Targeted Agents May Be Moving Closer to Frontline for Treatment of mCRC

Treatment targeting molecular pathways such as <em>BRAF, </em>HER2<em>,</em> and <em>RAS</em> has typically been reserved for later lines of therapy for patients with metastatic colorectal cancer. Benjamin A. Weinberg, MD, said that agents targeting these pathways are not yet ready for the upfront setting, but data from ongoing trials suggest that these agents may eventually have a role to play in first- and second-line treatment.

Benjamin A. Weinberg, MD

Treatment targeting molecular pathways such asBRAF,HER2,andRAShas typically been reserved for later lines of therapy for patients with metastatic colorectal cancer (mCRC). Benjamin A. Weinberg, MD, said that agents targeting these pathways are not yet ready for the upfront setting, but data from ongoing trials suggest that these agents may eventually have a role to play in first- and second-line treatment.

“We think about HER2 a lot in breast cancer, obviously; also, in other GI cancers there are patients with colon and rectal cancers that areHER2amplified,” Weinberg, an assistant professor of medicine at Georgetown-Lombardi Comprehensive Cancer Center, told an audience at the 2019 Gastrointestinal Oncology Conference. “While we're screening for [microsatellite instability—high] MSI-H, we also want to know theirRASandBRAFstatus upfront. You can make an argument that knowing HER2 status is very important as well.”

In HERACLES, investigators enrolled 27 patients with HER2-positive mCRC that was

refractory to standard of care, including cetuximab (Erbitux) or panitumumab (Vectibix), into a phase II trial at 4 medical centers in Italy. These patients were assigned to intravenous trastuzumab (Herceptin) and oral lapatinib (Tykerb) until evidence of disease progression.

The overall response rate at a median follow-up of 94 weeks was 30%. One patient (4%) had a complete response (CR) and 7 (26%) had partial responses (PRs).1

Those findings are similar to observations from MyPathway, an ongoing, phase IIa, multiple basket study (NCT02091141). In results published inLancet Oncologyin April 2019, patients withHER2-amplified mCRC were assigned to trastuzumab plus pertuzumab (Perjeta). One (2%) patient had a CR and 17 (30%) had PRs for an ORR of 32% (95% CI, 20%-45%).2

The median progression-free survival (PFS) was 2.9 months (95% CI, 1.4-5.3) with a median overall survival (OS) of 11.5 months (95% CI, 7.7-not evaluable).

That combination was further evaluated in the CETIRI trial. Investigators separated patients withRAS/BRAFwild-type mCRC across 2 distinct cohorts. In cohort 1 (n = 98), patients were assigned to trastuzumab/pertuzumab and investigators testedHER2amplification using dual in situ hybridization.3

Cohort 2 (n = 70), which included 16 patients withHER2amplification and 54HER2-nonamplified control patients who had received prior anti-EGFR therapy, was assigned to receive cetuximab plus irinotecan followed by trastuzumab/pertuzumab after progression.

The median PFS in cohort 1 favoredHER2-nonamplified patients (2.8 vs 8.1 months; HR, 7.05; 95% CI, 3.4-14.9;P<.001). Investigators validated those findings in cohort 2, in which the median PFS for amplified patients was 2.8 months compared with 9.3 months for nonamplified (HR, 10.66; 95% CI, 4.5-25.1;P<.001).

Multivariable analyses confirmedHER2amplification as a single independent predictor for poor PFS on anti-EGFR therapy in both cohort 1 (HR, 6.48; 95% CI, 3.1-13.6;P<.001) and cohort 2 (HR, 10.1; 95% CI, 4.3-23.9;P<.001).

BRAF-Targeted Therapies

BRAFis B for bad,” Weinberg said. “It's a bad mutation to have.”

In an updated analysis of data from the phase III TRIBE trial published in 2015, investigators found thatBRAFmutations are associated with poor outcomes in patients with unresectable mCRC. Adults aged 18 to 70 years were assigned to frontline bevacizumab (Avastin) plus FOLFIRI (irinotecan, fluorouracil, and folinic acid) or FOLFOXIRI (irinotecan, fluorouracil, folinic acid, and oxaliplatin) and investigators assessed treatment efficacy in patients withRASorBRAFmutations.

