Search

Purpose: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy., Patients and Methods: Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point., Results: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively., Conclusion: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Purpose: Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma., Methods: Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria., Results: ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded., Conclusion: The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Purpose: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker., Patients and Methods: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported., Results: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts., Conclusion: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Purpose: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases., Methods: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS G12C -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS G12C -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy., Results: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction., Conclusion: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Patients with Kirsten rat sarcoma viral oncogene homolog ( KRAS )-mutated non-small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRAS G12C -mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRAS G12C -mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRAS G12C inhibitor to prospectively demonstrate IC activity in patients with KRAS G12C -mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.

Purpose: Although several agents targeting epidermal growth factor receptor ( EGFR ) exon 20 insertions (ex20ins) have recently been approved by the US Food and Drug Administration, toxicities related to the inhibition of wild-type (WT) EGFR are common with these agents and affect overall tolerability. Zipalertinib (CLN-081, TAS6417) is an oral EGFR tyrosine kinase inhibitor (TKI) with a novel pyrrolopyrimidine scaffold leading to enhanced selectivity for EGFR ex20ins-mutant versus WT EGFR with potent inhibition of cell growth in EGFR ex20ins-positive cell lines., Methods: This phase 1/2a study of zipalertinib enrolled patients with recurrent or metastatic EGFR ex20ins-mutant non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy., Results: Seventy-three patients were treated with zipalertinib at dose levels including 30, 45, 65, 100, and 150 mg orally twice a day. Patients were predominantly female (56%), had a median age of 64 years, and were heavily pretreated (median previous systemic therapies 2, range 1-9). Thirty six percent of patients had received previous non-ex20ins EGFR TKIs and 3/73 (4.1%) patients received previous EGFR ex20ins TKIs. The most frequently reported treatment-related adverse events of any grade included rash (80%), paronychia (32%), diarrhea (30%), and fatigue (21%). No cases of grade 3 or higher drug-related rash or diarrhea were observed at 100 mg twice a day or below. Objective responses occurred across all zipalertinib dose levels tested, with confirmed partial response (PR) observed in 28/73 (38.4%) response-evaluable patients. Confirmed PRs were seen in 16/39 (41%) response-evaluable patients at the dose of 100 mg twice a day., Conclusion: Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR ex20ins-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.

Purpose: Adagrasib, a KRAS G12C inhibitor, has demonstrated clinical activity in patients with KRAS G12C -mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS G12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRAS G12C mutation., Methods: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRAS G12C -mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety., Results: As of October 1, 2022, 64 patients with KRAS G12C -mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients., Conclusion: Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS G12C -mutated solid tumors.

Purpose: Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site., Methods: CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5., Results: In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively., Conclusion: Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy., Competing Interests: Keunchil ParkConsulting or Advisory Role: AstraZeneca, Lilly, Ono Pharmaceutical, Bristol Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, LOXO, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, JNJ, Eisai, Puma BiotechnologySpeakers' Bureau: Boehringer IngelheimResearch Funding: AstraZeneca, MSD Oncology Eric B. HauraConsulting or Advisory Role: Janssen Oncology, Revolution Medicines, Ellipses Pharma, Janssen Research & Development, AmgenResearch Funding: Janssen, Novartis, Revolution Medicines, AstraZeneca, Incyte, Genentech, Spectrum PharmaceuticalsPatents, Royalties, Other Intellectual Property: Protein-Protein Interactions as Biomarkers Patent Natasha LeighlHonoraria: Boehringer IngelheimConsulting or Advisory Role: XcoveryResearch Funding: Novartis, Roche Canada, Guardant Health, MSD, EMD Serono, LillyTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Nektar, GlaxoSmithKline, Roche, AstraZeneca Paul MitchellHonoraria: MSD, AstraZeneca, RocheConsulting or Advisory Role: Roche, Specialised Therapeutics, PUMA Biotechnology, AstraZeneca, Boehringer Ingelheim, BMS, MSD, Amgen Catherine A. ShuConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Genentech/RocheResearch Funding: Celgene, Genentech/Roche, Janssen, MedImmuneTravel, Accommodations, Expenses: Genentech/Roche Nicolas GirardEmployment: AstraZenecaConsulting or Advisory Role: Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Bristol Myers Squibb, MSD, Takeda, GlaxoSmithKline, AbbVie, Pharmamar, Janssen, SanofiResearch Funding: Roche, AstraZeneca, Boehringer IngelheimTravel, Accommodations, Expenses: Roche, AstraZeneca, Bristol Myers Squibb, MSD Oncology Santiago ViteriConsulting or Advisory Role: Roche, Bristol Myers Squibb, Janssen, Takeda, Reddy Pharma Iberia, Merck KGaASpeakers' Bureau: Bristol Myers Squibb, RocheTravel, Accommodations, Expenses: Roche, MSD, Merck KGaA Ji-Youn HanHonoraria: Roche, AstraZeneca, Bristol Myers Squibb, TakedaConsulting or Advisory Role: MSD Oncology, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Takeda, PfizerResearch Funding: Roche, Pfizer, Ono Pharmaceutical, Takeda Chee Khoon LeeHonoraria: AstraZeneca, Pfizer, Amgen, Takeda, Yuhan, Boehringer IngelheimConsulting or Advisory Role: Novartis, Boehringer Ingelheim, Takeda, AstraZeneca, Yuhan, AmgenResearch Funding: AstraZeneca, Roche, Merck KGaA Joshua K. SabariConsulting or Advisory Role: AstraZeneca, Janssen Oncology, Navire, Pfizer, Regeneron, Medscape, Takeda Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, LAM Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Dong-Wan KimResearch Funding: Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Chong Kun Dang Pharmaceutical, BridgeBio Pharma, GlaxoSmithKlineTravel, Accommodations, Expenses: Daiichi Sankyo, Amgen Ki Hyeong LeeConsulting or Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Pfizer, Lilly Rachel E. SanbornHonoraria: AstraZeneca, AmgenConsulting or Advisory Role: Genentech/Roche, AstraZeneca, EMD Serono, Blueprint Medicines, Daiichi Sankyo/Lilly, Janssen Oncology, MacrogenicsResearch Funding: Bristol Myers Squibb, MedImmune, Merck, AstraZenecaTravel, Accommodations, Expenses: AstraZeneca José TrigoConsulting or Advisory Role: Takeda, Boehringer Ingelheim, Bristol Myers Squibb, Merck SeronoSpeakers' Bureau: MSD Oncology, AstraZeneca, Merck Serono, RocheTravel, Accommodations, Expenses: MSD Oncology, Bristol Myers Squibb, AstraZeneca Koichi GotoHonoraria: Guardant Health, Janssen, Daiichi Sankyo Co Ltd, Amgen, Eisai, Kyowa Kirin Co Ltd, Bristol Myers Squibb, AstraZeneca Japan, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Ono Pharmaceutical, Novartis, Lilly Japan, Boehringer Ingelheim, Life Technologies, MSD K.K, Nippon Kayaku, Takeda, OtsukaConsulting or Advisory Role: OtsukaResearch Funding: Medical & Biological Laboratories Co Ltd, Kyowa Kirin Co Ltd, Amgen Astellas BioPharma, Kissei Pharmaceutical, Merck, Merus, NEC Corporation, Spectrum Pharmaceuticals, Shanghai HaiHe Pharmaceutical, MSD K.K, AstraZeneca Japan, Taiho Pharmaceutical, Chugai Pharma, Boehringer Ingelheim, Ono Pharmaceutical, Sumitomo Dainippon Pharma Co Ltd, Takeda, Astellas Pharma, Eisai, Lilly Japan, Pfizer, Bristol Myers Squibb, Ignyta, Life Technologies, Janssen, Xcoo, Loxo, Sysmex, Amgen James Chih-Hsin YangHonoraria: Boehringer Ingelheim, Roche, MSD, AstraZeneca, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, Takeda, Lilly, PfizerConsulting or Advisory Role: Boehringer Ingelheim, Novartis, AstraZeneca, Clovis Oncology, Lilly, MSD Oncology, Merck Serono, Celgene, Bayer, Pfizer, Ono Pharmaceutical, Bristol Myers Squibb, Yuhan, Hansoh, Blueprint Medicines, Daiichi Sankyo, G1 Therapeutics, AbbVie, Takeda Oncology, Amgen, Incyte, Merck Serono, Jenssen, GSK, Takeda, Daiichi Sankyo, NovartisTravel, Accommodations, Expenses: Pfizer Ramaswamy GovindanHonoraria: Genentech/AbbVie, AbbVie, Geneplus-Beijing InstituteConsulting or Advisory Role: Genentech/Roche, AbbVie, AstraZeneca/MedImmune, Pfizer, Bristol Myers Squibb, Nektar, Jounce Therapeutics, F. Hoffmann La Roche AG, Janssen, Amgen, Achilles Therapeutics Joshua M. BaumlConsulting or Advisory Role: Bristol Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron, Inivata, Novartis, Foundation MedicineResearch Funding: Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen, Pfizer, Mirati Therapeutics Pilar GarridoConsulting or Advisory Role: Roche Pharma AG, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Takeda, Lilly, Pfizer, Novartis/Pfizer, Boehringer Ingelheim, AbbVie, Amgen, Bayer, Gebro Pharma, Nordic Group, Boehringer Ingelheim, Janssen Biotech, Janssen Oncology, GlaxoSmithKlineSpeakers' Bureau: Roche Pharma AG, Takeda, AstraZeneca, MSD Oncology, BMS, Pfizer, Novartis, Boehringer Ingelheim, Nordic Group, Janssen, Boehringer Ingelheim, Janssen OncologyTravel, Accommodations, Expenses: AstraZeneca, Roche, Bristol Myers SquibbOther Relationship: Janssen Oncology, Novartis Matthew G. KrebsHonoraria: RocheConsulting or Advisory Role: Roche, Achilles Therapeutics, Janssen, Seattle Genetics, OM Pharma, BayerSpeakers' Bureau: Roche, JanssenResearch Funding: RocheTravel, Accommodations, Expenses: AstraZeneca, BerGenBio, Immutep Karen L. ReckampConsulting or Advisory Role: Amgen, Tesaro, Boehringer Ingelheim, Takeda, AstraZeneca, Seattle Genetics, Calithera Biosciences, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Lilly, Merck KGaAResearch Funding: Bristol Myers Squibb, Pfizer, ARIAD, Xcovery, Adaptimmune, Genentech/Roche, Boehringer Ingelheim, AbbVie, ACEA Biosciences, Loxo, GlaxoSmithKline, Guardant Health, Janssen Oncology, Seattle Genetics, Zeno Pharmaceuticals, Calithera Biosciences, Elevation Oncology, Daiichi Sankyo/Astra Zeneca John XieEmployment: JNJStock and Other Ownership Interests: JNJ Joshua C. CurtinEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/Janssen Nahor Haddish-BerhaneEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Amy RoshakEmployment: Janssen Pharmaceutical Company of Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Dawn MillingtonEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & Johnson/JanssenTravel, Accommodations, Expenses: Janssen Research & Development Patricia LorenziniEmployment: Janssen Pharmaceuticals of Johnson & Johnson Meena ThayuEmployment: Janssen OncologyStock and Other Ownership Interests: Johnson & Johnson/JanssenOther Relationship: Janssen Oncology Roland E. KnoblauchEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & JohnsonTravel, Accommodations, Expenses: Johnson & Johnson Byoung Chul ChoLeadership: Gencurix Inc, Interpark Bio Convergence CorpStock and Other Ownership Interests: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence CorpConsulting or Advisory Role: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol Myers Squibb, Yuhan, Pfizer, Janssen, Takeda, MSD, Ono Pharmaceutical, Eli Lilly, Medpacto, Blueprint Medicines, KANAPH Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec IncResearch Funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence CorpPatents, Royalties, Other Intellectual Property: Champions OncologyOther Relationship: DAAN BiotherapeuticsNo other potential conflicts of interest were reported.

