Cetuximab Plus Pembrolizumab Well Tolerated in RAS Wild-Type mCRC

Patrick Boland, MD

The combination of cetuximab (Erbitux) and pembrolizumab (Keytruda) was found to be well tolerated in patients with RAS wild-type metastatic colorectal cancer (mCRC), according to findings of a phase Ib/II study presented at the 2018 Gastrointestinal Cancers Symposium.

In this trial, 9 patients with RAS wild-type mCRC with an ECOG performance status 0 to 2 were enrolled to receive pembrolizumab at a fixed dose of 200 mg for 3 weeks with standard cetuximab at a 400 mg/m² loading dose followed by 250 mg/m² weekly. Additionally, correlative serial biopsies were performed both at baseline and at 9 weeks. Primary objectives for this study were to examine the adverse event (AE) profile of the combination and estimate the objective response rate (ORR), as well as the 6-month progression-free survival (PFS).

Monotherapy with cetuximab has previously demonstrated a median PFS of 4.4 months and an ORR of 19.8%. Investigators note that an anti-EGFR monoclonal antibody such as cetuximab may have immunomodulatory impact, including via antibody-dependent cell-mediated cytotoxicity.

Findings presented at the 2018 Gastrointestinal Cancers Symposium by lead author Patrick Boland, MD, showed that the most common AEs were xerosis, dermatitis acneiform rash, hypomagnesemia, vomiting, and fatigue. Although there were minimal grade 3 toxicities, 3 patients experienced grade 3 hypomagnesemia. Grade 3 rash, urticarial, hypocalcemia, elevated alkaline phosphatase, and ascites were also observed. Out of the 9 patients enrolled, 6 achieved stable disease lasting more than 16 weeks.

"At this point, we have shown this to be safe with no new AEs. It remains to be seen whether this is better than just giving cetuximab alone, it is still early," said Boland, an assistant professor of oncology at Roswell Park Cancer Institute, in an interview with OncLive.

Investigators concluded that the combinations of cetuximab and pembrolizumab was well tolerated and is safe to be administered at full dosages. Additionally, disease control was demonstrated in the majority of patients.

Cetuximab is approved in patients with metastatic CRC who are of RAS wild-type histology, and preclinical data suggest that it triggers immunogenic cell death. This agent was initially approved in 2004 as a second-line treatment for patients with EGFR-expressing mCRC in combination with irinotecan. However, in 2012, the approval was expanded to include first-line treatment of patients with KRAS wild-type mCRC in combination with irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI). This decision was based on the retrospective analyses of the CRYSTAL trial of cetuximab and FOLFIRI, as well as the OPUS trial, which added folinic acid, 5-FU, and oxaliplatin (FOLOX-4).

Pembrolizumab is currently approved for unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H or dMMR colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan. This approval occurred in May 2017, and was based on the data from 149 patients with MSI-H or dMMR cancers enrolled across 5 single-arm clinical trials. Ninety of those patients had CRC, and the ORR in that population was 36%. Overall, the ORR with pembrolizumab was 39.6% (95% CI, 31.7%-47.9%), including a 7.4% complete response rate (n = 11) and a 32.2% partial response rate (n = 48).

"Since this was conceived and started we have started to think differently about what tumors we treat with cetuximab or panitumumab in terms of left-sided or right sided, or if it should be given upfront as initial therapy as opposed to later on in therapy," Boland added.

Next steps with this combination include a phase II study, which will enroll an additional 33 patients (NCT02713373). This study will assess the true efficacy of cetuximab plus pembrolizumab, with dual primary endpoints of ORR and a PFS of 6 months.

This phase II trial is currently recruiting patients who are RAS wild-type and have received at least 1 prior systemic therapy in the metastatic or unresectable disease setting, are naïve to anti-EGFR therapy, and have measurable disease per RECIST 1.1 criteria.

Boland PM, Hutson A, Maguire O, et al. A phase Ib/II study of cetuximab and pembrolizumab in RAS-wt mCRC. J Clin Oncol. 2018;36(suppl 4S; abstr 834).

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