Actionable Subsets of Patients With CRC Drive Progress

Kristen K. Ciombor, MD, MSCI

With an overall 5-year survival survival rate of under 15% in patients with metastatic colorectal cancer (CRC), investigators have sought to parse mutational analyses to increase gains. In addition to the observed upswing for HER2-directed therapies for this population, other therapeutic advances have made headway for larger subtypes and the overall population. For instance, a focus on the negative prognostic marker BRAF, which is mutated in up to 10% of patients with CRC, has produced gains in addressing the feedback loops that lead to therapeutic resistance.¹ Further, investigators have pushed the needle in moving therapies to the frontline setting as well as evaluating novel approaches with the addition of immune checkpoint inhibitors.

“As exciting as seeing [progress in] these different subsets [of patients with CRC] and seeing how actionable they are becoming, it is also frustrating because you see that only 2% of your population has a particular actionable mutation,” moderator Kristen K. Ciombor, MD, MSCI, said in a recent OncLive Peer Exchange®. “But I think it really behooves us to keep looking for those and treating them accordingly and encourages our cancer centers and our community sites, which help identify these patients to continue the effort to do so and to continue clinical trials.” Ciombor was joined by experts in gastrointestinal oncology to discuss the latest findings presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) as well as next steps for several established regimens and the trials that may lead to breakthroughs in the field.

BRAF V600E: Unpacking the Mutations

Nearly 90% of patients with CRC harboring a BRAF mutation have BRAF V600E–mutant disease, which has an approximate overall survival (OS) of 20 months.1-3 “BRAF in the metastatic setting for CRC is a little bit more prevalent than HER2 amplification—approximately 8% to 10% in some series—and…it strikes fear in my heart just knowing [a patient has this mutation] because it’s such a negative prognostic factor,” Ciombor said. “We typically see that BRAF V600E–mutant [disease] has a very aggressive phenotype. We knew from the beginning that it was prognostic but now we know it’s a predictive biomarker, too, which is important and exciting.” Ciombor noted that it is crucial to keep in mind where the mutation occurs, specifically if it is at codon 600. “[To detect if it is] truly the V600E mutation or one of the more atypical [mutations], we typically will detect that mostly by NGS [next-generation sequencing] but also by PCR [polymerase chain reaction]. In the metastatic setting, we often can clinically tell even before we know the results that this may be a more aggressive BRAF mutation.” Joel R. Hecht, MD, added that this is a population for whom adverse outcomes can occur before treatment can begin. “I can think of patients who progressed [as treatments are] getting set up,” he said. He added that these patients do not perform particularly well with chemotherapy, which may be explained by rebound ERK activation.³

For patients with CRC who harbor a BRAF V600E mutation, the standard of care is the chemotherapy regimen FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus the VEGF inhibitor bevacizumab (Avastin).^2,3 This is followed by the combination of BRAF inhibitor encorafenib (Braftovi) plus the EGFR inhibitor cetuximab (Erbitux), which was approved for use in the second-line setting based on data from the phase 3 BEACON CRC trial (NCT02928224).^3,4

“We know that single-agent inhibition doesn’t work particularly well [for these patients]…we know that there are feedback loops from a lot of work from [laboratories] showing that by blocking upstream with an anti-EGFR [agent], a combination was much more effective and made this [approach] a lot more effective than single agent,” Hecht said. “As [data from] BEACON show, the combination is much more effective than chemotherapy.” In the phase 3 study, patients were randomly assigned to receive the triplet of encorafenib, binimetinib (Mektovi) plus cetuximab (n = 224), encorafenib plus cetuximab (n = 220), or the control arm of investigator’s choice of chemotherapy plus cetuximab.⁵ The median OS for the triplet vs the control was 9.3 months (95% CI, 8.2-10.8) vs 5.9 (95% CI, 5.1-7.1) with an HR of 0.60 (95% CI, 0.47-0.75). The HR for the doublet vs the control was similar at 0.61 (95% CI, 0.49-0.77), with the doublet eliciting a median OS of 9.3 months (95% CI, 8.0-11.3).⁵

“In [data from] earlier trials it looked like the triplet might be better,” Hecht said. “But that’s why we do randomized studies…we know that 3 drugs are probably a little bit more toxic. Even though numerically there were some small differences, it looked that both the triplet and the doublet were far superior to chemotherapy alone but there wasn’t a huge difference between the triplet and the doublet. That led to encorafenib and cetuximab [being approved].”

