Pembrolizumab plus chemotherapy before surgery and thereafter as a single agent after surgery has demonstrated benefit over preoperative chemotherapy alone in non-small cell lung cancer (NSCLC) resectable in stage II, IIIA or IIIB.
Based on a subgroup analysis, the improvement in event-free survival (EFS) with the pembrolizumab-based regimen was consistent across all subgroups with PD-L1 expression, histology and stage. Within perioperativeexploratory subgroup analysis showed a reduction in the risk of recurrence, progression, or death (EFS) whether or not there is a complete pathological response (pCR). KEYNOTE-671 is the eighth positive study evaluating a regimen with pembrolizumab in the early stages of the disease and the seventh in lung cancer.
Treatment of early stage lung cancer
Immunotherapy in early stage lung cancer pembrolizumabbefore and after surgery improves event-free survival and reduces the risk of recurrence. This is demonstrated by the positive results of the Phase 3 pivotal study KEYNOTE-671 evaluating pembrolizumab as a perioperative treatment regimen, comprising treatment before surgery (neoadjuvant) and after surgery (adjuvant), for patients with lung cancer stage II, IIIA or IIIB resectable non-small cell (NSCLC).
At the median follow-up of 25.2 months, pembrolizumab neoadjuvant plus chemotherapy followed by resection and adjuvant pembrolizumab as single agent significantly improved event-free survival (EFS), reducing the risk of recurrence, progression or death by 42% (HR=0.58 [95% CI, 0,46-0,72]; p<0,00001) nei pazienti con non-small cell lung cancer (NSCLC) resectable stage II, IIIA or IIIB, vs placebo e neoadjuvant chemotherapy followed by adjuvant placebo. In pembrolizumab-treated patients, median event-free survival (EFS) was not reached (95% CI, 34.1-NR) versus 17 months (95% CI, 14.3-22) survival for those treated with chemotherapy alone.
Patient survival
The study continues to allow for further follow-up of overall survival (OS), which is the other primary endpoint. A favorable trend of overall survival (OS) was observed for the con regimen pembrolizumab compared to h (HR=0,73 [95% CI, 0,54-0,99] p=0.02124); with only 177 events this data of OS are not mature and have not reached statistical significance at the time of the interim analysis. The safety profile of the pembrolizumab regimen was consistent with the safety profile in early and metastatic NSCLC. These results will be presented today in the scientific symposium entitled “The Promise of Neoadjuvant Immunotherapy Across Solid Tumors” during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting and will be published simultaneously in the New England Journal of Medicine.
In a subgroup analysis, the improvement in event-free survival with the pembrolizumab regimen was consistent across subgroups regardless of both PD-L1 (tumor proportion score [TPS] ≥50% [n=266] HR=0,42 [95% CI, 0,28-0,65]; TPS 1-49% [n=242] HR=0,51 [95% CI, 0,34-0,75]; TPS <1% [n=289] HR=0,77 [95% CI, 0,55-1,07]), and by histology (non-squamous [n=453] HR=0,58 [95% CI, 0,43-0,78]; scaly [n=344] HR=0,57 [95% CI, 0,41-0,77]) and from the stage (stage II [n=239] HR=0,65 [95% CI, 0,42-1,01]; stage IIIA [n=442] HR=0,54 [95% CI, 0,41-0,72]; stadio IIIB [n=116] HR=0,52 [95% CI, 0,31-0,88]).
Lo studio KEYNOTE
Despite achieving the complete pathological response (pCR) is a predictor of best outcome, exploratory subgroup analysis showed that the reduction in risk of recurrence, progression, or death (EFS) with the perioperative pembrolizumab regimen was observed in both patients with pCR (HR=0,33 [95% CI, 0,09-1,22]), and in patients without pCR (HR=0,69 [95% CI, 0,55-0,86]).
“Historically, more than half of patients with early stages of surgically removed non-small cell lung cancer recur – explains Federico Cappuzzo, Director of Medical Oncology 2, ‘Regina Elena’ National Cancer Institute of Roma -. The results of the study KEYNOTE–671 show that the pembrolizumab-based regimen before and after surgery significantly reduces the risk of recurrence, progression or death by 42% compared to the preoperative chemotherapyregardless of the expression of PD-L1 and whether or not there is a complete pathological response. These event-free survival data are very encouraging and support the potential of this perioperative approach for patients with stage II, IIIA, or IIIB resectable non-small cell lung cancer, who are treated with curative intent”.
