Juullockhart1645

PURPOSE Genomic alterations in DNA damage repair (DDR) genes other than BRCA may confer synthetic lethality with PARP inhibition in metastatic castration-resistant prostate cancer (mCRPC). To test this hypothesis, the phase 2 TRITON2 study of rucaparib included patients with mCRPC and deleterious non-BRCA DDR gene alterations. PATIENTS AND METHODS TRITON2 enrolled patients who had progressed on 1 to 2 lines of next-generation androgen receptor (AR)-directed therapy and 1 taxane-based chemotherapy for mCRPC. Key endpoints were investigator-assessed radiographic response per modified RECIST/PCWG3 and prostate-specific antigen (PSA) response (≥50% decrease from baseline). RESULTS TRITON2 enrolled 78 patients with a non-BRCA DDR gene alteration (ATM [n = 49], CDK12 [n = 15], CHEK2 [n = 12], and other DDR genes [n = 14]). Among patients evaluable for each endpoint, radiographic and PSA responses were observed in a limited number of patients with an alteration in ATM (2/19 [10.5%] and 2/49 [4.1%], respectively), CDK12 (0/10 [0%] and 1/15 [6.7%], respectively), or CHEK2 (1/9 [11.1%] and 2/12 [16.7%], respectively), including no radiographic or PSA responses in 11 patients with confirmed biallelic ATM loss or 11 patients with ATM germline mutations. Responses were observed in patients with alterations in the DDR genes PALB2, FANCA, BRIP1, and RAD51B. Conclusions In this prospective, genomics-driven study of rucaparib in mCRPC, we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2 However, patients with alterations in other DDR-associated genes (eg, PALB2) may benefit from PARP inhibition. Copyright ©2020, American Association for Cancer Research.BACKGROUND Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. METHODS We performed fluorescence in-situ hybridization and/or next-generation sequencing on 207 post-treatment tissue (n=101) or plasma (n=106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed activity of ALK/MET blockade in ALK-positive cell lines and two patients with MET-driven resistance. RESULTS MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation inhibitor in the first-line setting were more likely to develop MET amplification than those who received next-generation ALK inhibitors after crizotinib (p=0.019). Two tumor specimens harbored an ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition re-sensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved responses to ALK/MET combination therapy. CONCLUSIONS Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may select for MET-driven resistance. SB225002 Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET. Copyright ©2020, American Association for Cancer Research.PURPOSE To review key aspects of the design and conduct of early clinical trials (ECT) of immunotherapy agents. DESIGN The Methodology for the Development of Innovative Cancer Therapies (MDICT) Task Force 2019 included experts from academia, non-profit organisations, industry and regulatory agencies. The review focus was on methodology for ECTs testing immune-oncology therapies (IO) used in combination with other IO or chemotherapy. RESULTS Although early successes have been seen, the landscape continues to be very dynamic, and there are ongoing concerns regarding the capacity to test all new drugs and combinations in clinical trials. CONCLUSIONS Optimisation of drug development methodology is required, taking in account early, late and lower grade intolerable toxicities, novel response patters, as well as pharmacodynamic data. Copyright ©2020, American Association for Cancer Research.PURPOSE Patients with recurrent or metastatic neuroendocrine neoplasms (NENs) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat 2nd line metastatic melanoma in China in 2018. EXPERIMENTAL DESIGN The multiple-center phase Ib trial enrolled patients with NENs (Ki-67≥10%) after failures of 1st line therapy to received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), progression free survival and overall survival. RESULTS Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (≥10%) or high tumor mutational burden (TMB) had better ORR than PD-L1 less then 10% (50.0% vs 10.7%, p=0.019) and TMB low patients (75.0% vs 16.1%, p=0.03). 3/8 (37.5%) responders harbored ARID1A mutations while only 1/27 non-responder was mutated (p=0.03). Of note, 1 exceptional responder with TMB-L, MSS and PD-L1 negative had multiple genomic arrangements with high prediction score for neoantigens. CONCLUSIONS Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%) and/or MSI-H might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit. Copyright ©2020, American Association for Cancer Research.