.D., Florentino Hernando-Trancho, M.D., Ph.D., Javier Martín-López, M.D., Alberto Cruz-Bermúdez, Ph.D., Bartomeu Massuti, M.D., and Atocha Romero, Pharm.D., Ph.D.

Source: N Engl J Med 2023; 389:504-513 DOI: 10.1056/NEJMoa2215530

Dr. Maen Hussein's Thoughts

Neoadjuvant chemotherapy trial with post op nivolumab for 6 months shows promising results.

BACKGROUND

Approximately 20% of patients with non–small-cell lung cancer (NSCLC) receive a diagnosis of stage III disease. There is no current consensus regarding the most appropriate treatment for these patients.

METHODS

In this open-label, phase 2 trial, we randomly assigned patients with resectable stage IIIA or IIIB NSCLC to receive neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months. The primary end point was a pathological complete response (0% viable tumor in resected lung and lymph nodes). Secondary end points included progression-free survival and overall survival at 24 months and safety.

RESULTS

A total of 86 patients underwent randomization; 57 were assigned to the experimental group and 29 were assigned to the control group. A pathological complete response occurred in 37% of the patients in the experimental group and in 7% in the control group (relative risk, 5.34; 95% confidence interval [CI], 1.34 to 21.23; P=0.02). Surgery was performed in 93% of the patients in the experimental group and in 69% in the control group (relative risk, 1.35; 95% CI, 1.05 to 1.74). Kaplan–Meier estimates of progression-free survival at 24 months were 67.2% in the experimental group and 40.9% in the control group (hazard ratio for disease progression, disease recurrence, or death, 0.47; 95% CI, 0.25 to 0.88). Kaplan–Meier estimates of overall survival at 24 months were 85.0% in the experimental group and 63.6% in the control group (hazard ratio for death, 0.43; 95% CI, 0.19 to 0.98). Grade 3 or 4 adverse events occurred in 11 patients in the experimental group (19%; some patients had events of both grades) and 3 patients in the control group (10%).

CONCLUSIONS

In patients with resectable stage IIIA or IIIB NSCLC, perioperative treatment with nivolumab plus chemotherapy resulted in a higher percentage of patients with a pathological complete response and longer survival than chemotherapy alone. (Funded by Bristol Myers Squibb and others; NADIM II ClinicalTrials.gov number, NCT03838159. opens in new tab; EudraCT number, 2018-004515-45. opens in new tab.)

Author Affiliations

From Hospital Universitario Puerta de Hierro–Majadahonda (M.P., V.C., R.S.-B., J.M.-L., A.C.-B., A.R.), Hospital Universitario Clínico San Carlos (J.L.G.-L., C.A.R., F.H.-T.), Hospital Universitario 12 de Octubre (S.P.), Hospital Universitario La Paz (J.C.), and the Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (R. Benítez), Madrid, Institut Català d’Oncologia, L’Hospitalet de Llobregat (E.N., R.P.), Vall d’Hebron Institute of Oncology, Hospital Universitari Vall d’Hebrón (A.M.-M.), the Medical Oncology Department Hospital Clinic and Translational Genomics and Targeted Therapies in Solid Tumors, Institut de Investigacions Biomèdiques (N.R.), and Instituto Oncológico Dr. Rosell, Dexeus University Hospital (A.A.), Barcelona, Hospital Universitario Virgen del Rocio, Seville (R. Bernabé), Institut Català d’Oncologia, Hospital Universitari Dr. Josep Trueta, Girona (J.B.-B.), Complejo Hospitalario Universitario de Vigo, Pontevedra (J.C.-R.), Fundación Instituto de Investigación Sanitaria, Hospital Clínico Universitario de Valencia (A.I.), and Hospital General Universitario de Valencia, Universidad de Valencia and Centro de Investigación Biomédica en Red Cáncer (C.C.), Valencia, Complejo Hospitalario Universitario A Coruña, A Coruña (J.M.), the Medical Oncology Intercenter Unit, Regional and Virgen de la Victoria University Hospitals, Instituto de Investigación Biomédica de Málaga, Málaga (M.C.), Hospital Universitario Cruces, Barakaldo (G.L.V.), Hospital Clínico Universitario de Valladolid, Valladolid (R.L.-C.), the Medical Oncology Department, Catalan Institute of Oncology, Badalona–Germans Trias i Pujol Hospital, Badalona Applied Research Group in Oncology, Fundació Institut de Investigado de Ciences de la Salut Germans Trias i Pujol, Department of Medicine, Universitat Autònoma de Barcelona, Campus Can Ruti, Badalona (T.M.), Hospital Universitario Reina Sofia, Córdoba (I.B.), Complejo Hospitalario Universitario Insular–Materno Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria (D.R.-A.), and Hospital Universitario Dr. Balmis Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante (B.M.) — all in Spain.

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.