Purpose: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma., Methods: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers., Results: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response., Conclusion: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed., Competing Interests: Adi DiabHonoraria: Array BioPharmaConsulting or Advisory Role: Nektar, CureVac, Celgene, IderaResearch Funding: Nektar, Idera, Celgene, Pfizer, Merck, ApexigenTravel, Accommodations, Expenses: Nektar Scott S. TykodiConsulting or Advisory Role: Merck, Intellisphere LLC, Natera, Bristol Myers Squibb, ExelixisResearch Funding: Genentech, Bristol Myers Squibb, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen GroupPatents, Royalties, Other Intellectual Property: Patent pending Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Amgen, Viralytics, Nektar, Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Sekwon JangConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, Novartis, Sanofi, Sun Biopharma, Genentech Ewa KalinkaHonoraria: Bristol Myers Squibb, MSD, AstraZeneca, Regeneron, Nektar, RocheConsulting or Advisory Role: Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, RocheResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Nektar, AstraZeneca, RocheTravel, Accommodations, Expenses: Roche Igor PuzanovStock and Other Ownership Interests: CelldexConsulting or Advisory Role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Daniel C. ChoConsulting or Advisory Role: Nektar, Pfizer, Werewolf TherapeuticsExpert Testimony: Genentech, Abbott/AbbVie Shanhong GuanEmployment: Nektar TherapeuticsStock and Other Ownership Interests: Nektar Therapeutics Erika PuenteEmployment: NektarStock and Other Ownership Interests: Nektar Tuan NguyenEmployment: Nektar, Theravance TherapeuticsStock and Other Ownership Interests: Nektar, Theravance Ute HochOther Relationship: Nektar Sue L. CurrieEmployment: NektarStock and Other Ownership Interests: Nektar Wei LinEmployment: Erasca Inc, NektarLeadership: Erasca IncStock and Other Ownership Interests: Nektar, Erasca IncTravel, Accommodations, Expenses: Nektar, Erasca Inc Mary A. TagliaferriEmployment: NektarLeadership: Nektar, ENZO BiochemStock and Other Ownership Interests: NektarPatents, Royalties, Other Intellectual Property: US 10576121Travel, Accommodations, Expenses: Nektar Jonathan ZalevskyEmployment: NektarLeadership: NektarStock and Other Ownership Interests: NektarTravel, Accommodations, Expenses: Nektar Mario SznolStock and Other Ownership Interests: Amphivena, Intensity Therapeutics, Adaptive Biotechnologies, Actym Therapeutics, Torque, Nextcure, EvolveImmune Therapeutics, Johnson & Johnson/Janssen, GlaxoSmithKlineConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Nektar, Lilly, Adaptimmune, Seattle Genetics, Pierre Fabre, Molecular Partners, AbbVie, Pieris Pharmaceuticals, Innate Pharma, Immunocore, Genocea Biosciences, Anaeropharma, Zelluna, Boston Pharmaceuticals, Alligator Bioscience, Servier, Dragonfly Therapeutics, Verastem, Boehringer Ingelheim, Agenus, Numab, BioNTech AG, Genentech/Roche, Gilead Sciences, Jazz Pharmaceuticals, Targovax, Sapience Therapeutics, Pfizer, Tessa Therapeutics, OncoSec, Trillium Therapeutics, StCube, Simcha, ITeos TherapeuticsOther Relationship: Haymarket Media, Physicians' Education Resource, DAVAOncology, CEC Oncology Michael E. HurwitzEmployment: Pfizer, Gamida Cell, ArvinasConsulting or Advisory Role: Nektar, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, ExelixisResearch Funding: Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, Achilles TherapeuticsNo other potential conflicts of interest were reported.

