Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study

Abstract

Background: Therapies targeting HER2 have improved clinical outcomes in HER2-positive breast and gastric cancers, and are emerging as potential treatments for HER2-positive metastatic colorectal cancer. MyPathway evaluates the activity of targeted therapies in non-indicated tumour types with potentially predictive molecular alterations. We aimed to assess the activity of pertuzumab and trastuzumab in patients with HER2-amplified metastatic colorectal cancer.

Methods: MyPathway is an ongoing, phase 2a, multiple basket study. Patients in this subset analysis were aged 18 years or older and had treatment-refractory, histologically confirmed HER2-amplified metastatic colorectal cancer with measurable or evaluable disease and an Eastern Cooperative Oncology Group performance status score of 2 or less, enrolled from 25 hospitals or clinics in 16 states of the USA. Patients received pertuzumab (840 mg loading dose, then 420 mg every 3 weeks, intravenously) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks, intravenously). The primary endpoint was the proportion of patients who achieved an objective response based on investigator-reported tumour responses. Analyses were done per protocol. This ongoing trial is registered with ClinicalTrials.gov, number NCT02091141.

Findings: Between Oct 20, 2014, and June 22, 2017, 57 patients with HER2-amplified metastatic colorectal cancer were enrolled in the MyPathway study and deemed eligible for inclusionin this cohort analysis. Among these 57 evaluable patients, as of Aug 1, 2017, one (2%) patient had a complete response and 17 (30%) had partial responses; thus overall 18 of 57 patients achieved an objective response (32%, 95% CI 20-45). The most common treatment-emergent adverse events were diarrhoea (19 [33%] of 57 patients), fatigue (18 [32%] patients), and nausea (17 [30%] patients). Grade 3-4 treatment-emergent adverse events were recorded in 21 (37%) of 57 patients, most commonly hypokalaemia and abdominal pain (each three [5%] patients). Serious treatment-emergent adverse events were reported in ten (18%) patients and two (4%) of these adverse events (ie, chills and infusion-related reaction) were considered treatment related. There were no treatment-related deaths.

Interpretation: Dual HER2-targeted therapy with pertuzumab plus trastuzumab is well tolerated and could represent a therapeutic opportunity for patients with heavily pretreated, HER2-amplified metastatic colorectal cancer.

Funding: F Hoffmann-La Roche/Genentech.

Conflict of interest statement

DECLARATION OF INTERESTS

FMB has served as a consultant for Dialecta and Sumitomo Dainipon; served on advisory committees for Inflection Biosciences, Pieris, and DarwinHealth; and received research funding from Aileron Therapeutics, AstraZeneca, Bayer, Calithera Biosciences, CytomX Therapeutics, Debiopharm Group, Genentech, Novartis, PUMA Biotechnology, Zymeworks, Pfizer, Jounce, eFFECTOR, Curis, Abbvie, and Taiho Pharmaceutical.

HH is employed by and owns stock in Roche/Genentech. He has served as a consultant for Acceleron Pharma, Bristol-Myers Squibb, Roche/Genentech, GlaxoSmithKline, Incyte, Lilly, Novartis, OncoMed, and TRACON Pharma; received honoraria from Roche/Genentech and Lilly/ImClone; and received travel, accommodation, and expense reimbursement from Roche/Genentech and TRACON Pharmaceuticals. His former institution (Duke University Medical Center) received research funding from Bristol-Myers Squibb, Roche/Genentech, GlaxoSmithKline, Lilly, Macrogenics, NCI, Novartis, Regeneron, and TRACON Pharma.

RRM has served on the advisory boards of Ipsen and Bristol-Myers Squibb.

MF has served on advisory boards for Amgen, Array, Genentech, Merck, Taiho, Seattle Genetics, and Sirtex; has received speaker fees from Amgen, Genentech, Sirtex, and Taiho; and has received research support (paid to his institution) from Amgen, AstraZeneca, and Novartis.

AV has received personal fees from AstraZeneca, Bristol-Myers Squibb, Roche/Genentech; has received grant funding from Amgen; and has received non-financial support from Caris Life Sciences.

