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BRAF-Mutant Colorectal Cancer: Latest Findings for Targeted Treatment


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The phase II ANCHOR CRC study, the largest prospective study of BRAF inhibitor–based therapy as first-line treatment of metastatic colorectal cancer, has met its primary endpoint, with 47.8% of patients with metastatic colorectal cancer responding to first-line treatment with encorafenib, binimetinib, and cetuximab, according to Eric Van Cutsem, MD, of University Hospital Leuven in Belgium.1

Eric Van Cutsem, MD

Eric Van Cutsem, MD

After a median follow-up of almost 5 months, median progression-free survival (a secondary endpoint) was 5.8 months, and median overall survival was 17.2 months, he reported at the ESMO World Congress on Gastrointestinal Cancers 2021.1

“Overall, the results reported with this combination are similar to that observed with recommended chemotherapy-based regimens in first-line BRAF-mutant metastatic colorectal cancer,” Dr. Van Cutsem noted. “These encouraging results support exploring the combination of encorafenib plus cetuximab with chemotherapy in the first-line setting.” This is now being done in the phase III BREAKWATER study.

Although BRAF-targeted therapy was proven effective as first-line therapy in this patient -population, the value of this approach as maintenance was not borne out in the MODUL trial, which evaluated fluorouracil (5-FU)/leucovorin plus cetuximab and vemurafenib after induction, other investigators reported at the Congress.2 Lessons were learned, however, about the molecular landscape of colorectal cancer.

ANCHOR CRC Background

For the 10% to 20% of patients with BRAF V600E mutations, the prognosis is poor. Treatment with chemotherapy has traditionally yielded disappointing outcomes, although recently, in the first randomized prospective study—FIRE-4.5—first-line treatment with FOLFOXIRI (5-FU, leucovorin, oxaliplatin, irinotecan) plus bevacizumab led to a 51% response rate, median progression-free survival of 8.3 months, and median overall survival of 16.8 months.3

Subsequently, BEACON evaluated targeted treatment with a doublet (encorafenib and cetuximab) and a triplet (encorafenib, binimetinib, and cetuximab) in the second and later lines, finding median overall survival to be 9.3 months with either regimen vs 5.9 months with standard chemotherapy.4 These results led to the design of the phase II ANCHOR CRC trial, Dr. Van Cutsem explained.

Study Details

ANCHOR CRC enrolled patients with BRAF V600E mutations previously untreated for metastatic disease. Dr. Van Cutsem presented the main analysis on 95 patients (median age, 65; 60% with right-sided or transverse tumors; 76% with ≥ 2 metastatic sites). The primary endpoint was objective response rate by investigator assessment.

“The primary endpoint was clearly met,” Dr. Van Cutsem announced. The objective response rate was 47.8% (95% confidence interval [CI] = 37.3%–58.5%), and the lower limit of the 95% confidence interval exceeded 30% (the specified threshold). Disease control was achieved by 88%, and the majority of patients experienced tumor regression. Subgroup analysis showed no meaningful differences in benefit, he said.

After a median follow-up of almost 5 months, median progression-free survival was 5.8 months. Median overall survival was 17.2 months, with 65% alive at 12 months, 49% alive at 18 months, and 29% alive at 24 months, Dr. Van Cutsem reported.

The median duration of exposure for encorafenib, binimetinib, and cetuximab was almost 5 months, and the relative dose intensity was 93% to 95% for each.

Most patients received subsequent therapies, which mostly included an oxaliplatin-based doublet with or without bevacizumab (22%) and FOLFOXIRI with or without bevacizumab (12.6%). At the time of this analysis, 21% of patients were still receiving study treatment.

The incidence of at least one adverse event was 52%, but grade ≥ 3 toxicities were uncommon, mostly anemia (10.5%) and decreased appetite (10.5%). Intestinal obstruction grade ≥ 3 was identified in 15% of patients (mainly due to metastases).

Three patients (3%) suffered an adverse event leading to death (two were possibly treated-related); 24% had one that led to discontinuation of at least one study drug; and 75% had a dose interruption or reduction. Quality of life, assessed with different instruments, showed no meaningful changes over baseline in patient-reported outcomes.

MODUL: No Impact of Maintenance Therapy

Despite the benefit shown for BRAF-targeted therapy in the first-line setting in Cohort 1 of the MODUL study, patients with metastatic BRAF-mutated colorectal cancer derived no benefit from maintenance therapy that included a BRAF-targeted agent, according to Michel Ducreux, MD, of Gustave Roussy in Villejuif, France, and Université Paris-Saclay.2

“Median progression-free survival appeared to be a little longer in the control arm, whereas median overall survival and response rate appeared to be longer in the experimental arm,” he reported at the Congress.

