In the Journals

Tumor mutational burden may guide treatment decisions in metastatic colorectal cancer

Marwan Fakih, MD
Marwan Fakih

Tumor mutational burden appeared to independently predict which patients with microsatellite instability-high metastatic colorectal cancer would respond to immune checkpoint inhibitors, according to study results published in Annals of Oncology.

“We're finding that microsatellite instabilities are molecularly heterogeneous, and tumor mutational burden is variable within these patients,” Marwan Fakih, MD, co-director of the gastrointestinal cancer program at City of Hope, told HemOnc Today. “Our findings are novel within this population because nobody has looked at tumor mutational burden as a biomarker of response within microsatellite instability-high colorectal cancer, and tumor genomics within this population may help physicians decide on the most beneficial treatment for each patient.”

Fakih and colleagues collected clinicopathologic data from 22 patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer treated with PD-1/PD-L1 inhibitors at five institutions. Nineteen (86.3%) of the 22 patients received pembrolizumab (Keytruda, Merck) monotherapy.

The researchers used univariate and multivariate analyses to identify potential biomarkers of response and time to progression.

Among all tested variables, tumor mutational burden showed the strongest association with objective response (P < .001) and PFS (P < .001 by univariate analysis; P < .01 by multivariate analysis). This also corresponded with a significant improvement in OS (P = .003) among patients with high tumor mutational burden.

Researchers estimated the optimal predictive cut point for tumor mutational burden between 37 mutations/megabyte and 41 mutations/megabyte.

All 13 patients with high tumor mutational burden responded to therapy. Among the nine patients with low tumor mutational burden, three exhibited disease control and six experienced disease progression.

After median follow-up of more than 18 months, median PFS had not been reached for patients with high tumor mutational burden but was 2 months for those with low tumor mutational burden.

After Fakih and colleagues identified tumor mutational burden as a predictive biomarker, they used the Foundation Medicine database to analyze a larger group of patients with colorectal cancer to define the relevance of the optimal tumor mutational burden cut point they identified.

Investigators used a data set of 18,140 patients, 4.5% of whom had MSI-high disease.

Results showed median tumor mutational burden in MSI-high cases was 46.1 mutations/megabyte (range, 6.1-819), compared with 3.5 mutations/megabyte (range, 0-871) among patients with microsatellite stable disease and 46.5 mutations/megabyte in the study’s clinical cohort.

The optimal tumor mutational burden cut point of 37 mutations/megabyte and 41 mutations/megabyte corresponded to the 35th percentile (37.4 mutations/megabyte) in the population identified through the Foundation Medicine database.

Patients who fall outside the cut-point range may be less likely to benefit from anti-PD-1/PD-L1 therapy, and treatment decisions for these patients require several considerations, Fakih said.

“There are questions we need to answer in future research,” Fakih told HemOnc Today. “Are these patients better off with combination immunotherapy? Might they respond better to a combination of a PD-1 and CTLA-4 inhibitor upfront, rather than receiving only a PD-1 inhibitor?”

However, results suggest patients with microsatellite instability-high metastatic colorectal cancer tumors and high tumor mutation score should be considered for first-line immunotherapy, the researchers concluded.

“These data offer a potential explanation for the heterogeneity in responses described with PD-1 inhibitors in recent prospective clinical trials in microsatellite instability-high colorectal cancer and support the integration of tumor mutational burden score as a potential decision tool in the sequencing of checkpoint inhibition and chemotherapy,” Fakih and colleagues wrote. – by Joe Gramigna

 

Reference:

Schrock AB, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdz134.

For more information:

Marwan Fakih, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: mfakih@coh.org.

Disclosures: Fakih reports consultant/advisory roles with Amgen, Array BioPharma, Bayer and Seattle Genetics; honoraria from Amgen; and research support to his institution from Amgen, AstraZeneca and Novartis. Please see the study for all other authors’ relevant financial disclosures.

