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684 Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960 . [Table: see text]

BackgroundCabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which might enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960), a multicenter phase 1b study, is evaluating the combination of cabozantinib with atezolizumab in advanced solid tumors; here we present efficacy and safety results in patients with triple negative breast cancer (TNBC), ovarian cancer (OC), and endometrial cancer (EC).MethodsEligible patients had locally advanced or metastatic TNBC, OC, or EC and had radiographically progressed on prior systemic anticancer therapy. One or two lines of prior therapy were permitted. Patients with OC were platinum resistant or refractory. Prior treatment with anti-PD-1 or anti-PD-L1 agents was allowed for patients with TNBC. Patients received cabozantinib, 40 mg PO QD, plus atezolizumab, 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 as assessed by investigator. Other endpoints included safety, duration of response (DOR), progression free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter.ResultsAs of February 19, 2021, 30–32 patients were enrolled in each of the cohorts. 47% of patients with TNBC, 47% with OC, and 40% with EC had received 2 lines of prior therapy. Median follow-up was 18.7 months, 20.8 months, and 19.0 months for the TNBC, OC, and EC cohorts, respectively. Grade 3/4 treatment-related adverse events occurred in 33% of patients with TNBC, 56% with OC, and 37% with EC. One Grade 5 treatment-related adverse event of pulmonary hemorrhage occurred in the TNBC cohort and one of encephalitis occurred in the OC cohort. Cabozantinib plus atezolizumab demonstrated clinical activity in all three tumor cohorts (table 1).Abstract 531 Table 1ConclusionsCabozantinib in combination with atezolizumab demonstrated encouraging clinical activity in patients with previously treated advanced cancers.AcknowledgementsMedical writing support provided by Suvajit Sen, PhD (Exelixis, Inc.)Trial RegistrationNCT03170960Ethics ApprovalYesConsentYes

TPS3176 Background: XL102 is an orally bioavailable, selective, and covalent small-molecule inhibitor of cyclin-dependent kinase 7 (CDK7). CDK7 is a serine/threonine kinase that is overexpressed in multiple tumor types. CDK7 controls cell cycle progression via the phosphorylation of CDKs (1, 2, 4, and 6) and regulates transcription through phosphorylation of RNA polymerase II. XL102 induced cell death in various cancer cell lines and caused tumor regression in multiple human tumor cell line to mouse xenograft tumor models. Here, we present the study design of an ongoing phase 1 trial in pts with advanced solid tumors, including hormone receptor-positive breast cancer (HR+BC), triple-negative breast cancer (TNBC), epithelial ovarian cancer (EOC), and metastatic castration-resistant prostate cancer (mCRPC). Methods: This first-in-human, open-label, phase 1 trial (NCT04726332) consists of a dose-escalation stage and a disease-specific cohort expansion stage. In the dose-escalation stage (modified interval 3+3 design), a maximum tolerated dose and/or recommended dose (MTD/RD) of XL102 will be established (primary endpoint) for use alone (solid tumors) and then for use in combination with standard dose fulvestrant (HR+BC) or abiraterone/prednisone (mCRPC); dose escalation will require ̃36 pts for the single-agent cohort and ̃15 pts for each combination cohort. Pts enrolled in the dose-escalation stage must have an unresectable or metastatic tumor for which available therapies are intolerable, ineffective, or do not exist. Upon determining the MTD/RD for each regimen, the cohort-expansion stage will enroll according to Simon’s Two-Stage Minimax design, assuming a power of 80% and one-sided α of 15%, for single-agent XL102 (HR+BC, TNBC, EOC, and mCRPC) and XL102 in combination therapy (HR+BC and mCRPC); the expansions will enroll ̃36 pts for each single-agent cohort and ̃44 pts for each combination cohort. Pts enrolled in the expansion stage must have measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), adequate organ function, and exposure to prior therapy, with specific therapy requirements based on the disease cohort. The primary endpoint of the expansion stage is objective response rate (ORR) of XL102 alone and in combination therapy as assessed by investigator per RECIST v1.1. Secondary endpoints are safety, tolerability, and pharmacokinetics. Exploratory endpoints include duration of response (DOR) and progression-free survival (PFS) as assessed by the investigator per RECIST v1.1, overall survival, and correlation of tumor and blood biomarkers with response. ORR, DOR, and PFS may also be assessed by blinded independent radiology committee in selected expansion cohorts. The study began enrolling pts in February 2021 and is ongoing. Total enrollment is estimated to be up to 298 pts. Clinical trial information: NCT04726332.

