Chiara Cremolini, MD, PhD, Assesses Panitumumab Plus Triplet vs Doublet Chemotherapy in RAS/BRAF Wild-Type Metastatic CRC

Chiara Cremolini, MD, PhD, discussed results from the phase 3 TRIPLETE study of triplet chemotherapy plus panitumumab in previously untreated patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.

Intensification of the upfront chemotherapy failed to demonstrate clinical benefit when combined with the anti-EGFR monoclonal antibody panitumumab (Vectibix) in patients with previously untreated, unresectable RAS/BRAF wild-type metastatic colorectal cancer (mCRC), according to results from the phase 3 TRIPLETE study (NCT03231722) presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Chiara Cremolini, MD, PhD, professor of medical oncology at the University of Pisa in Italy and chief investigator of this study, discussed these new data in an interview with CancerNetwork®.

In this prospective, open-label study, patients with previously untreated RAS/BRAF wild-type mCRC were randomized to receive either doublet chemotherapy consisting of leucovorin, fluorouracil (5-FU), and oxaliplatin (mFOLFOX6) or triplet chemotherapy consisting of the same regimen plus irinotecan (mFOLFOXIRI), both with the addition of panitumumab. No significant differences in outcomes between the experimental group (arm B; n = 218) and the control group (arm A, n = 217) emerged in the data. The overall response rate (ORR) was 73% (n = 160) in arm B and 76% (n = 165) in arm A (OR. 0.87; 95% CI, 0.56-1.34; P = .526). Moreover, no differences were observed between arms A and B for early tumor shrinkage (58% vs 57%, respectively; P = .878), depth of response (47% vs 48%; P = .845), or R0 resection rate (29% vs 25%; P = .317). Investigators thus concluded that triplet chemotherapy failed to improve outcomes and meanwhile increased rates of gastrointestinal (GI) toxicity vs doublet chemotherapy in patients with molecularly selected and mostly left-sided mCRC.

CancerNetwork®: What was the rationale for the TRIPLETE study?

Cremolini: One of the treatment options for patients with RAS and BRAF wild-type mCRC is a combination of doublet chemotherapy with an anti-EGFR monoclonal antibody [like panitumumab]. While there are a lot of data supporting intensification of the upfront chemotherapy backbone when given in combination with bevacizumab [Avastin], at least in some clinically selected patients, [there’s not a lot of data showing the same with] anti-EGFR antibodies [like panitumumab]. Several phase 2 trials have investigated chemotherapy in combination with anti-EGFR, but they did not provide conclusive results.

[However], triplet chemotherapy plus an anti-EGFR antibody was associated with a promisingly high ORR and conversion to resectability in those trials. The only caveat was a high incidence of some specific grade 3/4 chemotherapy-related adverse events [AEs], which led us to modulate the schedule of FOLFOXIRI by reducing the dose of both 5-FU and irinotecan.

As such, the aim of the TRIPLETE study was to verify whether treatment with the anti-EGFR antibody panitumumab [benefits from] an intensification of the upfront chemotherapy regimen in a molecularly-selected patient population with RAS and BRAF wild-type mCRC. The aim was to determine if this intensification provides any added value, especially in terms of clinical activity.

How did this regimen perform this patient population?

The regimen performed quite well—we observed an ORR of 73%. However, the trial unfortunately failed to meet the primary end point because the control arm, [consisting of those treated with] FOLFOX plus panitumumab, reported an objective response rate of 76% which far exceeded our expectations based on the data available at the time. [In other words], triplet chemotherapy plus panitumumab showed a high level of activity in terms of early tumor shrinkage and depth of response but did not outperform doublet chemotherapy plus panitumumab. Similarly, there was no difference in PFS and there was an increase in the rate of some grade 3/4 AEs, particularly diarrhea, in the triplet chemotherapy arm.

Did anything else stand out regarding the safety profile?

FOLFOXIRI treatment is feasible [given reductions] in the dosage of 5-FU from 3200 mg/m2 to 2400 mg/m2 and in the irinotecan dosage from 165 mg/m2 to 150 mg/m2. These are reduced dosages compared with the classic FOLFOXIRI regimen, but [even still] there was an increased burden of GI toxicity, especially diarrhea, [and so these safety data] did not support the use of this regimen given the lack of a clear efficacy advantage.

Are there any plans for future analyses based on this research?

This was a huge effort because 435 patients were enrolled in this study and because we collected tissue and plasma samples. There’s an ongoing translational analysis program examining the usefulness of liquid biopsies, both at baseline and during treatment. [These could help us] monitor responses to treatment by prospectively evaluating if alterations associated with acquired resistance to anti-EGFR therapy emerge at the same time as radiological evidence of disease progression. This is just one of the questions the translational analysis program will likely answer.

What are some of the implications of these trial results?

I’m happy about the negative results of this trial because this is good news for patients: we do not need to intensify chemotherapy. [Triplet chemotherapy] only increased the burden of AEs in the patient population most likely to benefit from these targeted agents.

Given these results and the overall body of data emerging from this ASCO Annual Meeting, doublet chemotherapy plus anti-EGFR therapy seems to be the preferred treatment for the vast majority of patients with RAS and BRAF wild-type, microsatellite stable mCRC.

Reference

Cremolini C, Rossini D, Lonardi S, 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. J Clin Oncol. 2022;40(17):LBA3505. doi: 10.1200/JCO.2022.40.17_suppl.LBA3505