Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial

Strickler, John H.; Zemla, Tyler; Ou, Fang‐Shu; Cercek, Andrea; Wu, Christina; Sanchez, Federico Augusto; Hubbard, Joleen M.; Jaszewski, Brandy L.; Bandel, Lorelei A.; Schweitzer, Brock L.; Niedzwiecki, Donna; Kemeny, Nancy E.; Boland, Patrick M.; Ng, Kimmie; Bekaii‐Saab, Tanios

doi:10.1093/annonc/mdz246.005

Cited by 84 publications

(68 citation statements)

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“…20 In addition, tucatinib in combination with trastuzumab is under investigation for the treatment of patients with HER2-positive metastatic colorectal cancer (MOUNTAINEER; NCT03043313). 21 In the pivotal HER2CLIMB study, the adverse event (AE) of elevated serum creatinine concentration was observed in a higher proportion of patients randomized to the tucatinib arm compared with those who received placebo (13.9% versus 1.5%, respectively). 19 In addition, increased creatinine as a laboratory abnormality was reported in 33% of patients in the tucatinib arm versus 6% in the placebo arm (all grade 1 or 2).…”

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confidence: 99%

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects

Topletz‐Erickson

Lee

Mayor

et al. 2020

The Journal of Clinical Pharma

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Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2-positive metastatic breast cancer and in development for other HER2-positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2-K (MATE2-K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2-, MATE1-, and MATE2-K-mediated transport of metformin, with IC 50 values of 14.7, 0.340, and 0.135 μM, respectively. Tucatinib also inhibited OCT2-and MATE1-mediated transport of creatinine, with IC 50 values of 0.107 and 0.0855 μM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin Cbased estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4-fold) and renal clearance decreased (29.99-17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2-K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2-and MATE1/2-K-mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

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confidence: 99%

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects

Topletz‐Erickson

Lee

Mayor

et al. 2020

The Journal of Clinical Pharma

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“…About 3% (16/609) of the patients with CRC in this cohort harbored ERBB2 / HER2 amplifications, 14 of which were KRAS wild type. Therefore, the 16 patients with MSS CRC and ERBB2 amplification may be candidates for HER2 ‐targeted therapies (e.g., trastuzumab + lapatinib/pertuzumab/tucatinib) [32]. We also found that all ( n = 10) of the CDK12 gene amplifications, located close to ERBB2 at 17q12, were concurrent with ERBB2 amplification.…”

Section: Resultsmentioning

confidence: 90%

Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer

Guo

Wang

et al. 2020

The Oncologist

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Background The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1–3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies. Methods Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer‐related genes, including single‐nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next‐generation sequencing–based computational algorithms also determined tumor mutational burden and MSI status. Results Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI‐high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T‐cell infiltration. Conclusion Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI‐high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes. Implications for Practice The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC.

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“…25 Recently, a study from Japan showed that ctDNA could be used for negative selection of candidates for this combination; patients with ctDNA alterations of RAS, BRAF, PIK3CA and HER2 did not benefit from the dual HER2 blockade. 71 Another dual combination comprising inhibitors of HER2, trastuzumab and tucatinib showed significant activity, with an ORR of 55% and median PFS of 6.2 months in 22 patients, 72 while pertuzumab and trastuzumab-emtansine (T-DM1) produced an ORR of 10%, which did not meet the primary endpoint. 73 With advancements in efficient HER2 blockades, including antibody-drug conjugates, bispecific antibodies, small molecule inhibitors or combinations with immunotherapy, 74 more innovative therapeutics could emerge in this field.…”

Section: Strategies Targeting Braf-mutant Crcmentioning

confidence: 99%

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

Kim

2020

ESMO Open

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Over the last few decades, molecularly targeted agents have been used for the treatment of metastatic colorectal cancer. They have made remarkable contributions to prolonging the lives of patients. The emergence of several biomarkers and their introduction to the clinic have also aided in guiding such treatment. Recently, next-generation sequencing (NGS) has enabled clinicians to identify these biomarkers more easily and reliably. However, there is considerable uncertainty in interpreting and implementing the vast amount of information from NGS. The clinical relevance of biomarkers other than NGS are also subjects of debate. This review covers controversial issues and recent findings on such therapeutics and their molecular targets, including VEGF, EGFR, BRAF, HER2, RAS, actionable fusions, Wnt pathway and microsatellite instability for comprehensive understanding of obstacles on the road to precision oncology in metastatic colorectal cancer.

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Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial

Cited by 84 publications

References 0 publications

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects

Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects

Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

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