Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study.

Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations. Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed. Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations. Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

Small-molecule targeted therapies induce dependence on DNA double-strand break repair in residual tumor cells.

Residual cancer cells that survive drug treatments with targeted therapies act as a reservoir from which eventual resistant disease emerges. Although there is great interest in therapeutically targeting residual cells, efforts are hampered by our limited knowledge of the vulnerabilities existing in this cell state. Here, we report that diverse oncogene-targeted therapies, including inhibitors of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and BRAF, induce DNA double-strand breaks and, consequently, ataxia-telangiectasia mutated (ATM)-dependent DNA repair in oncogene-matched residual tumor cells. This DNA damage response, observed in cell lines, mouse xenograft models, and human patients, is driven by a pathway involving the activation of caspases 3 and 7 and the downstream caspase-activated deoxyribonuclease (CAD). CAD is, in turn, activated through caspase-mediated degradation of its endogenous inhibitor, ICAD. In models of EGFR mutant non-small cell lung cancer (NSCLC), tumor cells that survive treatment with small-molecule EGFR-targeted therapies are thus synthetically dependent on ATM, and combined treatment with an ATM kinase inhibitor eradicates these cells in vivo. This led to more penetrant and durable responses in EGFR mutant NSCLC mouse xenograft models, including those derived from both established cell lines and patient tumors. Last, we found that rare patients with EGFR mutant NSCLC harboring co-occurring, loss-of-function mutations in ATM exhibit extended progression-free survival on first generation EGFR inhibitor therapy relative to patients with EGFR mutant NSCLC lacking deleterious ATM mutations. Together, these findings establish a rationale for the mechanism-based integration of ATM inhibitors alongside existing targeted therapies.

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

NTRK1 Fusions identified by non-invasive plasma next-generation sequencing (NGS) across 9 cancer types.

BACKGROUND: Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. METHODS: We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. RESULTS: NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. CONCLUSION: Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation.

INTRODUCTION: Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. METHODS: Data were retrospectively collected from three academic institutions. Two treatment groups (CNS-penetrant TKI alone versus TKI + CNS radiation therapy) were compared for both EGFR- and ALK-positive cohorts. Outcome variables included time to progression, time to intracranial progression, and time to treatment failure, measured from the date of initiation of CNS-penetrant TKI therapy. RESULTS: A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial progression (14.8 versus 20.5 mo, p = 0.51 [EGFR] and 18.1 versus 21.8 mo, p = 0.65 [ALK]), or time to treatment failure (13.8 versus 8.6 mo, p = 0.26 [EGFR] and 13.5 versus 23.2 mo, p = 0.95 [ALK]). CONCLUSIONS: These results provide preliminary evidence that intracranial activity of CNS-penetrant TKIs may enable local radiation to be deferred in appropriately selected patients without negatively affecting progression.

Patient-Reported Outcomes with Selpercatinib Treatment Among Patients with RET-Mutant Medullary Thyroid Cancer in the Phase I/II LIBRETTO-001 Trial.

BACKGROUND: Medullary thyroid cancer (MTC) standard of care includes multikinase inhibitors (MKIs), which can exacerbate disease-related diarrhea, primarily because of non-RET kinase inhibition. We report diarrhea and other patient-reported outcomes (PROs) with selpercatinib, a highly selective RET inhibitor, among patients with RET-mutant MTC in the ongoing, phase I/II LIBRETTO-001 trial. MATERIALS AND METHODS: Instrument completion time points were baseline (cycle 1, day 1) and approximately every other 28-day cycle until cycle 13 (every 12 weeks thereafter) for the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, and baseline, weekly during cycle 1, and day 1 of every cycle for the modified Systemic Therapy-Induced Diarrhea Assessment Tool (mSTIDAT). A ≥10-point change from baseline in domain score was considered clinically meaningful. PROs were summarized through cycle 13 in all patients and by subgroups with or without prior exposure to MKIs vandetanib and/or cabozantinib (V/C). RESULTS: Among the overall MTC population (n = 226), 88 (39%) and 124 (55%) patients comprised the V/C-naïve and previous V/C subgroups, respectively. Compliance was >85% for both instruments at each time point. Most patients maintained/improved in all health-related quality of life (HRQoL) subscales throughout treatment. Improvements in diarrhea were clinically meaningful in 43.5% of patients overall and in 36.8% and 51.3% of V/C-naïve and previous V/C subgroups, respectively. At baseline, 80.4% of all patients reported diarrhea on mSTIDAT. The percentage of patients who reported diarrhea was reduced to less than half of all patients (range: 33.3%-48.3%) after cycle 2. CONCLUSION: These interim results demonstrate that patients with RET-mutant MTC improved/remained stable on all domains of HRQoL during treatment with selpercatinib. Future analyses will be conducted as the data mature.

Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.

