Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR–Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer

Author(s): James Chih-Hsin Yang, MD, PhD¹; Dae Ho Lee, MD, PhD²; Jong-Seok Lee, MD, PhD³; Yun Fan, MD⁴; Filippo de Marinis, MD, PhD⁵; Eiji Iwama, MD, PhD⁶; Takako Inoue, MD⁷; Jerónimo Rodríguez-Cid, MD⁸; Li Zhang, MD⁹; Cheng-Ta Yang, MD¹⁰; Emmanuel de la Mora Jimenez, MD¹¹; Jianying Zhou, MD¹²; Maurice Pérol, MD¹³; Ki Hyeong Lee, MD, PhD¹⁴; David Vicente, MD¹⁵; Eiki Ichihara, MD, PhD¹⁶; Gregory J. Riely, MD, PhD¹⁷; Yiwen Luo, PhD¹⁸; Diana Chirovsky, PhD¹⁸; M. Catherine Pietanza, MD¹⁸; Niyati Bhagwati, MD¹⁸; Shun Lu, MD, PhD¹⁹

Source: https://doi.org/10.1200/JCO.23.0274

Dr. Maen Hussein's Thoughts

Pembrolizumab in addition to chemotherapy DID NOT help, recall now we have new approval for those patients (datopotamab).

PURPOSE

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837).

METHODS

Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS.

RESULTS

Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients.

CONCLUSION

Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Author Affiliations

¹National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; ²Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; ³Seoul National University Bundang Hospital, Seoul, South Korea; ⁴Zhejiang Cancer Hospital, Hangzhou, China; ⁵Istituto Europeo di Oncologia, IRCCS, Milan, Italy; ⁶Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ⁷Osaka International Cancer Institute, Osaka, Japan; ⁸Oncology Center, Medica Sur Hospital, Mexico City, Mexico; ⁹Peking Union Medical College Hospital, Beijing, China; ¹⁰Chang Gung Memorial Hospital, Taoyuan, Taiwan; ¹¹Instituto Jalisciense de Cancerología, Guadalajara, Mexico; ¹²The First Affiliated Hospital, Zhejiang University, Zhejiang, China; ¹³Centre Léon Bérard, Lyon, France; ¹⁴Chungbuk National University Hospital, Cheongju-si, South Korea; ¹⁵Hospital Universitario Virgen Macarena, Sevilla, Spain; ¹⁶Okayama University Hospital, Okayama, Japan; ¹⁷Memorial Sloan Kettering Cancer Center, New York, NY; ¹⁸Merck & Co, Inc, Rahway, NJ; ¹⁹Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China;

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.

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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.