Michel Ducreux, MD

Michel Ducreux, MD

MODUL is an adaptable, phase II signal-seeking trial testing novel agents as first-line therapy for predefined subgroups of patients with metastatic colorectal cancer. It is the largest randomized umbrella maintenance study in the first-line metastatic colorectal setting and the largest chemoimmunotherapy study to date.

Previously untreated patients received up to eight cycles of induction treatment with FOLFOX and bevacizumab and then were randomly assigned to experimental maintenance in one of four biomarker-driven cohorts or to the control arm. Cohort 1 involved 90 patients with BRAF-mutant disease, almost all with synchronous metastases. The primary endpoint was progression-free survival (surgery-censored).

Ultimately, 60 patients were randomly assigned after induction treatment to one of the following arms in a 2:1 ratio:

  • Experimental treatment: 5-FU/leucovorin every 2 weeks plus cetuximab every 2 weeks and vemurafenib daily (n = 40).
  • Control: 5-FU/leucovorin every 2 weeks or capecitabine orally plus bevacizumab every 2 weeks (n = 20).

MODUL’s translational studies include an exploratory genomic analysis performed on tissue or blood at the beginning of the treatment and on plasma samples collected upon disease progression or at the end of treatment. Investigators compared variants identified at the two different time points to look at drivers of acquired resistance to cetuximab plus vemurafenib.

Clinical Outcomes With Maintenance

Despite longer exposure to the experimental treatment (36 vs 21 weeks), no major differences were observed between the experimental and control arms in terms of progression-free survival. Median progression-free survival was 10.0 months with targeted treatment and 11.6 months with standard chemotherapy (hazard ratio [HR] = 0.95; P = .087). For overall survival, the difference was slightly more in favor of the experimental arm, with a median overall survival of 24.0 months vs 21.3 months (HR = 0.69; P = .29). Objective response rates were 50% and 25%, respectively (P = .06).

In the biomarker analysis of 49 patients, baseline samples of both tissue and plasma showed no differences between the arms in mutations, copy number, alterations, and rearrangements. But in samples evaluated at the end of treatment or after disease progression, clear differences emerged, most strikingly an enrichment in alterations in MAP kinase pathway genes in the experimental arm. “This means that with this treatment, we are inducing something in the tissue that can be seen with circulating tumor DNA evaluation,” Dr. Ducreux said.

“Due to events unrelated to Cohort 1, the MODUL study was closed to enrollment prematurely,” he indicated. “Results from the Cohort 1 efficacy analysis should therefore be considered descriptive.” 

DISCLOSURE: Dr. Van Cutsem has served as a consultant or advisor to Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Daiichi Sankyo, GSK, Halozyme, Incyte, Lilly, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; and has received institutional research funding from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Lilly, Merck, Merck KGaA, Novartis, Roche, and Servier. Dr. Ducreux has an immediate family member who has been employed by Sandoz; has received honoraria from Amgen, Bayer, Celgene, Ipsen, Lilly, Merck Serono, MSD Oncology, Novartis, Roche/Genentech, and Servier; has served as a consultant or advisor to Amgen, Celgene, HalioDx, Ipsen, Lilly, Merck Serono, Novartis, Roche, Pierre Fabre, and Servier; has participated in a speakers bureau for Bayer, Celgene, Ipsen, Merck KGaA, and Roche; has received institutional research funding from Keocyt and Roche; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Bayer, Ipsen, Merck Serono, and Roche.

REFERENCES

1. Van Cutsem E, Taieb J, Yaeger R, et al: ANCHOR CRC: A single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E-mutant metastatic colorectal cancer. ESMO World Congress on Gastrointestinal Cancers 2021. Abstract O-10. Presented July 2, 2021.

2. Ducreux M, Tabernero J, Grothey A, et al: 5-FU/LV + cetuximab + vemurafenib as maintenance therapy for BRAFmut metastatic colorectal cancer: Efficacy, safety, and exploratory biomarker findings from Cohort 1 of the MODUL trial. ESMO World Congress on Gastrointestinal Cancers 2021. Abstract O-9. Presented July 2, 2021.

3. Stintzing S, Heinrich K, Tougeron D, et al: Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: The phase-II FIRE-4.5 study (AIO KRK-0116). J Clin Oncol 39 (suppl):3502, 2021.

4. Kopetz S, Grothey A, Van Cutsem E, et al: Encorafenib plus cetuximab with or without binimetinib for BRAF V600E-mutant metastatic colorectal cancer: Quality-of-life results from a randomized, three-arm, phase III study versus the choice of either irinotecan or FOLFIRI plus cetuximab (BEACON CRC). J Clin Oncol 38(suppl):8, 2020.


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