4504 Background: C, a multitargeted receptor tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment that may enhance response to immune checkpoint inhibitors (ICIs). COSMIC-021, a multicenter phase 1b study, is evaluating C + A (anti‒PD-L1 therapy) in various solid tumors (NCT03170960). C + A demonstrated encouraging clinical activity in cohort 2 of COSMIC-021 in patients (pts) with UC previously treated with platinum-containing chemotherapy (chemo) (Pal S et al. ASCO 2020. Abstract 5013). Outcomes of C + A from 3 other UC cohorts (C3, C4, C5) are presented. Methods: Pts with inoperable locally advanced/metastatic UC with transitional cell histology and ECOG PS 0‒1 were eligible. Pts enrolled in C3 and C4 had no prior therapy and were cisplatin-based chemo ineligible (C3) or eligible (C4). C5 enrolled pts with one prior ICI and no prior VEGFR-TKI therapy. Pts received C 40 mg PO QD and A 1200 mg IV Q3W. CT/MRI scans were performed Q6W for first year and Q12W thereafter. The primary endpoint is objective response rate (ORR) per RECIST v1.1 by investigator. Other endpoints: safety, duration of response (DOR), PFS, and OS. Results: Thirty pts each were enrolled in C3 and C4, and 31 in C5. Baseline characteristics for C3, C4, and C5, respectively: median age, 74 y, 66 y, 68 y; male, 67%, 73%, 55%; ECOG PS 1, 63%, 57%, 74%; lung/liver metastasis; 33%/17%, 40%/20%, 58%/23%; ≥3 tumor sites, 30%, 43%, 45%; bladder as primary site, 67%, 70%, 71%. As of Nov 30, 2021, the median follow-up for C3, C4, and C5 was 27.9, 19.1, and 32.9 mo, respectively, with 1, 6, and 1 pts on treatment. C + A demonstrated clinical benefit across all cohorts (Table). Most common treatment-related adverse events (TRAEs) of any grade across C3, C4, and C5, respectively, were diarrhea (43%, 33%, 35%), nausea (27%, 17%, 26%), fatigue (27%, 27%, 48%), and decreased appetite (33%, 27%, 39%); grade 3/4 TRAEs occurred in 63%, 43%, and 45%, and there was no grade 5 TRAE. Conclusions: C + A demonstrated encouraging clinical activity with manageable toxicity in inoperable locally advanced/metastatic UC as first-line systemic therapy in cisplatin-based chemo eligible/ineligible pts and as second- or later line in pts who received prior ICI. Clinical trial information: NCT03170960. [Table: see text]

121 Background: Cabozantinib, a multiple receptor tyrosine kinase inhibitor, promotes an immune-permissive environment which may enhance the activity of immune checkpoint inhibitors. COSMIC-021 (NCT03170960) is evaluating the combination of cabozantinib with atezolizumab, an anti-PD-L1 inhibitor, in patients with advanced solid tumors. Outcomes in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine-containing therapy are presented. Methods: Pts with mCRC and an ECOG PS of 0–1 who progressed during or following systemic chemotherapy including fluoropyrimidine plus oxaliplatin or irinotecan were eligible. Up to 2 prior lines of anti-cancer therapy including EGFR-targeted therapy were allowed. Microsatellite instability high (MSI-H) and/or mismatch repair (MMR)-deficient pts were excluded. Pts received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W. The primary endpoint was objective response rate (ORR) per RECIST 1.1 by investigator. Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). CT/MRI scans were performed Q6W for the first year and Q12W thereafter. Results: 31 pts received cabozantinib plus atezolizumab (median age, 60 y [range 31, 79]; male, 58%; ECOG PS 1, 61%; 2 prior lines of therapy, 71%; prior EGFR inhibitor, 16%; ≥3 tumor sites, 52%; tumors in left colorectum, 71%). Median follow-up was 28.1 mo (range, 24.2, 31.3) as of July 21, 2021. Cabozantinib plus atezolizumab demonstrated clinical activity in pts with mCRC (Table). Patients with wild-type RAS (n = 12) had numerically longer PFS and OS and higher ORR vs those with mutations (n = 19) (Table). Treatment-related adverse events (TRAEs) of any grade occurred in 28 (90%); the most common were diarrhea (52%), fatigue (42%), and nausea (35%). Grade 3-4 TRAEs occurred in 16 (52%); the most common were hypertension (10%), fatigue (6%), and lipase increased (6%); no Grade 5 events were reported. Conclusions: Cabozantinib plus atezolizumab demonstrated encouraging clinical activity with manageable toxicity in pts with previously treated advanced non-MSI-H/MMR-proficient CRC. Clinical trial information: NCT03170960. [Table: see text]