PURPOSE:Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations. PATIENTS AND METHODS:In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). RESULTS:Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities. CONCLUSION:Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.

PURPOSE:Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions. METHODS:Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS). RESULTS:Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals. CONCLUSION:This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

TPS3187 Background: Topoisomerase 1 (TOP1) inhibitors effectively kill a diverse range of tumor cells but have limited clinical utility due to severe off-target toxicities. Targeted therapeutic strategies have been developed to circumvent these limitations, although there remains an unmet need for antigen-agnostic tumor targeting. CBX-12 is a peptide conjugate that uses a novel pH-low insertion peptide (pHLIP) linked to TOP1 inhibitor exatecan to selectively target the low-pH tumor microenvironment and deliver the payload intracellularly. Recently published results of the first-in-human study of CBX-12 (NCT04902872) demonstrated single-agent activity in 4 patients, including a complete response in a patient with ovarian cancer. The predominant reported toxicity was myelosuppression with the most common grade 3/4 treatment-related adverse event being neutropenia in 28.6% of patients. Here we report our new pharmacodynamic (PD) biomarker-driven pilot study of CBX-12 in patients with advanced solid tumors. The primary objective of this study is to assess the effects of CBX-12 on biomarkers of DNA damage response (DDR) in biopsy specimen to establish the degree and duration of CBX-12 target engagement. The secondary objectives are to assess the effects of CBX-12 on TOP1 molecular response; determine any association between tumor TOP1 levels, DDR modulation, and plasma exatecan levels; evaluate the effect of CBX-12 on CD8+ T cell infiltration and activation in the tumor microenvironment; assess the objective response rate using RECIST v 1.1; and assess safety and tolerability of CBX-12. The planned PD endpoints aim to confirm and further enrich knowledge of the mechanisms underlying response or resistance to CBX-12 treatment, and guide future complementary treatment combination strategies. The study results may also help identify future patient populations likely to benefit from CBX-12 treatment. Methods: CBX-12 will be administered intravenously once weekly in 28-day cycles at the recommended phase 2 dose. Mandatory biopsies will be collected at baseline, 24-36 hours post first dose, and on cycle 3 day 1 to assess both short- and long-term effects of CBX-12 on the tumor. Mandatory research blood samples will be collected at specified timepoints for pharmacokinetic, circulating tumor cell, and cell-free DNA analyses. Clinical trial information: NCT05691517 .

3 Background: CaboNivo and CaboNivoIpi showed promising efficacy and safety in a dose-escalation phase I study in patients (pts) with metastatic genitourinary (mGU) tumors. We now report the final results from a pooled analysis of the phase I dose-finding and 7 subsequent expansion cohorts. Methods: Pts with mGU tumors in the phase I cohort received 8 escalating doses of CaboNivo or CaboNivoIpi. In the 7 expansion cohorts, pts received the recommended phase II dose for CaboNivo (cabo 40mg qd + nivo 3mg/kg q2wks in 28-day cycles) and for CaboNivoIpi (CaboNivo same dose + ipi 1mg/kg q3wks in 21-day cycles x 4 cycles followed by CaboNivo). The CaboNivo expansion cohorts included pts with urothelial carcinoma (UC); clear cell renal cell carcinoma (RCC), bladder adenocarcinoma (BlaAdeno), and other rare mGU tumors. The CaboNivoIpi expansion cohorts included, UC, RCC, and penile carcinoma (penile). The objectives of the study were to determine the clinical activity, safety and tolerability of both combinations. A secondary objective was the detection of EpCAM+ circulating tumor cells (CTCs). Biomarker correlatives of plasma VEGFA/VEGFR2, PIGF, and inflammatory cytokines will be presented. Results: A total of 120 pts (median age 59; range 20-82) were enrolled: 54 in the phase I and 66 in the dose expansion cohorts. 64 pts received CaboNivo and 56 CaboNivoIpi. Median follow-up was 40.4 months (range 2.2-62.2 months). The ORR for 108 evaluable pts was 38% (95% CI: 28.8-47.8%) with 12 complete responses (CRs) (11.1%) and 29 partial responses (26.9%). The ORRs for the following mGU tumors were: UC 42.4% (n=33) with CR=21.2%; RCC 62.5% (n=16); prostate cancer 11.1% (n=9); germ cell tumor no responses (n=6); BlaAdeno 20% (n=15); penile 44.4% (n=9); bladder squamous 85.7 (n=7); renal medullary 50% (n=2); bladder small cell 33.1 (n=3). The median overall survival for the entire population was 15.9 months (95% CI: 11.6-23.9); 24.9 months (95% CI: 11.8-41.6) for pts with UC (n=39); and 38.6 months (95% CI: 19.4-not estimable) for RCC (n=16). Median duration of response was 22.8 months (95% CI: 18.3-40.1 months) for all pts, 32.1 months [95% CI: 20.3-NE)] for the UC pts and 20.1 months (95% CI: 5.8-NE) for RCC pts. Grade 3 or 4 treatment related adverse events (AEs) occurred in 84% and 80% of pts treated with CaboNivo and CaboNivoIpi pts respectively, and included hypophosphatemia (25% and 16%), lipase elevation (20% and 20%), fatigue (20% and 18%), ALT elevation (5% and 14%), AST elevation (9% and 11%), diarrhea (9% and 11%), and thromboembolic event (11% and 4%). One pt had Grade 5 pneumonitis on CaboNivoIpi. Baseline EpCAM+ CTC count of < 5 vs. > 5, was associated with longer median OS (24.3 vs. 12.3 months p=0.037). Conclusions: CaboNivo and CaboNivoIpi demonstrated promising clinical activity and manageable safety in many mGU histologies including rare tumors. Clinical trial information: NCT02496208.

