Mary Caffrey

As was the theme of many of the presentations during the 2019 NCCN Annual Conference, changes to the guidelines in colorectal cancer (CRC) focused on expanded biomarker testing to guide treatment.

Work is needed in this area to fill the knowledge gaps in metastatic CRC, which has a 5-year survival rate of just 11%, said Wells A. Messersmith, MD, co-director of the developmental therapeutics program at the University of Colorado Cancer Center.

CRC has 4 consensus subtypes, known as CMS1, CMS2, CMS3, and CMS4, with varying lengths of overall survival (OS), said Messersmith.

He explained that while there are 13 FDA-approved drugs for CRC, until recently only 4 were biomarker-driven. The 2019 update adds treatment based on

The cost of expensive combination therapy is driving the quest for better biomarkers, Messersmith explained, citing data from his university&rsquo;s pharmacy that showed 24 to 30 months of combination therapy in metastatic  CRC exceeded $300,000 by 2013. At the same time, OS has increased incrementally. Spending more for better biomarker studies makes more sense than spending billions on therapies that don&rsquo;t work or could be harmful, he said.

With that, he reviewed studies and key updates for 2019:

an additional option was added for unresectable stage IV mCRC: mFOLFOXIRI plus the EGFR inhibitor panitumumab (Vectibix) for

wild-type metastatic CRC were randomized in a 2:1 ratio to mFOLFOXIRI plus panitumumab (n = 63) or mFOLFOXIRI alone (n = 33). The objective response rate (ORR) with the addition of panitumumab was 85.7% compared with 54.5% with mFOLFOXIRI alone.

Although microsatellite instability (MSI) and mismatch repair (MMR) is usually not inherited, this does not rule out Lynch syndrome, which is seen in 1% of cancers with

Germline testing is indicated if there is a strong family history.

The latest guidelines also include additional explanation of MMR immunohistochemistry testing for the 4 genes known to be mutated in Lynch:

New frontline immunotherapy treatment options listed in the NCCN guidelines for advanced or metastatic CRC are nivolumab (Opdivo) or pembrolizumab (Keytruda), or a combination of nivolumab and ipilimumab (Yervoy), both in dMMR and MSI-H only. These recommendations are category 2B and are intended for patients who are not appropriate candidates for cytotoxic combination regimens. These same immunotherapy options are also listed in the guidelines as second- and third-line recommendations for dMMR/MSI-H patients.

Larotrectinib (Vitrakvi) is now a second-line treatment option

gene fusion positive, based on a pivotal 2018 paper published in the

The pivotal analysis was also the basis of the FDA&rsquo;s November 2018 approval of larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an

gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The pivotal trial included 4 patients with CRC, 1 of whom achieved an objective response.

Combination therapies added to the guidelines as second-line options are: (1) dabrafenib (Tafinlar;

), plus cetuximab or panitumumab (EGFR mAb), (2) encorafenib (Braftovi; BRAF) plus binimetinib (Mektovi; MEK) plus cetuximab or panitumumab (EGFR mAb).

The regimen of encorafenib/binimetinib and an EGFR inhibitor is supported by findings from the safety lead-in phase of the phase III BEACON trial. In 30 patients with

V600E-mutant metastatic CRC, the estimated median progression-free survival with encorafenib/binimetinib plus cetuximab was 8.0 months and the estimated median OS was 15.3 months with a median duration of follow-up of 18.2 months.

The ORR was 48% by local assessment, with 3 patients achieving a complete response.

Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).

. 2017;35(15 suppl):3511 DOI: 10.1200/JCO.2017.35.15_suppl.3511.

Drilon A, Lactsch TW, Kummar S, et al. Efficacy of lacrotrectinib in TRK fusionpositive cancers in adults and children.

. 2018;378:731-739. DOI: 10.1056/NEJMoa1714448.

Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.

Articles

Wells A. Messersmith, MD, reviews key updates to the NCCN guidelines for the treatment of colorectal cancer.

Mary Caffrey | Authors

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New NCCN CRC Guidelines Include Updates in Testing, Treatment Options