The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC.

Introduction: Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods: Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results: Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions: The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.

Exceptional response to lorlatinib and cabozantinib in ROS1-rearranged NSCLC with acquired F2004V and L2086F resistance.

Patients with ROS1-rearranged NSCLC demonstrate excellent disease control with ROS1-targeted therapy, but acquired resistance is inevitable. Of particular interest is the ROS1 L2086F kinase domain mutation which is refractory to all currently available ROS1 TKIs apart from cabozantinib. We present a case of a patient with metastatic ROS1-rearranged NSCLC with dual ROS1 F2004V and L2086F resistance mutations who radiographically responded to the combination of lorlatinib and cabozantinib in a patient with metastatic NSCLC. Furthermore, the patient experienced exceptional clinical improvement and tolerance with the combined use of lorlatinib and cabozantinib. This case builds the case for cabozantinib as an agent to overcome ROS1 L2086F resistance. It also highlights the efficacy and safety of using combination of ROS1 TKIs to overcome complex resistance patterns.

MET alterations in advanced non-small cell lung cancer.

Targeting the MET pathway in advanced NSCLC has been of particular interest due to its role as both a primary oncogenic driver and secondary oncogenic driver of acquired resistance. Activation of the MET pathway can occur through several mechanisms, which can complicate the diagnostic and treatment approach. Recently, several MET-directed therapies have been developed with promising results. In this narrative review, we summarize the biology and mechanism of MET as a clinically relevant driver mutation, distinct MET alterations including diagnostic challenges, significance in the setting of acquired resistance, and novel treatment strategies in advanced NSCLC.

Sugemalimab, a novel PD-L1 inhibitor for treatment of advanced or metastatic non-small cell lung cancer.

Nearly two-thirds of patients with non-small cell lung cancer (NSCLC) have locally advanced or metastatic disease at the time of diagnosis, and many patients with early-stage disease will eventually experience metastatic recurrence. In the absence of a known driver alteration, treatment of metastatic NSCLC is limited to immunotherapy with or without cytotoxic chemotherapy. For most patients with locally advanced unresectable NSCLC, the standard of care involves concurrent chemoradiation followed by consolidative immunotherapy. Several immune checkpoint inhibitors have been developed and approved for NSCLC in both the metastatic and adjuvant settings. This review will discuss sugemalimab, a novel programmed cell death 1 ligand 1 (PD-L1) inhibitor, for the treatment of advanced NSCLC.

ROS1 Targeted Therapies: Current Status.

PURPOSE OF REVIEW: Molecular drivers are increasingly identified as therapeutic targets for non-small cell lung cancer (NSCLC). This review focuses on the role of ROS1 inhibitors in treating relapsed/metastatic ROS-1 altered (ROS1+) NSCLC. RECENT FINDINGS: Four FDA-approved drugs have significant activity against ROS1+ NSCLC: crizotinib, ciritinib, lorlatinib, and entrectinib. Each drug yields an overall response rates exceeding 60% with ciritinib, lorlatinib, and entrectinib possessing intracranial activity. The drugs have manageable toxicity profiles. ROS1 alterations are rare molecular drivers of NSCLC that can be effectively treated with a variety of ROS1-targetd drugs. New agents are being identified that may treat resistance mutations.

New Persistent Opioid and Benzodiazepine Use After Curative-Intent Treatment in Patients With Breast Cancer.

BACKGROUND: Opioid and benzodiazepine use and abuse is a national healthcare crisis to which patients with cancer are particularly vulnerable. Long-term use and risk factors for opioid and benzodiazepine use in patients with breast cancer is poorly characterized. METHODS: We conducted a retrospective population-based study of patients with breast cancer diagnosed between 2008 and 2015 undergoing curative-intent treatment identified through the SEER-Medicare linked database. Primary outcomes were new persistent opioid use and new persistent benzodiazepine use. Factors associated with new opioid and benzodiazepine use were investigated by univariate and multivariable logistic regression. RESULTS: Among opioid-naïve patients, new opioid use was observed in 22,418 (67.4%). Of this group, 611 (2.7%) developed persistent opioid use at 3 months and 157 (0.7%) at 6 months after treatment. Risk factors for persistent use at 3 and 6 months included stage III disease (odds ratio [OR], 2.16; 95% CI, 1.49-3.12, and OR, 3.48; 95% CI, 1.58-7.67), surgery plus chemotherapy (OR, 1.44; 95% CI, 1.10-1.88, and OR, 2.28; 95% CI, 1.40-3.71), surgery plus chemoradiation therapy (OR, 1.47; 95% CI, 1.10-1.96, and OR, 2.34; 95% CI, 1.38-3.96), and initial tramadol use (OR, 2.66; 95% CI, 2.05-3.46, and OR, 3.12; 95% CI, 1.93-5.04). Among benzodiazepine-naïve patients, new benzodiazepine use was observed in 955 (10.3%), and 111 (11.6%) developed new persistent use at 3 months. Tamoxifen use was statistically significantly associated with new persistent benzodiazepine use at 3 months. CONCLUSIONS: A large percentage of patients receiving curative-intent treatment of breast cancer were prescribed new opioids; however, only a small number developed new persistent opioid use. In contrast, a smaller proportion of patients received a new benzodiazepine prescription; however, new persistent use after completion of treatment was more likely and particularly related to concurrent treatment with tamoxifen.

A teledermatology care management protocol for tracking completion of teledermatology recommendations.

In July 2009 we implemented a 3-year store-and-forward teledermatology project to provide dermatology care to veterans living in rural and underserved areas of the US Pacific Northwest. We also developed a follow-up protocol and tracking system. Information about all completed teledermatology consultations was entered into a database, and major procedures and select medications were tracked. In the first 21 months, 8202 dermatology conditions in 5232 veterans were treated and 3370 major procedures carried out. Ninety-five percent of conditions were associated with no more than two teledermatology consultations, and no condition required more than ten consultations. In total, 1454 conditions were reviewed for clinical pathological correlation, and in 310 (21%) there was a subsequent clinical pathological correlation conference, resulting in a change in final diagnosis for 93 conditions. The follow-up was important in ensuring high quality patient care.