AbstractPurpose: NCI–MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. Patients and Methods: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31–80), and half of all patients had ≥3 prior therapies (range, 1–11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%–28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0–4.1), and median OS 9.4 months (90% CI 5.0–18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. Conclusions: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.

Supplementary Figures S1-S2; Supplementary Tables S1-S3.

Supplementary Tables 1-3. Supplemental Table 1. Plasma pharmacokinetics of DMS612 metabolites. Supplemental Table 2. Pharmacodynamic assessment of !-H2AX detection in PBMCs. Mean values for !-H2AX foci per cell with DMS612 doses of 1.5, 3, 5, 7, 9 and 12 mg/m2 at the indicated time in hours (h). Supplemental Table 3. Pharmacodynamic assessment of !-H2AX detection in hair follicles. Mean values for cell with more than 4 !-H2AX foci per cell in plucked scalp hairs with DMS612 doses of 1.5, 3 and 9 mg/m2 at the indicated time in hours (h). Supplemental Figure 1. Pharmacokinetics of DMS612 Metabolites.

Supplementary Figure 6: (A) PFS and (B) OS of patients based on presence of concurrent mutation in PI3K-AKT pathway.

1) Eligible mutations/fusions, 2) identified mutations/fusions, 3) Treatment-related toxicities, 4) Number of treatment cycles and reasons for discontinuation

Supplementary Tables 1-3. Supplemental Table 1. Plasma pharmacokinetics of DMS612 metabolites. Supplemental Table 2. Pharmacodynamic assessment of !-H2AX detection in PBMCs. Mean values for !-H2AX foci per cell with DMS612 doses of 1.5, 3, 5, 7, 9 and 12 mg/m2 at the indicated time in hours (h). Supplemental Table 3. Pharmacodynamic assessment of !-H2AX detection in hair follicles. Mean values for cell with more than 4 !-H2AX foci per cell in plucked scalp hairs with DMS612 doses of 1.5, 3 and 9 mg/m2 at the indicated time in hours (h).

Supplementary Figure 2: "Swimmer's plot as in Figure 2B also demonstrating mutation locations in individual patients, showing treatment duration for all 32 evaluable patients and their occurrence of response (*), disease progression (+) and death (#)