BACKGROUND: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors. We report interim patient-reported outcomes in patients with RET fusion-positive non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) version 3.0 at baseline (cycle 1, day 1), approximately every other 28-day cycle until cycle 13, and every 12 weeks thereafter. Data were evaluated through cycle 13 as few patients had reached later time points. A change of ≥10 points from baseline in domain scores was considered clinically meaningful. RESULTS: Among 253 selpercatinib-treated patients, 239 were categorized into subgroups by prior therapy: treatment-naïve (n = 39), one prior line of therapy (n = 64), or two or more prior lines of therapy (n = 136). The QLQ-C30 was completed by >85% of patients at each time point. Most patients overall and in each subgroup maintained or improved in all health-related quality of life (HRQoL) domains during treatment. The percentage of patients who experienced clinically meaningful improvements ranged from 61.1% to 66.7% for global health status, 33.3% to 61.1% for dyspnea, and 46.2% to 63.0% for pain. The 61.1% of patients with improved dyspnea had two or more prior lines of therapy; median time to first improvement was 3.4 months. At the first postbaseline evaluation (cycle 3), 45.9% of all patients reported a ≥10-point reduction in pain. CONCLUSION: In this interim analysis, the majority of patients with RET fusion-positive NSCLC remained stable or improved on all QLQ-C30 subscales at each study visit, demonstrating favorable HRQoL as measured by the QLQ-C30 during treatment with selpercatinib.

Therapeutic Advances in the Management of Patients with Advanced RET Fusion-Positive Non-Small Cell Lung Cancer.

OPINION STATEMENT: Screening for activating driver gene alterations at the time of diagnosis is the standard of care for advanced non-small cell lung cancer (NSCLC). Activating RET fusions are identified in approximately 1-2% of NSCLCs and have emerged as a targetable driver alteration. Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy. As with use of TKIs in other oncogene-addicted NSCLCs, development of acquired resistance is pervasive and should be specifically delineated through use of repeat tissue biopsy with genetic profiling at the time of disease progression. If an actionable resistance mechanism emerges for which there is a candidate targeted therapy, combination inhibition should be considered. Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects. Single-agent immunotherapy has minimal activity in RET fusion-positive NSCLC. The role of combination chemotherapy and immunotherapy requires further study but may be considered, particularly in the presence of an activating KRAS alteration. While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

PURPOSE: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non-small cell lung cancers (NSCLC). PATIENTS AND METHODS: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed. RESULTS: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population. CONCLUSIONS: Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.

Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer.

PURPOSE: MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor (EGFR)-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance. METHODS: A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination. RESULTS: The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%. CONCLUSION: Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

A tyrosine kinase inhibitor-induced interferon response positively associates with clinical response in EGFR-mutant lung cancer.

Tyrosine kinase inhibitors (TKIs) targeting EGFR-mutant lung cancers promote a range of tumor regression responses to yield variable residual disease, a likely incubator for acquired resistance. Herein, rapid transcriptional responses induced by TKIs early in treatment that associate with the range of patient responses were explored. RNAseq was performed on EGFR mutant cell lines treated in vitro with osimertinib and on tumor biopsies of eight EGFR mutant lung cancer patients before and after 2 weeks of TKI treatment. Data were evaluated for gene expression programs altered upon TKI treatment. Chemokine and cytokine expression were measured by ELISA and quantitative RT-PCR. IκB Kinase (IKK) and JAK-STAT pathway dependence was tested with pharmacologic and molecular inhibitors. Tumor sections were stained for the T-cell marker CD3. Osimertinib stimulated dynamic, yet wide-ranging interferon (IFN) program regulation in EGFR mutant cell lines. IL6 and CXCL10 induction varied markedly among the EGFR mutant cell lines and was sensitive to IKK and JAK-STAT inhibitors. Analysis of matched patient biopsy pairs revealed marked, yet varied enrichment of IFN transcriptional programs, effector immune cell signatures and T-cell content in treated tumors that positively correlated with time to progression in the patients. EGFR-specific TKIs induce wide-ranging IFN response program activation originating within the cancer cell. The strong association of IFN program induction and duration of clinical response indicates that the TKI-induced IFN program instructs variable recruitment and participation of immune cells in the overall therapeutic response.

Durvalumab for Stage III EGFR-Mutated NSCLC After Definitive Chemoradiotherapy.

INTRODUCTION: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown. METHODS: We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab. RESULTS: Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib. CONCLUSIONS: In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment.

Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non-small-cell lung cancers (NSCLCs). In patients with RET fusion-positive NSCLC, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with advanced RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated separately in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response) as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 105 consecutively enrolled patients with RET fusion-positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event. CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion-positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Tumor evolution in epidermal growth factor receptor mutated non-small cell lung cancer.

As the incidence of cancer increases worldwide there is an unmet need to understand cancer evolution to improve patient outcomes. Our growing knowledge of cancer cells' clonal expansion, heterogeneity, adaptation, and relationships within the tumor immune compartment and with the tumor microenvironment has made clear that cancer is a disease that benefits from heterogeneity and evolution. This review outlines recent knowledge of non-small cell lung cancer (NSCLC) pathogenesis and tumor progression from an evolutionary standpoint, focused on the role of oncogenic driver mutations as epidermal growth factor receptor (EGFR). Understanding lung cancer evolution during tumor development, growth, and under treatment pressures is crucial to improve therapeutic interventions and patient outcomes.

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

INTRODUCTION: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. METHODS: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines. RESULTS: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. CONCLUSIONS: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

Role of MPR as an Early Signal for Efficacy in Neoadjuvant Studies.

Overall survival and disease-free survival have been the gold standard primary endpoints for neoadjuvant clinical trials. Major pathologic response is a clinically proven surrogate of efficacy and when used as the primary endpoint, can allow for more efficient evaluation of drugs in the neoadjuvant setting.See related article by Cascone et al., p. 3525.