Purpose: Gene rearrangements involving NTRK1/2/3 can generate fusion oncoproteins containing the kinase domains of TRKA/B/C, respectively. These fusions are rare in non-small cell lung cancer (NSCLC), with frequency previously estimated to be <1%. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion-positive NSCLCs are not well characterized., Methods: We compiled a database of NSCLC cases harboring NTRK fusions. We characterized the clinical, molecular, and histologic features of these cases with central review of histology., Results: We identified 11 NSCLC cases harboring NTRK gene fusions verified by next-generation sequencing (NGS) and with available clinical and pathologic data, forming the study cohort. Fusions involved NTRK1 (7 cases) and NTRK3 (4 cases), with 5 and 2 distinct fusion partners, respectively. Cohort patients were 55% male, with a median age at diagnosis of 47.6 years (range 25.3-86.0) and a median pack year history of 0 (range 0-58). 73% of patients had metastatic disease at diagnosis. No concurrent alterations in KRAS , EGFR , ALK , ROS1 , or other known oncogenic drivers were identified. Nine cases were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features; one was squamous cell carcinoma; and one was neuroendocrine carcinoma. By collating data on 4872 consecutively screened NSCLC cases from unique patients, we estimate a frequency of NTRK fusions in NSCLC of 0.23% (95% CI 0.11-0.40)., Conclusion: NTRK fusions occur in NSCLCs across genders, ages, smoking histories, and histologies. Given the potent clinical activity of TRK inhibitors, we advocate that all NSCLCs be screened for NTRK fusions using a multiplexed NGS-based fusion assay., Competing Interests: Relevant conflicts of interest: AFF has received consultant fees from AbbVie, PharmaMar, Loxo Oncology; research funding (to institution) from Loxo Oncology, Ignyta, AstraZeneca, AbbVie, Merck, Bristol Myers-Squibb, Novartis. RCD has received consultant/advisory board fees from Ariad, Takeda, AstraZeneca, Spectrum, and Ignyta; licensing fees from Abbott Molecular and Ignyta; stock ownership in Rain Therapeutics. VWZ has received honoraria from AstraZeneca, Roche/Genentech, Takeda, and Biocept, and consultant fees from TP Therapeutics. DLA has received consultant fees from Bristol-Myers Squibb and AbbVie LPL has equity interest and royalties from exclusive license of AMP technology to ArcherDx and has received consultant fees from ArcherDx AJI has received consulting fees for Debiopharm Group, Constellation Pharmaceuticals, Chugai Pharmaceutical, and Roche, research Funding from Blueprint Medicines, and has equity interest and royalties from exclusive license of AMP technology to ArcherDx. SHIO has received consultant/advisory board fees from ARIAD/Takeda, Pfizer, Genentech/Roche, Astra Zeneca, Novartis, Ignyta, Foundation Medicine Inc, member of the speaker bureau of Genentech/Roche, AstraZeneca, ARIAD/Takeda, and Merck; a member of the scientific advisory board of TP Therapeutics Inc and stock ownership in TP Therapeutics Inc. ATS has received consultant fees from Pfizer, Novartis, Ariad/Takeda, Genentech/Roche, Ignyta, Loxo Oncology, Blueprint medicines, KSQ therapeutics, Natera. MMK has received consultant fees from Merrimack Pharmaceuticals and H3 Biomedicine. AD has received consultant/advisory board fees from Ignyta, Loxo Oncology, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad. MST, SK, AIS, TAB, EBH, MEA, RB, NKH, JKL have no relevant disclosures.

Purpose: Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort., Patients and Methods: Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment., Results: One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%)., Conclusion: Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.