C. Swanton has received honoraria or consultant fees from Roche/Genentech, Ventana, Celgene, Pfizer, Novartis, and Bristol-Myers Squibb; owns stock in GRAIL, Epic Biosciences, Apogen Biotech, and Achilles Therapeutics (co-founder); and has received grants from Pfizer and AstraZeneca.

RK has received grants from Incyte, Roche/Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, and Konica Minolta; consulting fees from LOXO, X-Biotech, Actuate Therapeutics, Roche/Genentech, and NeoMed; and has an ownership interest in CureMatch.

HB has received research funding for his institution from Roche/Genentech, Bristol-Myers Squibb, Incyte, Tarveda Therapeutics, Mersana Therapeutics, AstraZeneca, MedImmune, Macrogenics, Novartis, Boehringer Ingelheim, Eli Lilly, Seattle Genetics, AbbVie, Bayer, Celldex Therapeutics, Merck, Celgene, Agios Pharmaceuticals, and Jounce Therapeutics.

C. Sweeney has served as a consultant for Astellas Pharma, AstraZeneca, Bayer, Tolmar, Genentech/Roche, Janssen Biotech, and Sanofi; owns stock in Leuchemix; and has patents with Leuchemix and Exelixis. His institution has received research funding from Astellas Pharma, Exelixis, and Janssen Biotech.

RB has served as a consultant for Roche/Genentech and has received honoraria from Genentech/Roche and Novartis and research funding from Puma Biotechnology.

DRS has served as a consultant for and received travel, accommodations, and expense reimbursement from AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, Roche/Genentech, Lilly, Novartis, and Pfizer; served on speakers’ bureaus for Novartis; and owned stock in Foundation Medicine and Illumina. His institution has received research funding from Amgen, Astex Pharmaceuticals, AstraZeneca, BIND Biosciences, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Clovis Oncology, CytRx Corporation, Daiichi Sankyo, EMD Serono, Genentech/Roche, ImClone Systems, Immunogen, Lilly, Novartis, Oncogenex, OncoMed, Peregrine Pharmaceuticals, Pfizer, University of Texas Southwestern Medical Center - Simmons Cancer Center, and Verastem.

MSB, SB, AS, KS, and VC are employed by and own stock in Roche/Genentech.

JH has received research funding for his institution from Astellas Pharma, AstraZeneca, Celgene, Roche/Genentech, Johnson & Johnson, Lilly, and Novartis.

All authors received non-financial support from Roche in the form of medical writing support for this manuscript

KPSR has no other potential conflicts of interest to disclose.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Trial Profile

HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer.

Figure 2:. (A) Best change in target lesion size by patient (n=54)a,b, and (B) time on treatment by patient (n=57)c for HER2-amplified mCRC treated with pertuzumab + trastuzumab

aThree patients are excluded from this plot: two patients (including one with a KRAS mutation) who discontinued treatment due to clinical progression without a post-baseline tumour assessment, and one patient with a discrepancy in the number of target lesions between screening and the post-baseline assessment. bOne patient with SD had a 41% reduction in target lesion size at his final assessment on study, but treatment was discontinued due to symptomatic deterioration. As such, the patient’s status was classified as a PD rather than a PR at the final assessment, with an overall best response of SD. cTreatment bars extend to three weeks (ie, one cycle) past the date of last drug administration in order to capture actual treatment duration. CR, complete response; HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3:. (A) Progression-free survival, and (B) overall survival in patients with HER2-amplified mCRC treated with pertuzumab + trastuzumab (n=57)

HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer.

Figure 4:. Exploratory analysis of (A) progression-free survival and (B) overall survival by KRAS status (n=56) in patients with HER2-positive mCRC

aTwo patients had missing tumour response data. bOne patient had missing tumour response data. CI, confidence interval; HER2, human epidermal growth factor receptor 2; mCRC, metastatic colorectal cancer; NE, not estimable; OS, overall survival; PFS, progression-free survival.