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Rechallenge with an EGFR inhibitor in addition to standard therapy led to significantly better progression-free survival (PFS) in third-line metastatic colorectal cancer (mCRC) versus standard therapy alone, a small randomized trial showed.

Median PFS improved modestly from 2.5 months with trifluridine-tipiracil (Lonsurf) alone to 4.0 months with the addition of panitumumab (Vectibix). Patients identified by circulating tumor (ct)DNA as having RAS/BRAF wild-type tumors had a median PFS of 6.0 months with panitumumab and at least a three-fold improvement in 6- and 12-month PFS rates.

The findings support the clinical utility of ctDNA-guided rechallenge with anti-EGFR therapy for patients with refractory mCRC, noted Teresa Troiani, MD, PhD, of Università Degli Studi Della Campania "Luigi Vanvitelli" in Naples, Italy, and colleagues in .

"With the limitations of a small trial, we provided evidence of improved clinical activity of anti-EGFR rechallenge therapy compared with the standard of care," the authors wrote. "These findings also support use of pretreatment plasma ctDNA for patient selection."

In addition to improvements in median, 6-month, and 12-month PFS, the risk of progression decreased and the objective response rate increased with the addition of the EGFR inhibitor, they added.

"Several anti-EGFR rechallenge trials are ongoing," the authors acknowledged. "Although these studies will define the most effective regimens, the supports the clinical benefit of liquid biopsy-guided anti-EGFR rechallenge therapy."

The results mirror to some extent those of a of ctDNA-guided rechallenge with panitumumab alone, which showed a 30% partial response rate and a disease control rate of 63%.

"This is a new path. This is not something we routinely do," Suneel Kamath, MD, of the Cleveland Clinic, told 名媛直播. "Usually, once there is progression on an EGFR inhibitor, we sort of move on from that and don't re-treat. I think it's a reasonable thing to do, but it certainly is a more moderate improvement."

"Another interesting aspect of this trial is that we haven't really combined an EGFR inhibitor with TAS-102, or Lonsurf [trifluridine-tipiracil], as was done in this study," he added. "It's a modest improvement, but I would say decently clinically meaningful because this is a very heavily pretreated population."

The trial definitely supports the use of ctDNA guidance to select patients for treatment, Kamath noted. A strength of the study is that it used a liquid biopsy panel that is used routinely in clinical practice, as opposed to a "homegrown" panel that would not be useful to oncologists who do not have a research laboratory.

EGFR inhibitors plus cytotoxic agents are standard first-line therapy for wild-type RAS mCRC, but emergence of resistance mutations eventually leads to treatment failure, Troiani and colleagues said. Most wild-type RAS cancer cells are killed by chemotherapy plus an EGFR inhibitor. Second-line treatment with chemotherapy and an anti-angiogenic agent, for example, could kill the mutant clones, potentially restoring the cancer's sensitivity to EGFR inhibition.

Regorafenib (Stivarga) or trifluridine-tipiracil are frequently used in third-line therapy, but have modest benefits, the authors continued. Rechallenge with an EGFR inhibitor has been proposed as an alternative third-line treatment, and several single-arm trials have supported the strategy. Key unanswered questions include what is the best approach to EGFR rechallenge and how does it compare with standard third-line therapy.

Troiani and team enrolled patients with refractory wild-type RAS mCRC from seven Italian centers, who had at least a partial response to first-line chemotherapy plus EGFR inhibition. All patients received trifluridine-tipiracil and were randomized to receive panitumumab or no additional therapy. The primary endpoint was PFS.

Data analysis included a subgroup of 62 patients who had pretreatment analysis by liquid biopsy for alterations in KRAS, NRAS, and BRAF^V600. The patients had a median age of 65-66, and men accounted for 58% of the study population.

The results showed that the addition of panitumumab reduced the hazard ratio for disease progression or death by 52% (95% CI 0.28-0.82, P=0.007). Three patients in the panitumumab arm had partial responses versus none in the control arm, and disease control for 4 months or longer occurred in 74.2% of the panitumumab group versus 38.4% of the control group (P=0.009).

Patients identified as having pretreatment plasma wild-type RAS/BRAF tumors had better 6- and 12-month PFS rates with panitumumab (38.5% vs 13.0%, 15.4% vs 0%, respectively). Fifteen patients who had tumors with wild-type NRAS, KRAS, BRAF^V600, EGFR, ERBB2, MAP2K1, and PIK3CA had a median PFS of 6.4 months. Two of the three partial responses occurred in this subgroup, and 11 others had stable disease.

Grade 3/4 adverse events (AEs) occurred in 16 of 31 (51.6%) patients in the panitumumab arm versus nine (29.0%) in the control group. No treatment-related deaths occurred in either arm, and no patients discontinued treatment because of AEs.

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