The median OS in theRASandBRAFwild-type subgroup was 37.1 months (95% CI, 29.7-42.7) compared with 25.6 months (95% CI, 22.4-28.6) in theRASmutation—positive subgroup (HR, 1.49; 95% CI, 1.11-1.99) and 13.4 months (95% CI, 8.2-2411) in theBRAFmutation—positive subgroup (HR, 2.79; 95% CI, 1.75-4.46;P<.0001).&shy;&shy;4

Weinberg said prelinical models showed that there was a synergistic effect to adding cytotoxic chemotherapy while blocking EGFR upstream and BRAF downstream. Kopetz et al tested that treatment in the SWOG S1406 trial.

A total of 109 patients with previously treatedBRAFV600—mutated and extendedRASwild-type mCRC were randomly assigned to irinotecan and cetuximab with (n = 49) or without vemurafenib (Zelboraf; n = 50).5

The median PFS favored the vemurafenib group (4.3 vs 2.0 months; HR, 0.48; 95% CI, 0.31-0.75;P= .001). The same was true for OS (9.6 vs 5.9 months; HR, 0.73; 95% CI, 0.45-1.17;P= .19).

“This cancer is not likeBRAFV600E—positivemelanoma, where you can get BRAF activity with monotherapy. Here you need to combine [agents] to hit multiple points on the cascade,” Weinberg said. “In [terms of] PFS, there was quite a significant improvement. These are patients who have a fairly poor prognosis, who don't often respond well to chemotherapy, or if they do, it's a very short-lived response. This [study shows] a doubling of the PFS.”

He added that OS was not statistically significant, but there was a trend towards improvement in the experimental arm.

These findings led to the phase III open-label, international, BEACON CRC trial of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab in patients with previously treatedBRAF-mutant CRC. A total of 665 patients withBRAFV600—mutant mCRC were randomly assigned to the triplet, encorafenib and cetuximab, or investigator’s choice of irinotecan or FOLFIRI and cetuximab as the control arm.

The median OS was 9.0 months in the triplet arm compared with 5.4 months in the standard-of-care arm, leading to a 48% reduction in the risk for death (HR, 0.52; 95% CI, 0.39-0.70; 2-sidedP<.0001). ORR also favored the triplet arm, 26% versus 2% (P<.0001).6

Weinberg noted that the triplet does not contain chemotherapy, avoiding the attendant toxicities.

When these results were presented at the 2019 World Congress on Gastrointestinal Cancers., Tanios S. Bekaii-Saab, MD, professor of medicine, Mayo Clinic, noted that the prognosis for these patients is “horrible.”

“This is a transformation of the way we treat this disease,” he said. “This is a transformational study for a group of patients who, typically, do not see much benefit from chemotherapy and sees no benefit, zero, from EGFR inhibitors and we did not have an option for them.”

The combination of encorafenib and cetuximab demonstrated a statistically significant improvement in ORR per blinded independent central review (BICR) at 20.4% versus 1.9% (P<.0001). The median OS was also improved with the doublet compared with the control arm at 8.4 months versus 5.4 months, respectively (HR, 0.60; 95% CI, 0.45-0.79;P= .0003).


  1. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial.Lancet Oncol. 2016;17(6):738-746. doi: 10.1016/S1470-2045(16)00150-9.
  2. Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study.Lancet Oncol. 2019;20(4):518-530. doi: 10.1016/S1470-2045(18)30904-5.
  3. Raghav K, Loree JM, Morris JS, et al. Validation of HER2 Amplification as a Predictive Biomarker for Anti—Epidermal Growth Factor Receptor Antibody Therapy in Metastatic Colorectal Cancer.JCO Precis Oncol.2019;3:1-13. doi: 10.1200/PO.18.00226.
  4. Cremolini C, Loupakis F, Antoniotti C, et al. FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.Lancet Oncol. 2015;16(13):1306-1315. doi: 10.1016/S1470-2045(15)00122-9.
  5. Kopetz S, McDonough SL, Lenz HR, et al. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG S1406).J Clin Oncol. 2017;35(suppl; abstr 3505). doi: 10.1200/JCO.2017.35.15_suppl.3505.
  6. Kopetz S, Grothey A, van Cutsem E, et al. BEACON CRC: a randomized, 3-arm, phase 3 study of encorafenib and cetuximab with or without binimetinib vs. choice of either irinotecan or FOLFIRI plus cetuximab in BRAF V600E. Presented at: 2019 World Congress on Gastrointestinal Cancers; July 3-6, 2019; Barcelona, Spain. Abstract LBA-006.