Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Efficacy and safety of utidelone for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer who have failed standard second-line treatment: A phase 2 clinical trial (BG01-1801).

Background: Chemotherapy remains the standard-of-care for many patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC), but acquired resistance presents challenges. The aim of this open-label, multicenter phase 2 clinical trial was to determine the efficacy and safety of utidelone, a novel genetically engineered epothilone analog and microtubule-stabilizing agent, as a third- or later-line treatment for locally advanced or metastatic NSCLC. Methods: Patients who had failed standard second-line treatment (including platinum-containing chemotherapy or targeted therapy) received utidelone (40 mg/m2 via intravenous injection daily, day 1-5) every 21 days. The primary endpoint was the objective response rate (ORR). Secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: From March 12, 2019 to January 18, 2021, 26 pretreated patients with locally advanced or metastatic NSCLC (100% of patients had received prior platinum and 65.4% patients had received prior taxane treatment) were enrolled (80.8% of patients had adenocarcinoma). At baseline, nine (34.6%) patients had received second-line treatment, 10 (38.5%) patients had received third-line treatment, and seven (26.9%) patients had received fourth- or later-line treatment. By the data cut-off date of August 10, 2021, the median follow-up was 7.49 months (range, 1.4-26.7 months). The ORR was 15.4% (95% confidence interval [CI], 4.4%-34.9%) in the intention-to-treat (ITT) cohort (N = 26) and 19.0% (95% CI, 5.4%-41.9%) in the per-protocol (PP) cohort (N = 21). The disease control rate was 69.2% (95% CI, 48.2%-85.7%) and 81.0% (95% CI, 58.1%-94.6%) in the ITT and PP cohorts, respectively. The median DoR was 4.1 months (95% CI, 3.1-5.1 months) in the ITT cohort. The median PFS was 4.37 months (95% CI, 2.50-5.29 months) in the ITT cohort and 4.37 months (95% CI, 2.50-9.76 months) in the PP cohort. The median OS was not reached, and the 12-month OS rate was 69% (95% CI, 45.1%-84.1%). Grade 3/4 treatment-emergent adverse events occurred in 38.5% of patients, and the most common was peripheral neuropathy (23.1%, all Grade 3), which was manageable with dose modifications. Conclusions: In this clinical trial, utidelone showed promising efficacy and had a manageable safety profile. Further clinical studies are warranted to confirm its role in NSCLC treatment. Trial registration: No.NCT03693547; https://classic.clinicaltrials.gov.

Long-lasting control with erlotinib in advanced non-small cell lung cancer (NSCLC). / Erlotinib no controlo tumoral prolongado do carcinoma do pulmão de não pequenas células avançado (CPNPC).

The authors present a clinical case of a caucasian male patient, 59 years-old, non-smoker, with an advanced non-small cell lung carcinoma (NSCLC), with 3 years of follow-up, received erlotinib for 18 months, after failure of more than one chemotherapy schedule, without evidence of oncologic progression. The patient evidences excellent quality of life, controlled sintomatology, recovery of the capacity of tolerance to the effort and it maintains his professional activities. The treatment with erlotinib has been well tolerated, although exhibiting grade 1 cutaneous toxicity. Rev Port Pneumol 2008; XIV (Supl 3): S9-S15.