Il Pembrolizumab
“The data of the studio KEYNOTE-671 are significant not only for patients and oncologists but also for thoracic surgeons, given the need for new treatment options that may improve event-free survival in stage II, IIIA, or IIIB non-small cell lung cancer – continues Prof. Hood -. Notably, the results demonstrated that the pembrolizumab-based perioperative regimen did not affect the opportunity for complete resection, and improvements were observed regardless of whether complete pathologic response was achieved. The key role of the multidisciplinary team therefore emerges for the adequate selection and correct management of patients with lung cancer”.
“These important new findings build on previous studies of pembrolizumab early in the disease in certain types of cancers, including non-small cell lung cancer”, declares Dr. Marjorie GreenVicepresidente senior e Direttore di late-stage oncology, global clinical development, Merck Research Laboratories. “Pembrolizumab demonstrated statistically significant and clinically relevant improvements in event-free survival in patients with stage II, IIIA, or IIIB non-small cell lung cancer treated with the perioperative pembrolizumab regimen compared to chemotherapy and surgery alone. We are working with the FDA and other global authorities to bring this new option to patients as quickly as possible”.
MSD previously announced that, based on these findings, the Food and Drug Administration (FDA) has accepted a new Biologics License Application (sBLA) for pembrolizumab for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by single agent as adjuvant treatment.
MSD has a large clinical development program for lung cancer and is conducting several pivotal studies, with research focused on early stages of the disease and on new combinations. As announced, data on more than 25 different cancer types, from the broad oncology portfolio and experimental pipeline of MSDwill be presented at the annual congress 2023 Of ASCO. The summary of the presentations and posters is available here
The KEYNOTE-671 study and supplemental data
KEYNOTE-671 is a randomized, double-blind, phase 3 study (ClinicalTrials.gov, NCT03425643) evaluating pembrolizumab neoadjuvant plus chemotherapy followed by adjuvant pembrolizumab as single agent versus placebo plus neoadjuvant chemotherapy followed by adjuvant placebo in patients with NSCLC stage II, IIIA or IIIB (T3-4N2) resectable. The two primary endpoints of the study are event-free survival (EFS) and overall survival (OS).
The primary secondary endpoints iThese include complete pathological response (pCR) and major pathological response (mPR). The study enrolled 797 patients who were randomized (1:1) to receive:
– Pembrolizumab plus chemotherapy as neoadjuvant therapy before surgery, followed by pembrolizumab as postoperative adjuvant therapy, or;
– Placebo plus chemotherapy as neoadjuvant therapy before surgery, followed by placebo as postoperative adjuvant therapy.
Adverse events
As previously announced, at the first interim analysis lo studio KEYNOTE-671 met the dual primary endpoint of EFS. At two years, 62.4% of patients treated with the regimen pembrolizumab was alive without having developed events, compared with 40.6% of patients treated with the regimen chemotherapy e placebo. The therapeutic regimen perioperative con pembrolizumab also demonstrated statistically significant and clinically relevant improvements in key secondary endpoints of pCR e mPR. In the study, 18.1% of patients treated with the pembrolizumab plus chemotherapy regimen achieved pCR compared with 4% of patients treated with preoperative chemotherapy (difference: 14.2% (95% CI: 10.1-18.7); p<0.00001).
Treatment-emergent adverse events (BRING) occurred in 96.7% of patients treated with the regimen pembrolizumab (n=396) and in 95% of those treated with the regimen chemotherapy-placebo (n=399); i Grade 3-5 TRAEs they were observed in 44.9% versus 37.3%, respectively. Treatment-related adverse events led to discontinuation of all study treatments in 12.6% of patients receiving the pembrolizumab regimen and 5.3% of those receiving chemotherapy. Treatment-related adverse events led to death in 1.0% of patients receiving the regimen pembrolizumab (n=4) and 0.8% of those who were treated with the regimen chemotherapy-placebo (n=3).
The adverse events (AEs) immune-mediated and infusion reactions of any grade occurred in 25.3% of patients treated with the pembrolizumab regimen and 10.5% of those treated with the chemotherapy-placebo regimen. The immune-mediated adverse events and the reactions toGrade 3-5 infusion they were observed in 5.8% versus 1.5%, respectively.
Lung cancer
It clung cancer it is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 81% of all cases. In Italia 117,800 people live after being diagnosed with lung cancer and, in 2022, there were 43,900 new cases.1
