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: DOI: 10.1056/NEJMoa2215530

Dr. Anjan Patel's Thoughts

The NADIM-II study looked at perioperative Nivo+chemo vs. chemo alone in stIIIA – stIIIB NSCLC. High pCR rates with chemoIO are again seen, as in the Checkmate 816 and NADIM-I study, they were even higher in this cohort (37%), suggesting higher-stage patients derive the biggest benefit from neoadjuvant chemoIO. Pretty impressive results, however, I still must point out that this was a phase II study with a small sample size, OS benefits have not been demonstrated and this has yet to make it on to NCCN.

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.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The phase 3 MARIPOSA trial compared amivantamab–lazertinib (Ami-Laz) to osimertinib (Osi) in untreated EGFR-mutated advanced non-small cell lung cancer (NSCLC), showing a significant overall survival (OS) benefit for Ami-Laz (3-yr OS was 60% vs 51%). Median OS was not reached for Ami-Laz vs 36.7 months for Osi, with a projected >12-month median OS advantage. Ami-Laz also improved time to symptomatic progression (43.6 vs 29.3 months) and showed durable intracranial control, though grade ≥3 adverse events (AEs) were higher (80% vs 52%), notably skin, venous thromboembolism (VTE), and infusion reactions. In short, Ami-Laz is emerging as a new standard for first-line EGFRm NSCLC, but we’ll need to be proactive about managing its toxicity profile in clinic and whether this is superior or equivalent to Osi + chemo is currently unclear.

Adagrasib versus docetaxel in KRASG12C-mutated non-small-cell lung cancer (KRYSTAL-12): a randomised, open-label, phase 3 trial

Adagrasib demonstrated a median progression-free survival (PFS) of 5.5 months compared to 3.8 months with docetaxel in patients with KRAS G12C-mutated tumors. Treatment-related adverse events occurred in 47% of patients receiving Adagrasib and 46% in the docetaxel group. In my experience, Adagrasib is also more tolerable, making it a favorable option for this patient population.

Overall Survival with Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer

There was a 28% reduction in mortality. Patients who achieved a complete response (CR) or clearance of circulating tumor DNA (ctDNA) also experienced better outcomes.