Safety and efficacy of pralsetinib in RET fusion–positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial

RET inhibition; Pralsetinib; Targeted therapyInhibición de RET; Pralsetinib; Terapia dirigidaInhibició de RET; Pralsetinib; Teràpia dirigidaBackground RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study. Patients and methods ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety. Results Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs. Conclusions Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.This work was supported by Blueprint Medicines Corporation and F. Hoffmann-La Roche, Ltd, Switzerland (no grant number)

Clinical Outcomes With Dabrafenib Plus Trametinib in a Clinical Trial Versus Real-World Standard of Care in Patients With BRAF-Mutated Advanced NSCLC

INTRODUCTION: BRAF mutations are rare in patients with NSCLC, and treatment options are limited. Dabrafenib plus trametinib (dab-tram) was approved for BRAF(V600)-mutated advanced NSCLC (aNSCLC), based on results from a phase 2 study (NCT01336634). This retrospective analysis compared the effectiveness of dab-tram, based on previously reported clinical trial data, versus real-world standard of care in patients with BRAF-mutated aNSCLC. METHODS: Real-world cohorts were derived from a deidentified real-world database (2011–2020) and included patients with BRAF-mutated aNSCLC receiving first-line platinum-based chemotherapy (PBC), first-line immune checkpoint inhibitors (ICIs) plus PBC, or second-line ICIs. Weighting by odds was used to estimate the average treatment effect of the treated. RESULTS: For first-line dab-tram versus PBC, the hazard ratio (HR; 95% confidence interval) for death in unweighted and weighted analyses was 0.65 (0.39–1.1) and 0.51 (0.29–0.92; p = 0.03), respectively; unweighted and weighted median overall survival was 17.3 (12.3–40.2) versus 14.5 (9.2–19.6) months and 17.3 (14.6-not reached) versus 9.7 (6.4–19.6) months, respectively. Hazard ratio of death in unweighted and weighted analyses was 0.56 (0.29–1.1) and 0.57 (0.28–1.17), respectively, with first-line dab-tram versus PBC plus ICI, and 0.65 (0.39–1.07) and not reported (Cox proportional-hazards assumption violated), respectively, with second-line dab-tram versus ICI. CONCLUSIONS: In this indirect comparison in patients with BRAF-mutated aNSCLC, the risk of death was lower and median overall survival was longer with first-line dab-tram versus PBC. In analyses of dab-tram versus first-line PBC plus ICI or second-line ICI, sample sizes were small and findings were inconclusive with overlapping confidence intervals. Despite some limitations, the study provides useful data for this rare patient population

Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC:Updated 5-Year Survival Rates and Genomic Analysis

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data. Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety. Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5–78.5) and 16.3 (range: 0.4–80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8–80.1) and 63.9% (46.2–79.2), median progression-free survival (95% CI) was 10.2 (6.9–16.7) and 10.8 (7.0–14.5) months, and median overall survival (95% CI) was 18.2 (14.3–28.6) and 17.3 (12.3–40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation. Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment

Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy

Lung cancer is the leading cause of cancer death in U.S. and represents a major public health burden. Epidemiologic data have suggested that lung cancer in women may possess different biological characteristics compared to men, as evidenced by a higher proportion of never-smokers among women with lung cancer. Emerging data indicate that female hormones such as estrogen and progesterone play a significant role in lung carcinogenesis. It has been reported that estrogen and progesterone receptors are expressed in lung cancer cell lines as well as in patient-derived tumors. Hormone related risk factors such as hormone replacement therapy have been implicated in lung carcinogenesis and several preclinical studies show activity of anti-estrogen therapy in lung cancer. In this review, we summarize the emerging evidence for the role of reproductive hormones in lung cancer and implications for lung cancer therapy

HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies

Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7–27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody–drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC

Durable Response of Leptomeningeal Disease With Osimertinib and Pemetrexed in EGFR-Mutated Metastatic NSCLC: A Case Report

Optimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy