Positive findings on the potential benefit of molecularly targeted drugs in patients with advanced colorectal cancer were presented at the 2020 Gastrointestinal Cancers Symposium, validating the purpose of ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR) study.1-3
TAPUR, the first clinical trial conducted by ASCO, is a multibasket trial that matches patients’ genomic alterations to commercially available targeted therapies. The aim is to learn how targeted agents perform outside of their U. S. Food and Drug Administration (FDA)-approved indications in patients with advanced cancer and few, if any, remaining treatment options.
In studies reported at the 2020 Gastrointestinal Cancers meeting, biomarker-driven matches were made for patients with colorectal cancer who had HER2 amplifications (and received trastuzumab plus pertuzumab), BRAF V600E mutations (and received cobimetinib plus vemurafenib), or high tumor mutational burdens (and were treated with pembrolizumab).
HER2-Positive Disease: Pertuzumab Plus Trastuzumab
HER2 amplification, overexpression, or mutation occurs in about 5% to 7% of colorectal malignancies. When 28 patients with HER2-positive colorectal cancer were treated with pertuzumab plus trastuzumab, a response rate of 25% and a disease control rate (response plus stable disease for at least 16 weeks) of 50% were observed, reported Ranju Gupta, MD, of Lehigh Valley Health Network.1
Ranju Gupta, MD
Both monoclonal antibodies bind to extracellular domains of the HER2 receptor. However, each agent targets different sites to prevent both HER2 homodimerization and heterodimerization, thereby blocking downstream signaling better than either agent alone.
Median progression-free survival was 17.2 weeks, and median overall survival was 108.6 weeks, or about 2 years. At 1 year, 58% of patients remained alive. Considering that 79% of the patients had received at least three prior lines of therapy, these outcomes were impressive, Dr. Gupta commented, noting that response rates of 10% are greater than the norm in this patient population.
The combination was well tolerated, with one patient (4%) experiencing a grade 3 adverse event (anemia and infusion reaction) and another experiencing a serious adverse event (left-ventricular dysfunction).
Dr. Gupta and colleagues are currently investigating whether the presence of RAS mutations influences the response to pertuzumab and trastuzumab in colorectal cancer, based on the known potential for RAS mutations to circumvent the effects of the HER2 blockade. The investigators would also like to see the pertuzumab/trastuzumab combination compared to chemotherapy in a phase III trial.
BRAF V600E–Mutated Disease: Cobimetinib Plus Vemurafenib
The BRAF V600E mutation can be found in approximately 10% of metastatic colorectal cancers. It is associated with an aggressive biology and short survival, according to Kelsey Klute, MD, of the University of Nebraska Medical Center, who described the novel treatment of this population in the TAPUR trial.2
Kelsey Klute, MD
A cohort of 28 patients with BRAF mutations were treated with the combination of cobimetinib and vemurafenib, a doublet approved for treating metastatic melanoma that harbors BRAF mutations. The two agents target the MAPK pathway at different points; by giving the MEK inhibitor cobimetinib with the BRAF inhibitor vemurafenib, the development of resistance to vemurafenib may be ameliorated. The 28 patients with the BRAF V600E mutation were heavily pretreated, with 63% having received at least three prior lines of therapy.
Combination cobimetinib/vemurafenib produced objective responses in 29% of patients and yielded a disease control rate of 57%. Median progression-free survival for the cohort was 15.8 weeks, and median overall survival was 38.9 weeks, or about 9 months, Dr. Klute reported.
She noted that the outcome seen in TAPUR is far better than is otherwise achieved. Only about 5% of such patients typically respond to standard second-line therapy, and their median progression-free survival is only 2 months. The investigators consider the results to be highly encouraging for this poor-prognosis population.
Grade 3 adverse events and serious adverse events were observed in 33% and 20%, respectively, which was not unexpected, given the known safety profile of these drugs. Close monitoring of patients and early intervention, therefore, are necessary. Future studies will include quality-of-life measures and other patient-reported outcomes.
Colorectal Cancer With High Tumor Mutation Burden: Pembrolizumab
Tumors with numerous chromosomal alterations express tumor-specific neoantigens that are good targets for activated immune cells and therefore immunotherapies. It is thought that colorectal cancers with high tumor mutational burden (TMB) might therefore respond to pembrolizumab—as do those that are microsatellite instability–high. This was the rationale for the TAPUR cohort of 27 patients with heavily pretreated metastatic colorectal cancer with high TMB—defined as having at least nine mutations per megabase—to receive treatment with pembrolizumab.3
Single-agent pembrolizumab produced responses in 11% and disease control in 28% of patients. Median progression-free survival was 9.3 weeks, median overall survival was 51.9 weeks, and 45.6% of patients remained alive at 1 year, reported Eyal Meiri, MD, of the Cancer Treatment Centers of America, Atlanta. The drug was well tolerated, with grade 3 adverse events observed in 7%.
Eyal Meiri, MD
Richard L. Schilsky, MD, FACP, FSCT, FASCO
In an interview with The ASCO Post, ASCO Chief Medical Officer Richard L. Schilsky, MD, FACP, FSCT, FASCO, said he is happy “to see the TAPUR results rolling out.” Dr. Schilsky noted that the findings come around the time of the 4-year anniversary of TAPUR’s launch in March 2016. “We’ve had about 2,200 patients enroll, and we’ve treated around 1,800 with novel therapies. Since every treatment we are studying represents an off-label use of an already marketed therapy, the data we are seeing support either using, or not using, a particular drug in a specific tumor type,” he said.
DISCLOSURE: Dr. Gupta reported no conflicts of interest. Dr. Klute has served in a consulting or advisory role for Bayer and has received research funding from AbbVie and Pharmacyclics. Dr. Meiri has been employed by and has an immediate family member who has been employed by Cancer Treatment Centers of America and has served in a consulting or advisory role for Amgen. Dr. Schilsky has received institutional research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Lilly, Merck, and Pfizer; and has been reimbursed for travel, accommodations, or other expenses by Varian.
1. Gupta R, Garrett-Mayer E, Halabi S, et al: Pertuzumab plus trastuzumab in patients with colorectal cancer with ERBB2 amplification or overexpression: Results from the TAPUR study. 2020 Gastrointestinal Cancers Symposium. Abstract 132. Presented January 25, 2020.
2. Klute K, Garrett-Mayer E, Halabi S, et al: Cobimetinib plus vemurafenib in patients with colorectal cancer with BRAF V600E mutations: Results from the TAPUR study. 2020 Gastrointestinal Cancers Symposium. Abstract 122. Presented January 25, 2020.
3. Meiri E, Garrett-Mayer E, Halabi S, et al: Pembrolizumab in patients with colorectal cancer with high tumor mutational burden: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study. 2020 Gastrointestinal Cancers Symposium. Abstract 133. Presented January 25, 2020.