PURPOSE Anaplastic lymphoma kinase (ALK) is an established therapeutic target in non-small cell lung cancer (NSCLC), predominantly identified in adenocarcinomas. However, ALK rearrangements also occur in de novo squamous and adenosquamous NSCLCs and their clinicogenomic features remain poorly defined. METHODS This multi-institutional retrospective analysis included patients with advanced ALK+ NSCLC. Patients with de novo ALK+ squamous and adenosquamous NSCLCs were identified and compared with an ALK+ adenocarcinoma cohort treated with first-line (1L) alectinib. Overall survival (OS), time to progression (TTP), and time to treatment discontinuation (TTD) were analyzed using the Kaplan-Meier methodology. RESULTS Among 177 patients, 29 had ALK+ squamous (n = 17) and adenosquamous (n = 12) NSCLCs and 148 had ALK+ adenocarcinoma treated with 1L alectinib. Among patients receiving 1L alectinib, OS was significantly shorter for patients with adenosquamous (median, 31.0 months [95% CI, 17.0 to not reached {NR}]) and squamous (27.0 months [95% CI, 5.0 to 35.0]) tumors compared with that for patients with adenocarcinoma (median NR; median follow-up 51.2 months; P < .001). TTP was shorter for squamous (median, 8.0 months [95% CI, 2.0 to 12.0]) versus adenocarcinoma (median, 19.0 months [95% CI, 12.6 to 25.0]) cohorts (P < .001), although the adenosquamous cohort had comparable TTP (median, 20.0 months [95% CI, 9.4 to 30.6]) with the adenocarcinoma cohort (P = .70). TTD was significantly shorter for squamous (median, 9.5 months [95% CI, 1.5 to 13.0]) and adenosquamous (median, 20.0 months [95% CI, 3.0 to 24.0]) versus adenocarcinoma cohorts (52.3 months [95% CI, 40.5 to 57.5]; P < .001). Genomic profiling revealed more frequent TP53 (53% v 25%; P = .026), PDGFRA (16% v 0%; P = .009), KIT (11% v 0%; P = .045), PIK3CA (11% v 0%; P = .045), and MYC (11% v 0%; P = .045) coalterations in the squamous/adenosquamous cohort. CONCLUSION ALK+ squamous and adenosquamous NSCLCs are rare, but biologically distinct, with inferior outcomes on 1L ALK TKI, highlighting the need for further research to develop effective treatment strategies.
RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.
PURPOSE:As targeted therapies are associated with improved outcomes in patients with non-small cell lung cancer (NSCLC) with genetic alterations, biomarker testing is recommended to identify actionable alterations (AAs). Here, we report findings on biomarker testing in the subset of patients with metastatic (m)NSCLC from the Molecularly Informed Lung Cancer Treatment in a Community Cancer Network: A Pragmatic Consortium Protocol 2 study. METHODS:In this prospective, noninterventional, observational study, patients 18 years and older with NSCLC (excluding stage IA) were enrolled from 18 community practices in the United States from 2020 to 2022 (ClinicalTrials.gov identifier: NCT05644808). Biomarker testing rates relative to timing of first-line (1L) therapy initiation, testing modalities, AAs, 1L therapies, next-generation sequencing (NGS) characteristics, and survival outcomes were examined. In addition, testing rates were compared with our previous retrospective analysis (Protocol 1). RESULTS:Among 556 patients with mNSCLC, 98.8% received testing for ≥1 biomarker at any time and 79.0% received ≥1 test result before initiating 1L therapy (versus 89.9% and 79.2%, respectively, in Protocol 1 [2018-2020]); 72.8% and 55.6% of patients received NGS testing and NGS results before 1L therapy, respectively (versus 37.0% and 5.0%, respectively, in Protocol 1); 63.5% and 44.1% of patients received guideline-compliant (8-gene) testing and 8-gene test results, respectively, before 1L therapy. Among patients who received biomarker test results before 1L therapy and had an AA (n = 94), 77.7% (n = 73) received 1L-targeted therapy. Survival outcomes trended favorably in these patients. CONCLUSION:Although guideline-compliant (8-gene) and NGS testing rates fall short of recommended guidelines, several improvements in testing rates from Protocol 1 were observed. In addition, almost 80% of patients, who received test results before 1L therapy and had an AA, received 1L targeted therapy. Improved survival outcomes in these patients highlight the importance of effective follow-through from testing to treatment.
