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Intensified Regimen for Metastatic CRC Fails to Improve Outcomes

— Combination of modified FOLFOXIRI/panitumumab also caused greater toxicity, study showed

MedpageToday

CHICAGO -- For metastatic colorectal cancer patients with RAS and BRAF wild-type disease, intensifying the upfront chemotherapy backbone in combination with the anti-EGFR antibody panitumumab (Vectibix) provided no additional benefit in terms of treatment activity, according to the phase III .

Among the population of 435 patients, those treated with a schedule of modified (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus panitumumab achieved objective response rates (ORRs) that were comparable to the control arm of (fluorouracil, leucovorin, oxaliplatin) plus panitumumab (73% vs 76%, respectively, P=0.526).

There were also no differences in terms of early tumor shrinkage, deepness of response, R0 resection rate, and progression-free survival (PFS), reported Chiara Cremolini, MD, PhD, of the University of Pisa in Italy.

There were, however, higher rates of grade 3/4 adverse events -- particularly diarrhea -- in the investigational arm.

"[Modified FOLFOXIRI] plus panitumumab should not be recommended as upfront therapy for RAS and BRAF wild-type metastatic colorectal cancer patients," Cremolini said at the American Society of Clinical Oncology (ASCO) annual meeting here. Full results of the study were published simultaneously in the (JCO) as well.

The ORR observed in the FOLFOX/panitumumab group was substantially higher than the expected rate of 60%, Cremolini noted.

She and ASCO invited discussant Smitha Krishnamurthi, MD, of the Cleveland Clinic in Ohio, both suggested this was due to the fact that 88% of the patients had left-sided tumors.

Krishnamurthi said that in the and studies -- both of which evaluated FOLFOX/panitumumab -- 78% of patients had left-side tumors, and ORRs were 68% and 64% in the two trials, respectively.

"For patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer, because this was mostly a left-sided population, FOLFOX plus panitumumab leads to a high response rate," she said. "Clearly there is no benefit to adding irinotecan, and we can spare our patients the toxicities of irinotecan."

Krishnamurthi said that even though TRIPLETE was a negative trial, the results are nonetheless practice changing "for those of us who have attempted [the FOLFOXIRI regimen] in the past."

"I have tried this, and now thanks to Dr. Cremolini and colleagues I won't be doing that again," she said.

In addition to the lack of difference in ORR, the study found no significant differences between the FOLFOXIRI and FOLFOX groups, respectively, when it came to:

  • Early tumor shrinkage: 57% vs 58%
  • Deepness of response: 48% vs 47%
  • R0 resection rate: 25% vs 29%
  • PFS: 12.7 vs 12.3 months

In subgroup analyses, the investigators observed two "significant" interactions for ORR, Cremolini reported. In particular, she said, it seemed that women and those with primary right-sided tumors appeared to derive more benefit from the traditional FOLFOX strategy:

  • Women: OR 0.43 (95% CI 0.21-0.88)
  • Right-side tumors: OR 0.26 (95% CI 0.08-0.85)

"These results were not confirmed in progression-free survival, thus, in my opinion, somehow limiting the reliability of these findings," she said.

Regarding safety, grade 3/4 adverse events were reported in 69% of patients in the FOLFOXIRI arm, and 57% in the FOLFOX group. There were higher rates of grade 3/4 diarrhea (23% vs 7%) and neutropenia (32% vs 20%) in the FOLFOXIRI arm, while skin rash was more frequent in the FOLFOX arm (29% vs 19%).

Serious adverse events occurred in 33% and 21% of patients in the investigational and control groups, respectively. Three deaths due to treatment-related adverse events (sepsis in one patient and diarrhea in two patients) were reported in the FOLFOXIRI group versus none in the FOLFOX group.

Trial Design

TRIPLETE was a prospective, open-label, multicenter, randomized phase III study that included patients with metastatic colorectal cancer recruited from 57 oncology units in Italy.

Eligible patients (ages 18-75 years; ECOG performance status of 0-2 for those ≤70 or ECOG score 0 if age 71 or above) had histologically confirmed colorectal adenocarcinoma and RAS (KRAS and NRAS exons 2, 3, and 4) and BRAF 600 wild-type status of the primary tumor and/or related metastasis. They also were required to have unresectable and measurable metastatic disease, and adequate bone marrow, hepatic, and renal function.

Patients were stratified according to performance status, primary tumor location, and liver-only metastases, and randomized 1:1 to either standard treatment with FOLFOX plus panitumumab or the intensified approach with modified FOLFOXIRI/panitumumab. In both arms of the study, induction therapy was administered for up to 12 cycles, and followed by maintenance therapy with 5-fluorouracil, leucovorin, and panitumumab until disease progression.

"A change in the schedule of FOLFOXIRI was required due to the high rate of grade 3 and 4 gastrointestinal toxicities," Cremolini noted. "As compared to the classic FOLFOXIRI regimen ... we adopted lower doses of both 5-fluorouracil and irinotecan."

Overall Response as Primary Outcome?

Cremolini and co-authors acknowledged in the JCO study that prolonging overall survival (OS) is the ultimate goal of systemic treatment for metastatic cancer, but that the choice of OS as a primary endpoint "would have hampered its feasibility." ORR was preferred, the researchers wrote, because of "its reliable association with OS in previous trials investigating anti-EGFR-based regimens, which was not demonstrated for PFS."

Krishnamurthi agreed with the decision to use ORR: "We would be using this regimen trying to convert patients with unresectable disease to resectable," she said. "So we really want to know the response rate."

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was supported by the GONO (Gruppo Oncologico del Nord Ovest) Foundation. Amgen provided panitumumab in the experimental arm and partial financial support for conduct of the study.

Cremolini reported financial relationships with Roche, Amgen, Bayer, Servier, MSD, Merck, Pierre Fabre, and Organon; co-authors also reported multiple relationships with industry.

Primary Source

American Society of Clinical Oncology

Cremolini C, et al "Modified FOLFOXIRI plus panitumumab (mFOLFOXIRI/PAN) versus mFOLFOX6/PAN as initial treatment of patients with unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC): Results of the phase III randomized TRIPLETE study by GONO" ASCO 2022; Abstract LBA3505

Secondary Source

Journal of Clinical Oncology

Rossini D, et al "Upfront modified fluorouracil, leucovorin, oxaliplatin, and irinotecan plus panitumumab versus fluorouracil, leucovorin, and oxaliplatin plus panitumumab for patients with RAS/BRAF wild-type metastatic colorectal cancer: The phase III TRIPLETE study by GONO" J Clin Oncol 2022; DOI: 10.1200/JCO.22.00839.