Rxdx-101, an Oral Pan-Trk, Ros1, and Alk Inhibitor, in Patients with Advanced Solid Tumors with Relevant Molecular Alterations

LBA11511 Background: The MyPathway study (NCT02091141) evaluates agents targeting the HER2, BRAF, Hedgehog (Hh), or EGFR pathways in non-indicated tumors with relevant genetic abnormalities. Early results from MyPathway merit pre-planned tumor-cohort expansion. Methods: Eligible pts had advanced solid tumors with no curative therapy and molecular alterations in HER2, BRAF, Hh, or EGFR. Pts received standard doses of trastuzumab + pertuzumab (for the HER2 pathway), vemurafenib (BRAF), vismodegib (Hh), or erlotinib (EGFR) based on alteration. The primary endpoint is investigator-evaluated response rate within a tumor-pathway cohort (RECIST 1.1). Cohort size and expansion is determined by Simon’s two-stage design criteria. Results: By December 14, 2015, MyPathway included 129 pts with available baseline assessments and alterations in HER2 (n = 82; 53 amplifications, 23 mutations, 5 both, 1 RBMS-NRG1 fusion), BRAF (n = 33; 18 V600E, 15 other), Hh (n = 8; 7 PTCH1, 1 SMO), or EGFR (n = 6). Pts had a median of 3 (range, 0–10) prior lines of therapy. Best responses (n = 118) are shown below; 11 pts had insufficient follow-up for reevaluation and were not analyzed. 22 pts had PR/CR (1 CR); current response durations were up to 11 months. Conclusions: Targeted therapy produced responses in pts with 9 different tumor types outside of current drug indications. As enrollment increases for all tumor-pathway cohorts, analyses of tumor responses based on specific alterations (eg, HER2 amplifications vs. mutations) are planned. The HER2 amplified colorectal, bladder, and biliary, and the BRAF lung cohorts will be expanded based on observed activity. Clinical trial information: NCT02091141. [Table: see text]

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MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3004 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3004-3004

Author(s):

Funda Meric-Bernstam ◽

John Hainsworth ◽

Ron Bose ◽

Howard A. Burris III ◽

Claire Frances Friedman ◽

...

Keyword(s):

Solid Tumors ◽

Targeted Therapies ◽

Objective Response ◽

Tumor Type ◽

Loading Dose ◽

Advanced Solid Tumors ◽

Wild Type ◽

Her2 Positive ◽

Molecular Alterations ◽

Kras Status

3004 Background: HER2 ( ERBB2) amplification and/or overexpression is observed in 2–3% of solid tumors, and is often associated with more aggressive disease. Thus far, HER2-targeted therapies are FDA-approved only for breast, gastric, and gastroesophageal cancers. MyPathway (NCT02091141) is a non-randomized, phase 2a multi-basket study assessing the activity of FDA-approved targeted therapies in non-indicated advanced solid tumors with relevant molecular alterations. We report results from the MyPathway HER2 basket, comprising a large, tissue-agnostic cohort of patients (pts) with HER2-altered tumors treated with P + H. Methods: Pts in this analysis were aged ≥18 years and had HER2-amplified and/or overexpressed tumors. Pts received P (840-mg IV loading dose, then 420-mg every 3 weeks [q3w]) + H (8-mg/kg IV loading dose, then 6-mg/kg q3w). The primary efficacy endpoint was investigator-assessed objective response rate (ORR). Other endpoints included disease control rate (DCR, defined by objective response or stable disease >4 mos) and duration of response (DOR). Subgroup analyses were completed by tumor type and KRAS status. Results: Pts were fully enrolled from April 14, 2014 to June 15, 2020. By January 22, 2021, 260 pts were efficacy-evaluable. Confirmed ORR (cORR) was 23.1% (60/260, including 5 complete responses; 95% confidence interval [CI] 18.1–28.7), DCR was 44.2% (115/260, 95% CI 38.1–50.5), and median DOR was 7.9 mos (95% CI 6.2–9.3). In 199 pts with wild-type KRAS tumors, cORR was 25.6% (51/199, 95% CI 19.7–32.3), DCR was 48.7% (97/199, 95% CI 41.6–55.9), and median DOR was 8.3 mos (95% CI 6.2–10.8). In comparison, in 26 pts with KRAS-mutated tumors, cORR was 3.8% (1/26, responder had colorectal cancer; 95% CI 0.1–19.6), DCR was 3.8% (1/26, 95% CI 0.1–19.6), and DOR was 2.7 mos. KRAS status was unknown in 35/260 pts (cORR 22.9% [8/35, 95% CI 10.4–40.1]; median DOR 6.7 mos [95% CI 2.5–12.7]). Clinical outcomes by tumor type are shown in the Table. Conclusions: P+H was active in a wide variety of KRAS wild-type HER2-amplified/overexpressed tumor types, but had limited activity in KRAS-mutated tumors. Clinical trial information: NCT02091141. [Table: see text]

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Basket of baskets (BoB): A modular, open label, phase II, multicenter study to evaluate targeted agents in molecularly selected populations with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps3151 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS3151-TPS3151

Author(s):

Irene Brana ◽

Christophe Massard ◽

Richard D. Baird ◽

Frans Opdam ◽

Richard F. Schlenk ◽

...

Keyword(s):

Solid Tumors ◽

New Technologies ◽

Single Agent ◽

Study Drug ◽

Tumor Board ◽

Advanced Solid Tumors ◽

Targeted Agents ◽

Companion Diagnostics ◽

Molecular Alterations ◽

Study Results

TPS3151 Background: Basket trials with targeted agents can show high response rates for tumors with specific molecular profiles, granting extension of the label of some drugs. In other cases, study results were disappointing, likely due to the rarity of molecular alterations, limits in trial design and the difficulties in applying molecular tumor profiling in the clinical setting. Methods: Basket of Baskets (BoB), NCT03767075, aims to bridge the gap between Academic Genomics and clinical applications (ready-to market multi-marker Companion Diagnostics) by providing a sustainable and adaptable (to new technologies, markers, and therapeutic agents) platform for co-development of drug/companion diagnostic. BoB is a novel platform trial from Cancer Core Europe, a recently established sustainable European network for innovative cancer research. This protocol has two parts: (1) Part A includes a molecular profiling program for subjects with advanced solid tumors (iPROFILER), a variant annotation tool, and a molecular tumor board to select the most appropriate treatment. It also enables testing/developing companion diagnostics linked with the therapeutic part (part B). (2) Part B includes iBASKET, a modular multi-arm basket trial for subjects with tumors harboing selected molecular alterations. Each module is focused on a certain molecular pathway or on certain molecular alterations that may confer sensitivity to the study drug or study drug combination evaluated in that module/arm. The current version of iBASKET (Module 1- Atezolizumab in genomically-selected patients) is open for enrollment for patients with advanced neoplasms bearing one of the following alterations: Arm 1A: BRCA1 or BRCA2; Arm 1B: MLH1, MSH2, MSH6, PMS2; Arm 1C: POLE, POLD1 mutations; Arm 1D: hypermutated tumors; Arm 1E: other mutations in DNA-repair genes; Arm 1F: PDL1 gene amplification. All patients enrolled in Module 1 will receive single-agent atezolizumab. New Modules for genomically selected populations can be added through amendments. Our final aim is to achieve drug repurposing of treatments, co-develop multi-marker companion diagnostics and a large database of knowledge in Precision Medicine. Clinical trial information: NCT03767075.

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