Marwan Fakih, MD
Marwan Fakih

Tumor mutational burden appeared to independently predict which patients with microsatellite instability-high metastatic colorectal cancer would respond to immune checkpoint inhibitors, according to study results published in Annals of Oncology.

“We're finding that microsatellite instabilities are molecularly heterogeneous, and tumor mutational burden is variable within these patients,” Marwan Fakih, MD, co-director of the gastrointestinal cancer program at City of Hope, told HemOnc Today. “Our findings are novel within this population because nobody has looked at tumor mutational burden as a biomarker of response within microsatellite instability-high colorectal cancer, and tumor genomics within this population may help physicians decide on the most beneficial treatment for each patient.”

Fakih and colleagues collected clinicopathologic data from 22 patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer treated with PD-1/PD-L1 inhibitors at five institutions. Nineteen (86.3%) of the 22 patients received pembrolizumab (Keytruda, Merck) monotherapy.

The researchers used univariate and multivariate analyses to identify potential biomarkers of response and time to progression.

Among all tested variables, tumor mutational burden showed the strongest association with objective response (P < .001) and PFS (P < .001 by univariate analysis; P < .01 by multivariate analysis). This also corresponded with a significant improvement in OS (P = .003) among patients with high tumor mutational burden.

Researchers estimated the optimal predictive cut point for tumor mutational burden between 37 mutations/megabyte and 41 mutations/megabyte.

All 13 patients with high tumor mutational burden responded to therapy. Among the nine patients with low tumor mutational burden, three exhibited disease control and six experienced disease progression.

After median follow-up of more than 18 months, median PFS had not been reached for patients with high tumor mutational burden but was 2 months for those with low tumor mutational burden.

After Fakih and colleagues identified tumor mutational burden as a predictive biomarker, they used the Foundation Medicine database to analyze a larger group of patients with colorectal cancer to define the relevance of the optimal tumor mutational burden cut point they identified.

Investigators used a data set of 18,140 patients, 4.5% of whom had MSI-high disease.

Results showed median tumor mutational burden in MSI-high cases was 46.1 mutations/megabyte (range, 6.1-819), compared with 3.5 mutations/megabyte (range, 0-871) among patients with microsatellite stable disease and 46.5 mutations/megabyte in the study’s clinical cohort.

The optimal tumor mutational burden cut point of 37 mutations/megabyte and 41 mutations/megabyte corresponded to the 35th percentile (37.4 mutations/megabyte) in the population identified through the Foundation Medicine database.

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Patients who fall outside the cut-point range may be less likely to benefit from anti-PD-1/PD-L1 therapy, and treatment decisions for these patients require several considerations, Fakih said.

“There are questions we need to answer in future research,” Fakih told HemOnc Today. “Are these patients better off with combination immunotherapy? Might they respond better to a combination of a PD-1 and CTLA-4 inhibitor upfront, rather than receiving only a PD-1 inhibitor?”

However, results suggest patients with microsatellite instability-high metastatic colorectal cancer tumors and high tumor mutation score should be considered for first-line immunotherapy, the researchers concluded.

“These data offer a potential explanation for the heterogeneity in responses described with PD-1 inhibitors in recent prospective clinical trials in microsatellite instability-high colorectal cancer and support the integration of tumor mutational burden score as a potential decision tool in the sequencing of checkpoint inhibition and chemotherapy,” Fakih and colleagues wrote. – by Joe Gramigna

 

Reference:

Schrock AB, et al. Ann Oncol. 2019; doi:10.1093/annonc/mdz134.

For more information:

Marwan Fakih, MD, can be reached at City of Hope, 1500 E. Duarte Road, Duarte, CA 91010; email: mfakih@coh.org.

Disclosures: Fakih reports consultant/advisory roles with Amgen, Array BioPharma, Bayer and Seattle Genetics; honoraria from Amgen; and research support to his institution from Amgen, AstraZeneca and Novartis. Please see the study for all other authors’ relevant financial disclosures.

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