MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors

Abstract

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.The MyPathway multiple-basket study (ClinicalTrials.gov identifier: NCT02091141) is evaluating targeted therapies in nonindicated tumors with relevant molecular alterations. We assessed pertuzumab + trastuzumab in a tissue-agnostic cohort of adult patients with human epidermal growth factor receptor 2 (HER2)-amplified and/or -overexpressed and/or -mutated solid tumors. The primary end point was objective response rate (ORR); secondary end points included survival and safety. At data cutoff (March 2022), 346 patients with HER2 amplification and/or overexpression with/without HER2 mutations (n = 263), or HER2 mutations alone (n = 83) had been treated. Patients with HER2 amplification and/or overexpression had an ORR of 25.9% (68/263, 95% CI, 20.7 to 31.6), including five complete responses (urothelial [n = 2], salivary gland [n = 2], and colon [n = 1] cancers). Activity was higher in those with wild-type (ORR, 28.1%) versus mutated KRAS (ORR, 7.1%). Among patients with HER2 amplification, ORR was numerically higher in patients with immunohistochemistry (IHC) 3+ (41.0%; 32/78) or 2+ (21.9%; 7/32), versus 1+ (8.3%; 1/12) or no expression (0%; 0/20). In patients with HER2 mutations alone, ORR was 6.0% (5/83, 95% CI, 2.0 to 13.5). Pertuzumab + trastuzumab showed activity in various HER2-amplified and/or -overexpressed tumors with wild-type KRAS, with the range of activity dependent on tumor type, but had limited activity in the context of KRAS mutations, HER2 mutations alone, or 0-1+ HER2 expression.

FIG 1.

(A) ORR,^a (B) PFS,^b and (C) OS in patients with HER2-amplified and/or -overexpressed tumors by KRAS status. (D) Best percentage change in sum of target lesions in patients with HER2 amplification and/or overexpression by tumor group (n = 263); the horizontal line represents the 30% decrease in the sum of diameters of target lesions, from baseline. (E) ORR in patients with HER2-amplified and/or -overexpressed + KRAS wild-type tumors by tumor group (n = 202). ^aResponse was assessed by the investigator using RECIST v1.1. ^bData for patients without disease progression or death were censored at the date of the last tumor assessment (or, if no tumor assessments were performed, after the baseline visit, at the date of first treatment). Kaplan-Meier curves are for descriptive purposes only. Bar graph whiskers represent 95% CI. A/O, amplified and/or overexpressed; GYN, gynecologic; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; KRAS, Kirsten rat sarcoma viral oncogene homolog; NE, not estimable; NSCLC, non–small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TL, target lesion; UNK, unknown; WT, wild-type.