In the JournalsPerspective

Molecular analysis may aid in tailoring treatment for certain patients with colorectal cancer

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.

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.

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.

    Perspective

    Mohamed Salem, MD 
    Mohamed Salem
    Alberto Puccini, MD 
    Alberto Puccini

    Biomarkers are becoming an essential part of precision medicine and personalized treatment of patients, enhancing our ability to better select the right patients for the right treatment.

    To date, RAS status is the only validated negative predictive biomarker for the use of the anti-epidermal growth factor receptor monoclonal antibodies (ie, panitumumab and cetuximab [Erbitux, Eli Lilly]) among patients with metastatic colorectal cancer (mCRC). About 50% of these patients harbor RAS mutations (including KRAS exons 2, 3 and 4 and NRAS exons 2, 3 and 4) and do not benefit from anti-EGFR treatments. Therefore, testing for RAS status before selection of targeted therapy in mCRC is recommended in all clinical guidelines. In fact, potential harm was observed to the population with RAS mutations when treated with anti-EGFR therapy, highlighting the importance of appropriate patient selection for this treatment.

    However, several genomic and nongenomic mechanisms of primary resistance to anti-EGFR therapy have been identified among patients with RAS wild-type mCRC. BRAF V600E mutations and tumor sidedness represent the most robust negative predictive biomarkers beyond the presence of a RAS mutation. Therefore, patients with left-sided, RAS and BRAF wild-type mCRC are considered optimal candidates for anti-EGFR therapy. Nonetheless, primary and acquired resistance to anti-EGFR therapy remains an important clinical issue.

    In this study, Morano and colleagues report a prespecified retrospective analysis of 199 evaluable patients with RAS and BRAF wild-type mCRC previously enrolled in the phase 2 VALENTINO trial. The aim of this study was to investigate the prognostic and predictive role of a more accurate analysis of multiple and less frequent genomic alterations (PRESSING panel) in combination with assessment of tumor sidedness for the selection of patients candidates for anti-EGFR antibody therapy. 

    The authors demonstrated that implementing the PRESSING panel together with tumor sidedness allowed a better negative selection of RAS and BRAF wild-type patients who were not likely to respond to anti-EGFR therapy. This finding has the potential to not only spare many patients unnecessary adverse effects, but also financial toxicity.

    PRESSING status was defined as positive if alterations occurred in any biomarker in the panel, whereas negative status applied when all biomarker alterations were wild-type.

    The authors demonstrated that patients with left-sided and PRESSING-negative tumors achieved the most favorable prognosis in both PFS (median, 13.7 months) and OS (2-year OS rate, 69.7%), whereas the subgroup with right-sided and PRESSING-positive tumors had the worst prognosis (median PFS, 7.7 months; 2-year OS rate, 40.9%).

    Moreover, researchers reported the strongest association with poor PFS (P = .001) and OS (P = .007) in the multivariable models for PRESSING-positive tumors. Conversely, sidedness was no longer significant, but this could be due to the low number of right-sided tumors in the study group. Nevertheless, a borderline correlation occurred between primary tumor sidedness and the PRESSING panel, with a higher rate of PRESSING positivity in right-sided tumors (37.9%) vs. left-sided tumors (22.3%).

    This study further corroborates previous reports showing that several genomic alterations, such as HER2 or MET amplification, ALK/ROS1/NTRKs/RET fusions, PIK3CA/PTEN/AKT1 and RAS mutations with low mutant allele fraction, microsatellite instability, and primary tumor side (right-sided tumors), may be responsible for primary resistance to anti-EGFR treatments. This suggests that the currently recommended evaluation of RAS and BRAF mutational status may not be enough in clinical practice to select patients suitable for panitumumab or cetuximab treatment in combination with chemotherapy in first and later lines of treatment.

    It is important to note that the authors could not investigate the predictive role of tumor sidedness and PRESSING panel status with regard to anti-EGFR therapy because both arms in the VALENTINO trial were treated with panitumumab. In addition, the authors were not able to distinguish the prognostic and/or predictive effect of each individual genomic alteration included in the PRESSING panel and, therefore, some could be falsely perceived as potential mechanisms of resistance just by being associated with the panel. However, given the rarity of these alterations, it may be logistically impossible to formally validate them in prospective clinical studies or in post hoc analyses of randomized clinical trials as negative predictive biomarkers for response to EGFR-targeted therapies. In addition, it is well-known that nongenetic alterations may also drive resistance to anti-EGFR therapy, particularly in right-sided tumors, which are not included in the PRESSING panel and deserve further study.

    In conclusion, this study sheds more light on anti-EGFR primary resistance mechanisms in patients with mCRC, which enhances our ability to better select patients for initial anti-EGFR-based therapy based on factors beyond tumor sidedness and RAS and BRAF status.

    Further studies are warranted to validate Morano and colleagues’ findings and to find novel mechanisms of primary and acquired resistance to anti-EGFR therapy. This will continue to help us to accurately tailor targeted treatment to individual patients with mCRC.

    References:

    Arnold D, et al. Ann Oncol. 2017; doi:10.1093/annonc/mdx175.

    Pietrantonio F, et al. Eur J Cancer. 2015;doi:10.1016/j.ejca.2015.01.054.

    Pietrantonio F, et al. JAMA Oncol. 2019;doi:10.1001/jamaoncol.2019.1467.

    Venook AP, et al. J Clin Oncol. 2017;doi:10.1200/JCO.2017.35.15_suppl.3503.

     

    Mohamed Salem, MD

    HemOnc Today Next Gen Innovator

    Levine Cancer Institute at Atrium Health

    Alberto Puccini, MD

    University of Genoa

    IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Disclosures: Salem reports speaker and consultant roles with Taiho, and a consultant role with Exelixis. Puccini reports no relevant financial disclosures.