TPS639 Background: The combination of the MEK inhibitor, Cobimetinib, with the PD-L1 antagonist, Atezolizumab, significantly improved progression-free survival (PFS) compared to Atezolizumab monotherapy in patients with advanced biliary tract cancer (BTC) following first-line chemotherapy (NCT03201458). Interrogation of biospecimens from this trial and parallel pre-clinical work showed that the addition of MEK inhibition enhanced tumor immunogenicity but simultaneously had detrimental effects on host T-cell activation and priming. The addition of immune co-stimulants rescues T-cell function in the setting of systemic MEK inhibition in vivo. Unlike other immune co-stimulatory markers, CD27 is one of the most positively differentially expressed receptors in the TME post-treatment with combined MEK inhibition and PD-L1 blockade. We hypothesize that addition of CD27 immune agonism to the combination of PD-L1 and MEK inhibition can improve immunotherapy outcomes in patients with BTC. Methods: We are conducting an open-label, randomized ph 2 trial evaluating a PD-L1 inhibitor (atezolizumab) in combination with a CD27 immune agonist (CDX-1127 [Varlilumab]) with or without addition of a MEK inhibitor (Cobimetinib) in patients with unresectable, previously treated, BTC. Key inclusion criteria include: adults with pathologically-confirmed BTC, s/p 1-2 lines of systemic therapy (including any FDA-approved targeted therapies) in the metastatic setting, measurable disease, ECOG performance status ≤1, adequate baseline organ and marrow function. Patients who have received gem-cis-durvalumab, and/or prior FGFR2/IDH1 targeted therapy are eligible for enrollment. The study is planned for 64 evaluable subjects (32 subjects per treatment arm) randomized in a 1:1 ratio, stratified by site of BTC location, to either Atezolizumab + CDX-1127 or Atezolizumab + CDX-1127 + Cobimetinib. During the 28-day treatment cycles, all patients receive Atezolizumab (840mg flat dose) and CDX-1127 (3mg/kg) infusions on D1 and D15. For those randomized to the triplet regimen arm, the additional Cobimetinib will be dosed orally at 60mg daily on days 1-21. Overall response rate and PFS are co-primary endpoints. A clinically meaningful improvement in ORR warranting further study is 20%. The primary correlative outcome is treatment-related changes in CD8+ infiltrating T cells. After an initial safety lead-in, a planned interim efficacy analysis will take place following enrollment of the first 18 patients in each treatment arm. Currently, 14 participants (n=6 [triplet arm], n=8 [doublet arm]), have been enrolled & treated on protocol. This study is sponsored by the NCI Cancer Therapy Evaluation Program and is open nationally at designated NCI Experimental Therapeutics Clinical Trials Network sites. Clinical trial information: NCT04941287 .

Supplemental Table S1. 48 genes included in the TruSeq Amplicon Cancer Panel (TSACP, Illumina). Panel includes 212 amplicons covering a total genomic region 35.84 kb.

Combinations of targeted chemotherapeutics can provide new options to treat cancer; however, the preclinical discovery of potentially beneficial therapeutic combinations is challenging given the heterogeneity of cancer. Complex tumor spheroids, consisting of combined patient-derived tumor cells and stromal cells (human umbilical vein endothelial cells and mesenchymal stem cells) serve as a physiologically relevant in vitro model of solid tumors that is amenable to high-throughput screening. In this study, ten anticancer agents with a range of targets including MEK, mTOR, RAF, PI3K, and the proteasome, were tested both alone and in combination with the ubiquitin activating enzyme inhibitor, TAK-243, or the pan-Akt inhibitor, ipatasertib. All anticancer agents were tested over a 3 log range of concentrations up to their clinical Cmax value, if known. The activities of single agents and combinations were evaluated in complex spheroids grown from patient-derived tumor cells from the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov), including ten colon and six pancreatic adenocarcinoma and four melanoma cell lines. The spheroids were allowed to grow for three days prior to the addition of anticancer agents and cell viability was measured seven days later using CellTiter-Glo 3D. TAK-243 was cytotoxic against all six pancreatic adenocarcinoma spheroids and all four melanoma spheroids, as well as several colon adenocarcinoma spheroids. The single agent BRAF V600E-selective inhibitor, vemurafenib, showed selective cytotoxicity against melanoma spheroids with the BRAF V600E/K variant. TAK-243 in combination with vemurafenib produced greater than additive cytotoxicity in most complex spheroid models. The overall cytotoxicity of the TAK-243 and vemurafenib combination was similar in melanoma spheroids containing WT BRAF and the BRAF V600E/K variant. The activity of vemurafenib and the BRAF V600E-selective inhibitor dabrafenib were not equivalent in this combination screen and greater than additive cytotoxicity was observed more frequently when TAK-243 was combined with vemurafenib than with dabrafenib. The combination of ipatasertib and vemurafenib had additive and greater than additive cytotoxicity in more than half of the complex spheroid models tested. Other notable agents combined with ipatasertib included the MEK inhibitors trametinib and selumetinib, both of which produced greater than additive cytotoxicity in spheroids derived from pancreatic cancer metastases. These results might inform the prioritization of drug combinations for further investigation by in vivo studies. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I. Citation Format: Nathan P. Coussens, John J. Wright, Ralph E. Parchment, René Delosh, Julie Laudeman, Russell Reinhart, Chad Ogle, Thomas Silvers, Thomas S. Dexheimer, Joel Morris, James H. Doroshow, Beverly A. Teicher. Screens of targeted agents combined with the ubiquitin activating enzyme inhibitor TAK-243 or the pan-Akt inhibitor ipatasertib identified combinations that are effective in patient-derived complex spheroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1055.