Response rates were numerically higher for patients in the triplet arm vs the doublet arm per blinded independent central review at 26.8% (95% CI, 21.1%33.1%) vs 19.5% (95% CI, 14.5%-25.4%), respectively. The response rate among patients in the control arm was 1.8% (95% CI, 0.5%-4.6%). The median duration of response was 4.4 months and 5.5 months in the triplet and doublet arms, respectively. In terms of ongoing response, 31.7% of responders in the triplet arm had a response lasting at least 6 months compared with 37% of responders in the doublet arm.5 The median progression-free survival (PFS) between the triplet and the control arm was 4.5 months (95% CI, 4.2-5.4) vs 1.5 months (95% CI, 1.5-1.9) with an HR of 0.42 (95% CI, 0.33-0.53). The HR for the doublet vs the control arm was 0.44 (95% CI, 0.35-0.55); the doublet elicited a median PFS of 4.3 months (95% CI, 4.1-5.4).⁵

Despite the successes seen with the combination therapies, Hecht noted that there is much room for progress. “We’re seeing patients with CRC who live for a long time with now median survivals bumping up against 3 years in some trials, and the percentage of individuals alive at 5 years is continuing to increase,” he said. “Those with BRAF V600E–mutant disease still don’t do well. This is what you see with a driver mutation, where you get resistance after a period of time. Yes, they do much better [than before] but the PFS of approximately 6 months and OS was still only at 9 months, is not so great in second line, but it certainly helps patients.”

Pashtoon M. Kasi, MD, MS, said that resistance mechanisms, such as KRAS, NRAS, and MAP2 kinase mutations, are not necessarily actionable until better drugs become available in that pathway for this patient population. Data from a genomic analysis of patients enrolled in the BEACON study showed that KRAS and NRAS mutations as well as MET amplification were the most prevalent acquired mutations among those in the triplet (40.2%, 25.0%, and 19.6%) and doublet (44.6%, 36.6%, and 17.0%) treatment arms. In the control arm no patients had acquired KRAS mutations or had MET amplification; however, 3.2% of patients had an NRAS mutation.⁶ Additional findings showed that 3.6% of patients treated with the triplet, 16.1% of patients treated with the doublet, and 3.2% of patients who received the control therapy had acquired MAP2K1 mutations.

At least 1 acquired mutation in KRAS, NRAS, and MAP2K1, and/or amplification of MET, KRAS, BRAF, and IGFR1 per patient was found in 62.5%, 63.4%, and 7.4% of triplet-, doublet-, or control-treated patients, respectively.⁶ “What I found intriguing with the data resented is the fact that in over 90% of these patients, investigators were able to detect the BRAF V600E mutation in baseline ctDNA,” Kasi said. In the analysis, among 404 patients, 91.1% of patients had detectable BRAF V600E. “Early identification is helpful—if you’re able to detect it, you can then subsequently follow along. Unfortunately, as we know, a lot of these patients don’t do well…but there are anecdotal published reports on the loss of these clones, which may bring up the question of potentially rechallenging [patients].”

Moving Therapies Forward

Moving therapies upward in the treatment cycle may also have advantages, according to the panel. Ciombor noted that prior to the findings from the BEACON study showing that the doublet of encorafenib plus cetuximab was comparable to the triplet adding binimetinib, the trio were evaluated in the single-arm ANCHOR CRC study (NCT03693170), in which the regimen was administered in the firstline setting for patients with BRAF V600E–mutated mCRC.⁷

The combination improved on findings from BEACON with a median PFS of 5.8 months (95% CI, 4.6-6.4), a median OS of 17.2 months (95% CI, 14.1-not estimable [NE]), and an ORR of 47.8% (95% CI, 37.3%-58.5%) among 92 evaluable patients. The disease control rate was 88%.⁷

Despite this, Joleen M. Hubbard, MD, said the role of chemotherapy cannot be denied, as investigators of the phase 3 BREAKWATER trial (NCT04607421) demonstrated in recent data.⁸

“In the ANCHOR study, the response rates were great, but not as great as when combined with chemotherapy. That’s telling us that chemotherapy is adding something to these patients in addition to adding more BRAF-directed therapy,” she said. In the trial, investigators tested the addition of mFOLFOX6 (modified leucovorin calcium, fluorouracil, and oxaliplatin) or FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) to the combination of encorafenib and cetuximab.⁹ Data from the safety lead-in portion of the trial, presented at 2023 ASCO GU, showed that among 19 patients who received frontline encorafenib/cetuximab and mFOLFOX6, the ORR was 68.4% (95% CI, 46.0%-84.6%), with a complete response rate of 5.3% and a partial response rate of 63.2%. An additional 21.2% of patients reported stable disease. The median PFS was 11.1 months (95% CI, 8.5-NE).

Twelve patients received the frontline encorafenib/cetuximab and FOLFIRI and the ORR was 75.0% (95% CI, 46.8%-91.1%), with a CR rate of 16.7% and a PR rate of 53.3%. Stable disease was reported in 16.7%, with no patients experiencing disease progression; therefore, the median PFS was NE (95% CI, 13.8-NE).

“The safety run-in showed really encouraging response rates of the combination with FOLFOX and FOLFIRI upward of 60% to 70%, which is great for this tumor type that we know is fairly resistant to chemotherapy upfront,” Kanwal P.S. Raghav, MBBS, MD, said. “You do not see those kind of responses with BRAF-mutant disease even with first-line chemotherapy…. Now comes the harder part, which is doing the randomized trial and seeing whether the addition of chemotherapy really made a difference or is it just that we just moved the BRAF therapy forward? We are eagerly waiting for this study to finish and hopefully, this will help our patients with BRAF-mutant disease much more than the BEACON.” In terms of safety, Hubbard noted: “We’ll probably be able to have less toxicities from the targeted therapies with the doublet BRAF-directed therapy and then the known adverse effects of cytotoxic therapy, which we are good at dealing with now. The BREAKWATER regimen is going to be a better- tolerated regimen and I think has the potential to even improve outcomes beyond what we’ve seen with the ANCHOR study outcomes.”

