Novel Combinations Explored in CRC With Rare Gene Mutations

Tanios S. Bekaii-Saab, MD

Tanios S. Bekaii-Saab, MD

In a case-based-style discussion, Tanios S. Bekaii-Saab, MD, and Wells Messersmith, MD, reviewed the treatment of patients with colorectal cancer (CRC) whose tumors express rare gene mutations or molecular signatures.

Promising responses observed with targeted therapies in these populations warrant the use of next-generation sequencing to determine who will benefit from precision treatment. The 2 experts led their discussion at the4th AnnualSchool of Gastrointestinal Oncology^™, hosted by Physicians’ Education Resource^®, LLC, in Washington, DC.¹

TargetingNTRKFusions

“[NTRK fusion] is an incredibly rare target, but it is a relevant target,” said Bekaii-Saab of the Mayo Clinic. “The NCCN [National Comprehensive Cancer Network] guidelines²have included a footnote stating that larotrectinib [Vitrakvi] would be an acceptable option for patients [with NTRK  fusion-positive metastatic CRC] who have progressed on first- and second-line therapy.”

The approval of larotrectinib was based on data from 3 trials that were published in the  New England Journal of Medicine  last year.³Of the 55 patients enrolled in the overall cohort, 4 had CRC. The primary endpoint of overall response rate showed that 75% of patients in the study experienced a partial response or better.

“That is  looking  at  all  of  the  tumors  combined,”  BekaiiSaab  said.  “For  colon  cancer,  the  actual  response  is  about 30% to 40%.”

Due to the rarity of this mutation, Bekaii-Saab warned that clinicians must consistently test patients to find the small subset who may benefit from TRK inhibitors.

Poor Prognosis WithBRAFV600E

In CRC,  BRAF  mutations occur at  a rate of  8%  to 15%,  and the predominant mutation is a single-base substitution of valine by glutamic acid at position 600 (V600E) within the activation segment.

“There’s an association with right-sided [cancers], female patients, older age, and MSI [microsatellite instability]—high status, which is an epigenetic mechanism,” said Messersmith of the University of Colorado School of Medicine.

Messersmith reminded the audience that BRAF  mutations have  historically  been  associated with  poor  prognosis. In  the phase III CRYSTAL trial, patients with  BRAF  wild-type (WT) status had better rates of overall survival compared with those who had  BRAF-mutant tumors, regardless of the therapy regimen.⁴

When targeted therapies were first used to target this mutation, it became clear that single-agent BRAF inhibitors were not enough to induce a tumor response. “The problem with BRAF is that when you inhibit it, you get overexpression of CRAF and ARAF, and you also have downstream expression of  signaling molecules  that  increase  EGFR  activation,” he said. This leads to adaptive feedback reactivation of MAPK signaling that is often mediated by EGFR.5  “Unfortunately, it is very difficult to try [to] block this [MEK/ERK] pathway, so just using 1 drug is not going to work,” he said.

Combination therapies that simultaneously target EGFR may be key to the success of BRAF inhibition, Messersmith said. Adding  the  BRAF  kinase  inhibitor  vemurafenib  (Zelboraf) to treatment with the EGFR inhibitor cetuximab (Erbitux)  and irinotecan  more than  doubled progression-free survival in patients with  BRAF  V600E mutations and  extended  RAS  WT  advanced  disease  compared  with those who received the cetuximab and irinotecan alone  (4.4 vs 2 months, respectively) in the phase II SWOG 1406 trial (HR, 0.42).⁶

Another strategy  for  BRAF-mutant  tumors  is  MEK  and BRAF  inhibitor combinations;  this is  being tested in  the BEACON CRC trial. This 3-arm trial is testing the combination  of encorafenib  (Braftovi), binimetinib  (Mektovi), and cetuximab. The 2 comparator arms are testing encorafenib or FOLFIRI (folinic acid, fluorouracil, and irinotecan), both in  combination with cetuximab.⁷Updated results  of the phase  III  trial  showed  26.1%  response  rate,  and  these  results are slated for submission to the FDA for market approval of the combination in the second half of 2019.

He discussed other anti-BRAF/MEK combinations, such as dabrafenib (Tafinlar) and trametinib (Mekinist), a promising combination that had a modest response rate (21%) when used in combination with the EGFR inhibitor panitumumab (Vectibix).⁵Both combinations have been added to the updated NCCN guidelines for second-line and subsequent treatment of CRC.²“Most of these [regimens] are not tested in non-V600E mutations,” Messersmith said.

Wells Messersmith, MD

Wells Messersmith, MD

Microsatellite-Unstable Tumors

Messersmith reviewed the relationship between mismatch repair (MMR) proteins, which repair base—base mismatches that occur during DNA replication and recombination, and microsatellites, which are short, repeated DNA sequences that are highly prone to such mutations. Correctly functioning MMR systems tend to target and repair microsatellite alterations. MSI is the result of impaired, or deficient, MMR.

MSI-high tumors can have either acquired or germline origins. In Lynch syndrome, germline mutations in 1 of the mismatch repair genesMLH1,MLH2,MSH6,PMS2, orEPCAMwill increase the patient’s lifetime risk of certain carcinomas, including CRC. For acquired MSI, hypermethylation of theMLH1promoter and epigenetic silencing ofMLH1may cause the aberration within the tumor.

Patients in the MSI-high subgroup have shown positive responses to anti—PD-1 therapy with nivolumab (Opdivo) and ipilimumab (Yervoy), a trend observed regardless of PD-L1 expression,BRAF/KRASmutational status, or clinical history of Lynch syndrome.⁸

“The key issue with immunotherapy is that…many clinicians have patients on these agents for years,” Messersmith concluded. “Now the question is: When can we take them off? When is it safe?”TT

References

1. Bekaii-Saab T, Messersmith W. Handling rare molecular subtypes in GI malignancies. Presented at: 4th Annual School of Gastrointestinal Oncology^™; April 27, 2019; Washington, DC.
2. NCCN Clinical Practice Guidelines in Oncology. Colon Cancer, version 2.2019. National Comprehensive Cancer Network website. bit.ly/2mCS0rT. Published May 15, 2019. Accessed May 16, 2019.
3. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.
4. Van Cutsem E, Kohne C-H, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutations status.J Clin Oncol. 2011;29(15):2011-2019. doi: 10.1200/JCO.2010.33.5091.
5. Corcoran RB, Andre T, Atreya CE, et al. Combined BRAF, EGFR, and MEK inhibition in patients with BRAFV600E-mutant colorectal cancer.Cancer Discov. 2018;8(4):428-443. doi: 10.1158/2159-8290.CD-17-1226.
6. Kopetz S, McDonough SL, Morris VK, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). J Clin Oncol. 2017;35(suppl 4; abstr 520). doi: 10.1200/JCO.2017.35.4_suppl.520.
7. Array Biopharma announces Braftovi + Mektovi + Cetuximab meet primary endpoints of ORR and OS in phase 3 BEACON CRC trial interim analysis for the treatment of BRAF(V600E)-mutant metastatic colorectal cancer [news release]. Boulder, CO; Array BioPharma, Inc.; May 21, 2019. bit.ly/2F1rkt7. Accessed June 7, 2019.
8. Andre T, Lonardi S, Wong M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142.J Clin Oncol. 2018;36(suppl 4; abstr 553). doi: 10.1200/JCO.2018.36.4_suppl.553.