Abstract Introduction Immune checkpoint inhibitors (ICI) have become standard of care for renal cell carcinoma (RCC) in the adjuvant, first-line and pre-treated settings. However, treatment patterns and outcomes of patients with RCC that progresses following ICI treatment are not well characterized. Methods A retrospective review of electronic health records from a US community oncology network included patients with metastatic clear cell RCC (mccRCC) that progressed after an initial ICI-containing regimen and received subsequent systemic therapy (index) between 01/01/2018 and 01/31/2023. Patient characteristics and treatment patterns were described. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed using Kaplan-Meier method by line of therapy (LOT) of the first ICI-containing regimen and index regimen class. Results Overall, 299 patients were included (median [IQR] age 68 [60-75] years, 73% male, 85% white, 87% intermediate or poor IMDC risk, median follow-up 11.3 months) with the first ICI-containing regimen initiated in the adjuvant (n = 5, 2%), first-line (n = 203, 68%) or second-line (n = 91, 30%) settings. Vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) monotherapy was the most common index (post-IO) regimen class (62% any VEGFR-TKI, 46% cabozantinib). Median (95% CI) rwPFS and OS were 6.0 (5.4, 6.8) and 14.3 (12.1, 16.4) months, respectively. No differences were observed in rwPFS and OS by LOT of the first ICI-containing regimen (P = 0.763, P = 0.885, respectively) or index regimen class (P = 0.721, P = 0.747, respectively). Conclusion In real-world patients with mccRCC that progressed to the post-ICI setting, VEGFR-TKI monotherapies were the most common post-ICI regimens and differences in clinical outcomes were not observed by LOT of the first ICI-containing regimen or index regimen class. There is high unmet need for novel therapies in the post-ICI setting.
576 Background: Inherited or germline BRCA mutations are found in about 1 in 400 people around the world and carry significant implications for cancer risk, therapeutic and preventive strategies. When somatic BRCA1/2 pathogenic or likely pathogenic variants are detected, guidelines recommend confirmatory germline testing due to implications for targeted treatment, family counseling, and cancer risk management. Nonetheless, evidence suggests that germline testing is underutilized in practice, even among patients meeting testing guidelines. Methods: This retrospective observational cohort study used electronic health record data from 11 practices in The US Oncology Network participating in the Genetic Risk Evaluation and Testing program to examine patterns of germline testing. Patients with somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes in solid tumors identified between 1 November 2021 and 1 November 2023 were included in the study. Patients were followed through 1 April 2024. The timing of germline testing (date of test order) relative to the date of somatic testing result was determined. Results: Among 526 patients identified with somatic BRCA1/2 mutations across 15 solid tumor cancer types, 289 (55%) also had germline testing. For most cancers, germline testing preceded somatic testing. These were generally cancers associated with hereditary BRCA mutation, including breast, ovarian, other gynecological cancers, and prostate cancer. Cancers for which germline testing was observed to be done after the somatic test results included non-small cell lung cancer, bladder, and esophageal cancers. Conclusions: Germline testing for BRCA1/2 is not performed consistently, particularly in cancers not traditionally linked to hereditary syndromes. Overall, almost half of patients with a known somatic BRCA mutation did not receive germline testing. This testing gap represents a missed opportunity for personalized therapy and familial risk assessment. Enhancing awareness and adherence to genetic testing guidelines in community oncology can improve cancer prevention, treatment decision-making, and care equity. Germline testing patterns for select solid tumor types in patients with pathogenic or likely pathogenic variants BRCA1 or BRCA2 mutation on somatic profiling. Overall (N=526) Breast Cancer (n=102) Ovarian Cancer (n=71) Non Small Cell Lung Cancer (n=71) Colon Cancer (n=51) Prostate Cancer (n=35) Bladder Cancer (n=19) Esophageal Cancer (n=18) Patients with a germline test, n (%) 289 (54.94%) 72 (70.59%) 61 (85.92%) 14 (19.72%) 21 (41.18%) 24 (68.57%) 8 (42.11%) 4(22.22%) Median days between germline test order and documented somatic test result* -74 -585 -221 16 -27 -14 19 10