Once more data in the up-front setting are released, Hecht noted that the work is not done as more questions will arise for those who go on to experience disease progression. “We also have the problem: What do we do next? Let’s say BREAKWATER is positive, as these are really good results,” Hecht said. “What do you do with the patient who’s now progressed on chemotherapy plus combination molecular therapy? Is there any benefit for keeping individuals on it even though we know they have resistance mechanisms? That’s always been the problem brought up with regimens such as FOLFIRINOX. What do you do next?”

However, as the panel noted in response, just getting patients to second-line therapy has been an ongoing struggle in the field, and this progress is not taken for granted. “One of the things that as a GI oncologist, you see if you go from trial to trial, you think that everyone who gets first-line treatment goes to second line,” Hecht said. “However, even among those without bad mutations, only approximately 60% to 70% who get first-line therapy ever get second-line therapy. They’re not all patients with BRAF-mutant disease. They fall off for other reasons, but this is a group that falls off quickly.” Raghav added: “It is a good question to answer but…for an aggressive tumor type, if you bring up all your treatment up front, you’re probably going to have that benefit. I would link this more to how we would treat pancreatic cancer, for example. The earlier you can bring the treatments, the better.” Another study the panel anticipates is from colleagues in Japan, which will evaluate encorafenib plus binimetinib plus cetuximab after progression on encorafenib plus cetuximab. The phase 2 BAYONET trial (jRCTs031210510) will test the hypothesis that patients who were refractory to treatment with a BRAF inhibitor and anti-EGFR may be sensitive to a triplet combination that includes a MEK inhibitor.⁹

“This approach is a kind of rechallenge,” Ciombor said. “Because the MET kinase pathway upregulation is a mechanism of resistance, maybe adding the MEK inhibition at that point will be a strategy we can employ, too. We have a lot of questions to answer in terms of sequencing, in terms of combinations, and BRAF in general, but at least we’re making some progress for our patients, which is the most important part.”

Digging Deeper in the Mutations

A subset of patients within BRAF V600E–mutant CRC are those who also present with microsatellite stability (MSS). To address this population, investigators have begun to explore combinations leveraging the anti–PD-1 immune checkpoint inhibitor nivolumab (Opdivo) in combination with encorafenib and cetuximab in the phase 2 SWOG 2107 trial (NCT05308446).¹⁰

“The rationale behind this study is that we’ve already established that in second-line or subsequent therapies, anti-EGFR plus a BRAF inhibitor combination is effective. It’s just not where we want it to be,” Raghav said. “We know from preclinical models that whenever you expose CRC to targeted therapies, whether it is anti-EGFR or a combination of a BRAF inhibitor and anti-EGFR, it creates this kind of genomic instability, which creates an MSI-H phenotype, a transient place where the tumors tend to have these mutations. That’s where we feel that is what could sensitize these cases with anti–PD-1 immunotherapy.” Data from a phase 1/2 single-center study (NCT04017650) support the initiation of the trial.10 At a median follow-up of 16.3 months, 22 patients were evaluable and had an ORR of 50% (95% CI, 28%-72%), with a median duration of response of 7.7 months. The median PFS was 7.4 months (95% CI, 5.6-NE) and the median OS was 15.1 month (95% CI, 7.7-NA). All patients who had a response had a PR; the disease control rate was 96% (95% CI, 77%-100%).¹¹

“This was a single-center study, which, fortunately because of its promising results, is now going into a cooperative group, national, randomized trial wherein you treated all patients who were BRAF, EGFR, PD-1 [inhibitor] naïve,” Raghav said. “Now, of course, we have to prove this in a randomized trial, whether this is really working or is the immunotherapy really adding something to this and that’s where the next randomized phase comes into picture. It will be interesting to see how these therapies and the combinations sort of evolve over a period.”

References

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8. Kopetz S, Yoshino T, Kim T, et al. BREAKWATER safety lead-in (SLI): encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41 (suppl 4):119. doi:10.1200/JCO.2023.41.3_suppl.119
9. Matsubara Y, Bando H, Kotani D, et al. BAYONET trial: a multicenter phase II trial of staged combination with encorafenib + binimetinib + cetuximab following encorafenib + cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer.J Clin Oncol. 2023;41(suppl 4):TPS271. doi:10.1200/JCO.2023.41.4_suppl.TPS271
10. Testing the addition of nivolumab to standard treatment for patients with metastatic or unresectable colorectal cancer that have a BRAF mutation. ClinicalTrials.gov. Updated March 27, 2023. Accessed April 1, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05308446
11. Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAF V600E metastatic colorectal cancer. J Clin Oncol. 2022;40(suppl 4):12. doi:10.1200/JCO.2022.40.4_suppl.012