Purpose: Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. BVD-523FB (ulixertinib) is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the sub-nanomolar range. Based on the reports of early clinical activity in the phase 1 trial, including in non-V600 BRAF mutations, subprotocol Z1L (EAY131-Z1L) sought to investigate the clinical activity of ulixertinib in patients with tumors harboring these alterations. Methods: In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). BRAF mutation status was determined by an analytically validated assay in a CLIA-certified laboratory for all patients. Results: From August 2019 to July 2020, 35 patients were enrolled and received protocol treatment on the trial. Among the 34 patients who were eligible, median age was 66.5; 50% were female, 88% were white, 9% black, 1% Asian. Performance status was ECOG PS 1 in 74% of patients, with remaining PS 0. Median number of prior therapies was >3.Tumor types included multiple gastrointestinal malignancies (N=16), lung cancer (N=3), and melanoma (N=3), among others. Mutations were centrally confirmed in 26 patients who were deemed analyzable per protocol. Twenty-two patients had a single nucleotide variant (SNV) in BRAF; one patient had an insertion/deletion (indel) in BRAF, and three patients harbored BRAF fusions. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.8 months (90% CI: 1.6, 2.2), 6-month PFS rate was 11% (90% CI: 4%, 22%), and median OS was 4.0 months (90% CI: 2.8, 7.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity; there were no grade 5 toxicities. Most common toxicities include anemia (n=11), diarrhea (n=16), nausea (n=16), vomiting (n=11), fatigue (n=16), increased creatinine (n=12), and acneiform rash (n=14). Conclusion: BVD-523FB (ulixertinib) had no demonstrable evidence of clinical activity in this small, heavily pre-treated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations Citation Format: Vivek Subbiah, Fengmin Fengmin, Ragini Kudchadkar, Ryan J. Sullivan, Edith P. Mitchell, John J. Wright, Helen X. Chen, Robert J. Gray, Xin Victoria Wang, Lisa M. McShane, Larry V. Rubinstein, David Patton, P. Mickey Williams, Tilak K. Sundaresan, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty. BVD-523FB (Ulixertinib) in Patients with Tumors with BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol EAY131-Z1L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT160.

PURPOSE Activating mutations in PIK3CA are observed across multiple tumor types. The NCI-MATCH (EAY131) is a tumor-agnostic platform trial that enrolls patients to targeted therapies on the basis of matching genomic alterations. Arm Z1F evaluated copanlisib, an α and δ isoform–specific phosphoinositide 3-kinase (PI3K) inhibitor, in patients with PIK3CA mutations (with or without PTEN loss). PATIENTS AND METHODS Patients received copanlisib (60 mg intravenous) once weekly on days 1, 8, and 15 in 28-day cycles until progression or toxicity. Patients with KRAS mutations, human epidermal growth factor receptor 2–positive breast cancers, and lymphomas were excluded. The primary end point was centrally assessed objective response rate (ORR); secondary end points included progression-free survival, 6-month progression-free survival, and overall survival. RESULTS Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the Protocol. Multiple histologies were enrolled, with gynecologic (n = 6) and gastrointestinal (n = 6) being the most common. Sixty-eight percent of patients had ≥ 3 lines of prior therapy. The ORR was 16% (4 of 25, 90% CI, 6 to 33) with P = .0341 against a null rate of 5%. The most common reason for protocol discontinuation was disease progression (n = 17, 68%). Grade 3/4 toxicities observed were consistent with reported toxicities for PI3K pathway inhibition. Sixteen patients (53%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity (CTCAE v5.0). Most common toxicities include hyperglycemia (n = 19), fatigue (n = 12), diarrhea (n = 11), hypertension (n = 10), and nausea (n = 10). CONCLUSION The study met its primary end point with an ORR of 16% ( P = .0341) with copanlisib showing clinical activity in select tumors with PIK3CA mutation in the refractory setting.

