Targeted Therapies Make Major Strides in mCRC Management


The treatment algorithm in metastatic colorectal cancer has gone from accounting only for the sidedness of the primary tumor, performance status, volume of disease, and potential resectability to also include the genetics of the tumor, particularly for patients in need of second-line therapy.

Christine M. Parseghian, MD

Christine M. Parseghian, MD

The treatment algorithm in metastatic colorectal cancer (mCRC) has gone from accounting only for the sidedness of the primary tumor, performance status, volume of disease, and potential resectability to also include the genetics of the tumor, particularly for patients in need of second-line therapy, explained Christine M. Parseghian, MD.

“For several years, we were stuck with regorafenib [Stivarga] and TAS-102 [trifluridine/tipiracil; (Lonsurf)], and thankfully just over the past few years, we’ve seen immunotherapy come in, HER2-directed therapy make its way from breast and gastric cancer over to CRC, as well as BRAF-mutated patients being eligible for BRAF inhibitors and seeing incredible responses with NTRK inhibitors in patients with NTRK fusions,” said Parseghian, an assistant professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, in a virtual presentation during the 39th Annual CFS®, a program hosted by the Physicians’ Education Resource® (PER®), LLC.1

BRAF V600E Mutations

BRAF V600E mutations are present in upward of 10% of patients with CRC and are associated with a median overall survival (OS) of 11 months vs 30 months in those without the mutation, said Parseghian. However, the results of the phase 3 BEACON CRC trial (NCT02928224) showed that patients with BRAF V600E mutations who received the combination of encorafenib (Braftovi) and cetuximab (Erbitux)––which is now FDA approved––with or without binimetinib (Mektovi) as second- or third-line therapy had a median OS of 9.3 months vs 5.9 months with standard chemotherapy.2

“Given the nice responses in the second- and third-line setting, we are now trying to see how we can improve outcomes in patients who we know are BRAF mutated from the get-go,” said Parseghian.

To that end, the phase 2 ANCHOR-CRC trial (NCT03693170) is evaluating the combination of encorafenib and cetuximab with binimetinib as frontline therapy in patients with mCRC. Preliminary findings from the study, which were presented at the 2021 Gastrointestinal Cancers Symposium, demonstrated that the triplet regimen elicited an objective response rate (ORR) of 47.8% (n = 44), with a “remarkable” disease control rate (DCR) of 88%, Parseghian explained.3

HER2 Overexpression

HER2 overexpression is more commonly found in left-sided tumors vs right-sided tumors, with a 5% prevalence rate in RAS wild-type tumors vs 2.5% in RAS-mutant tumors, said Parseghian.

Several anti-HER2 combinations have been studied in patients with chemotherapy-refractory HER2-positive mCRC, such as in the phase 2 HERACLES (NCT03225937) and My Pathway (NCT02091141) trials. In HERACLES, patients who received the combination of trastuzumab (Herceptin) and lapatinib (Tykerb) experienced a “really nice” ORR of 30% and a median duration of response (DOR) of 8.7 months, Parseghian said.4 Notably, in the study, HER2 positivity was defined as immunohistochemistry (IHC) of 3+ or IHC of 2+ and fluorescence in situ hybridization positivity.

“The regimen was very well tolerated in the refractory setting, with some gastrointestinal toxicities and hypokalemia,” said Parseghian.

In My Pathway, patients who received the combination of trastuzumab and pertuzumab (Perjeta) experienced an ORR of 32% and a median DOR of 6.1 months, showing similar activity and tolerability as trastuzumab/lapatinib, said Parseghian.5

Parseghian also called attention to the phase 2 MOUNTAINEER (NCT03043313) and DESTINY-CRC01 (NCT03384940) trials.

In MOUNTAINEER, patients with chemotherapy- and VEGF-refractory disease who received the combination of trastuzumab and tucatinib (Tukysa) derived an ORR of 55%, in patients with RAS wild-type disease, and a median progression-free survival (PFS) of 6.2 months, in the overall population.6

“We’re seeing really incredible responses with this combination considering a lot of these patients had more than 2 prior lines of therapy,” said Parseghian.

In DESTINY-CRC01, patients who had received at least 2 prior regimens experienced an ORR of 45% with the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu).7 One caveat of the study that distinguishes it from prior HER2-directed trials is that patients could have received prior HER2-directed therapy, said Parseghian.

“This combination is really a nice option even for patients who have progressed on dual HER2-directed therapy,” said Parseghian.

“Dual HER2-directed therapy and ADCs have robust activity in HER2-positive mCRC with a favorable toxicity profile, and exceed outcomes as expected from second-line options, which is very exciting,” said Parseghian.

Microsatellite Instability–High (MSI-H)

Although pembrolizumab (Keytruda) has been approved since 2017 for patients with pretreated MSI-H mCRC, only recently reported was its move into the frontline setting, explained Parseghian, citing the phase 3 KEYNOTE-177 trial (NCT02563002). In the study, patients with MSI-H mCRC experienced improved PFS (HR, 0.59) when treated with frontline pembrolizumab vs investigator’s choice chemotherapy.8 The median PFS was 16.5 months vs 8.2 months, respectively. Although the median OS was not reached vs 36.7 months (HR, 0.74), respectively, OS benefit was not proven. Notably, 60% of patients crossed over to the pembrolizumab arm, which may have confounded the results, said Parseghian.

