October 15, 2019
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Molecular analysis may aid in tailoring treatment for certain patients with colorectal cancer

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Federica Morano, MD
Federica Morano

Patients with RAS and BRAF wild-type metastatic colorectal cancer appeared to have significantly worse survival outcomes after first-line anti-EGFR-based therapy if they had uncommon molecular alterations of anti-EGFR primary resistance, according to results of an exploratory analysis of the phase 2 VALENTINO trial.

Those genomic alterations included HER2/MET amplifications; gene fusions involving ALK, ROS1, NTRK and RET; PI3KCA exon 20 mutations, PTEN and AKT1 mutations; microsatellite instability; and RAS mutations with low mutant allele fraction.

Based on these data, researchers recommended the combined assessment of colorectal tumor sidedness and these molecular alterations of anti-EGFR primary resistance to identify patients with inferior outcomes from initial anti-EGFR-based regimens.

“Unraveling the molecular mechanisms underlying the resistance — both primary and acquired — to anti-EGFR therapy in metastatic colorectal cancer has always been one of the main topics of our research,” Federica Morano, MD, researcher at Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori in Milan, Italy, told HemOnc Today. “At present, all the main guidelines recommend the use of anti-EGFR-base therapy solely after the evaluation of RAS and BRAF mutational status, but it is becoming increasingly clear that this may not be enough.”

Morano and colleagues previously observed the promising negative predictive impact of a panel of uncommon molecular alterations linked to primary resistance to EGFR inhibition among patients with RAS and BRAF wild-type metastatic colorectal cancer who had been treated with anti-EGFR monoclonal antibodies.

“We were able to identify a panel of rare genomic alterations — [the PRESSING] panel — that had a negative predictive role for the selection of patients who were candidates for anti-EGFR antibodies,” Morano told HemOnc Today.

To further validate their findings, Morano and colleagues conducted a prespecified exploratory analysis of the potential prognostic and predictive role of primary tumor sidedness and PRESSING panel tumor alterations among 199 patients with RAS and BRAF wild-type metastatic colorectal cancer.

The patients had participated in the phase 2, multicenter, randomized, open-label VALENTINO trial, which assessed the PFS noninferiority of maintenance therapy with single-agent panitumumab (Vectibix, Amgen) compared with panitumumab plus fluorouracil and leucovorin after a 4-month induction regimen that consisted of panitumumab plus FOLFOX-4.

For the current analysis, researchers assessed the association between PRESSING tumor status and tumor sidedness with overall response rate, PFS and OS.

Median follow-up was 26 months.

Overall, 85.4% of patients (n = 170) had left-sided tumors and 14.6% (n = 29) had right-sided tumors. Moreover, 75.4% were PRESSING-negative tumors and 24.6% were PRESSING-positive tumors.

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Researchers consistently observed inferior outcomes for right-sided tumors compared with left-sided tumors in terms of ORR (55.2% vs. 74.1%; P = .037), PFS (8.4 months vs. 11.5 months; P = .026) and OS (2-year rate: 50.2% vs. 65.1%). They observed similarly inferior outcomes for PRESSING-positive vs. -negative tumors (ORR = 59.2% vs. 75.3%; P = .03; PFS = 7.7 months vs. 12.1 months; P < .001; 2-year OS rate = 48.1% vs. 68.1%; P = .021).

Among patients who received single-agent panitumumab, researchers observed “extremely poor” outcomes among those with right-sided tumors (median PFS, 7.7 months; 2-year OS, 38.5%) and PRESSING-positive tumors (median PFS, 7.4 months; 2-year OS, 47%).

Conversely, researchers observed a PFS benefit with maintenance panitumumab plus fluorouracil plus leucovorin, independent of tumor sidedness and PRESSING tumor status, although this did not reach statistical significance.

As precision oncology in colorectal cancer advances, the VALENTINO study “adds another piece to the biomarker puzzle,” Raghav Sundar, MBBS, MMed, researcher in the department of hematology-oncology at National University Cancer Institute in Singapore, and colleagues, wrote in an accompanying editorial.

“This study highlights the presence of additional negative predictive and prognostic biomarkers for anti-EGFR therapy. These are beyond the standard-of-care RAS/BRAF testing and may only be identied using larger panels, such as PRESSING. However, PRESSING was a complex panel involving various assays, and it may not be easily replicated in daily clinical practice. With the burgeoning number of biomarkers that need to be tested to assign appropriate therapy, multigene next-generation sequencing panels are more likely to be used routinely in clinical practice.”

Morano and colleagues plan to conduct subsequent research on the liquid biopsy samples.

“This will potentially give us information on the dynamic behavior of resistance mechanisms and how this is related to the clinical outcomes,” Morano told HemOnc Today. “We also plan to analyze, via RNA sequencing, the tissue samples collected at enrollment to investigate the prognostic role of molecular subtypes, such as consensus molecular subtypes. Most importantly, pooled analyses of our translational data with those obtained by other ongoing trials will help to obtain potentially practice-defining data.” – by Jennifer Southall

For more information:

Federica Morano, MD, can be reached at Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, via Giacomo Venezian 1, 20133 Milan, Italy; email: federica.morano@istitutotumori.mi.it.

Disclosures: Morano reports honoraria from Servier and travel expenses/accommodations from Sano and Servier. Please see the study for all other authors’ relevant financial disclosures. Sundar reports a consultant/advisory role with Bristol-Myers Squibb and Eisai; honoraria from Bristol-Myers Squibb, Eli Lilly and Merck Sharp & Dohme; research funding from Paxman; and travel expenses/accommodations from AstraZeneca, Roche and Taiho Pharmaceutical. Please see the editorial for all other authors’ relevant financial disclosures.