Supplementary Figure from Cabozantinib plus Nivolumab Phase I Expansion Study in Patients with Metastatic Urothelial Carcinoma Refractory to Immune Checkpoint Inhibitor Therapy

3010 Background: NCI-MATCH (EAY131) is a platform trial enrolling patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on matching genomic alterations (NCT02465060). Subprotocol Arm T evaluated vismodegib (GDC0449), a hedgehog signaling pathway inhibitor with anti-tumor activity in pts with tumors harboring PTCH1 and SMO mutations. Methods: Pts whose tumors had SMO or PTCH1 mutations were eligible; results were confirmed by NCI-MATCH central labs if possible. Pts received oral vismodegib (150 mg daily) for 4-week cycles until progression/toxicity. Tumor response was assessed every 2 cycles. Primary endpoint was ORR; secondary endpoints included PFS, 6-month PFS, OS, and predictive biomarkers. Cutaneous basal cell carcinomas were excluded. Results: Of 34 pts enrolled (6/20/16 – 9/22/20); 2 were ineligible and 1 did not start therapy. The 31 analyzable pts’ demographics were primary tumor sites/histology [gastrointestinal (n = 9), skin/soft tissue (n = 7), gynecologic (n = 5), lung (n = 4), unknown primary (n = 4), ductal breast (n = 1), meningioma (n = 1)]; median age 64 (range 19-81); 48.4% women; 61.3% (19/31) > 3 lines of prior therapy; 74% (23/31) > 1 co-occurring mutation [median 2 co-alterations (range 1-20)]. 8/31 > 4 co-occurring alterations. 9 pts had SMO mutant tumors (all SNVs); 5/9 had > 1 co-occurring gene alterations. 22 pts had PTCH1 alterations (7 SNVs and 15 indels); 18/22 pts had > 1 additional gene alteration. Of 31 analyzable pts, 22 were MATCH-confirmed (i.e. had central confirmation of tumor PTCH1/SMO mutations). MATCH-confirmed pts had ORR 9.1% (2/22) while all analyzable pts had ORR 6.5% (2/31). 2 PRs were seen in pts with a skin/soft tissue sarcoma ( PTCH) and a meningioma ( SMO) with a median duration of response 14 months. The 6-month PFS rate was similar in MATCH-confirmed and analyzable pts (22.4% and 23.2% respectively) and median PFS was identical at 1.8 months. Median OS was 9.1 months in MATCH-confirmed and 7.3 months in analyzable pts. Within analyzable SMO variants: 1 PR, 3 SD, 4 PD, and 1 unevaluable responses were documented. Within analyzable PTCH1 variants: 1 PR, 7 SD, 10 PD, and 4 unevaluable responses were seen. 4 pts (12.9%) discontinued therapy due to AE. Among 33 pts starting therapy, 18 (54.5%) had grade 1-2 toxicity, while 2 (6.1%) had grade 3 treatment-related toxicity. Most common toxicities: grade 1-2 fatigue (n = 11), anorexia (n = 8), weight loss (n = 7), alopecia (n = 7), and dysgeusia (n = 6). There were 4 on-study deaths, but none were treatment related. Conclusions: Although the primary endpoint was not reached, vismodegib was well-tolerated with mostly grade 1-2 toxicities and substantial responses were seen in patients with SMOPro641Ala and PTCHGlu947Ter alterations. Further study of the impact of concomitant molecular alterations may yield additional insights into vismodegib mechanisms of response. Clinical trial information: NCT02465060.