Other checkpoint inhibitors that have been studied in the pretreated setting include nivolumab (Opdivo) alone and in combination with ipilimumab (Yervoy) in the phase 2 CheckMate 142 trial (NCT02060188). In the study, nivolumab led to an ORR of 31%, a 69% DCR at 12 weeks, and a 1-year PFS rate of 50%.9 With the combination, an ORR of 55% was reported, with an 80% DCR, and a 1-year PFS rate of 71%.10

“This dual checkpoint approach is really a nice option for patients with good performance status,” said Parseghian. “We do see some increase in the immunogenic adverse effects, but really not significant enough to withhold this as an option.”

Another checkpoint inhibitor now approved for use is dostarlimab-gxly (Jemperli), which received an accelerated approval for patients with mismatch repair-deficient recurrent or advanced solid tumors, as determined by an FDA-approved test, who have progressed on or following previous treatment and who have no satisfactory alternative options.11

The approval was based on findings from the multicohort phase 1 GARNET trial (NCT02715284), in which the PD-1 inhibitor led to an ORR of 36.2% in patients with CRC.12

NTRK Fusions

Fusions, although enriched in MSI-H tumors, are rare, occurring in less than 1% of patients with mCRC. However, patients with gene fusions can experience deep and durable response when paired with the appropriate targeted therapy, explained Parseghian. In the case of NTRK, both larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are approved for use, having shown ORRs of 50% and 25%, respectively, in patients with CRC.13,14

“We’re seeing really wonderful data [with these agents], which represent nice options [for patients],” said Parseghian.

KRAS G12C Mutations

Finally, Parseghian highlighted the most recent druggable target on the block, KRAS G12C, for which there are now 2 investigational agents under study in mCRC: sotorasib (Lumakras) and adagrasib.

“We’ve been trying to target KRAS for decades, so this is really the first time that we’ve been able to do something [for these patients],” said Parseghian.

To date, both agents have been studied alone and in combination with EGFR inhibitors. In the case of sotorasib, the agent induced an ORR of 7.1% and a median DCR of 73.8% in the phase 1 CodeBreaK 101 trial (NCT04185883); when paired with panitumumab (Vectibix), the ORR and DCR was 27% and 81%, respectively.15

In the phase 1/2 KRYSTAL study (NCT03785249), adagrasib monotherapy led to an ORR of 22% and a median DCR of 87%; in combination with cetuximab (Erbitux), the ORR and DCR rate was 43% and 100%, respectively.16

“[Sotorasib and adagrasib] are oral drugs, especially when they’re given as monotherapy, and they’re extremely well tolerated in patients who would otherwise be getting very toxic third-line agents,” said Parseghian.

“We wouldn’t have been able to make these advances had it not been for these very recent trials, so it’s really important that we encourage all our patients to join these big clinical trials as new and exciting therapies come their way,” concluded Parseghian.


  1. Parseghian CM. Targeted therapies based on sequencing in GI malignancies. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY.
  2. Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39(4):273-284. doi:10.1200/JCO.20.02088
  3. Van Cutsem E, Taieb J, Yaeger R, et al. O-10 ANCHOR CRC: results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer. Ann Oncol. 2021;32(suppl 3):S222. doi:10.1016/j.annonc.2021.05.014
  4. 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
  5. 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
  6. Strickler JH, Zemla T, Ou FS, et al. 4795 - Trastuzumab and tucatinib for the treatment of HER2 amplified metastatic colorectal cancer (mCRC): Initial results from the MOUNTAINEER trial. Ann Oncol. 2019;30(suppl 5):v198-v252. doi:10.1093/annonc/mdz246
  7. Siena S, Di Bartolomeo M, Raghav K, et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2021;22(6):779-789. doi:10.1016/S1470-2045(21)00086-3
  8. Andre T, Shiu KK, Kim TW, et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). J Clin Oncol. 2021;39(suppl 15):3500. doi:10.1200/JCO.2021.39.15_suppl.3500
  9. Overman MJ, McDermott R, Leach JL, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182-1191. doi:10.1016/S1470-2045(17)30422-9
  10. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi:10.1200/JCO.2017.76.9901
  11. GSK receives FDA accelerated approval for JEMPERLI (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors. News release. GlaxoSmithKline. August 17, 2021. Accessed November 5, 2021.
  12. Andre T, Berton D, Curigliano G, et al. Safety and efficacy of anti–PD-1 antibody dostarlimab in patients (pts) with mismatch repair-deficient (dMMR) solid cancers: Results from GARNET study. J Clin Oncol. 2021;39(suppl 3):9. doi:10.1200/JCO.2021.39.3_suppl.9
  13. 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
  14. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi:10.1016/S1470-2045(19)30691-6
  15. Fakih M, Falchook GS, Hong DS, et al. 434P - CodeBreaK 101 subprotocol H: Phase Ib study evaluating combination of sotorasib (Soto), a KRASG12C inhibitor, and panitumumab (PMab), an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer (CRC). Ann Oncol. 2021;32(suppl 5):S530-S582. doi:10.1016/annonc/annonc698
  16. Weiss J, Yaeger RD, Johnson ML, et al. LBA6 - KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (Cetux) in patients (Pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
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