EGFR-MET Bispecific Antibody Shows Promise for Metastatic Head & Neck Cancer

Amivantamab achieved a 75% clinical benefit rate and 45% overall response rate in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), according to preliminary results from the phase 1b/2 OrigAMI-4 study.

Background

Most patients with head and neck cancer present with locally advanced disease. Though many patients are treated with the intention of curing the cancer, about half will experience a recurrence.

“Most patients who develop recurrent or metastatic disease that is not amenable to further surgery or radiation will be treated initially with immunotherapy, either alone or in combination with standard chemotherapy. However, most of these patients will ultimately have disease progression and will need a second line of therapy,” says Jessica Geiger, MD, a medical oncologist with Cleveland Clinic’s Head & Neck Oncology team.

“There’s been no consensus or standard treatment beyond frontline therapy in these patients. The objective response rates of current second-line treatments is 15-20% and there are limited treatment options, so there’s a huge unmet need within this population.”

The majority of patients with this disease overexpress epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) factor receptor, which is associated with poor outcomes. The bispecific antibody amivantamab is already approved in EGFR-mutated advanced non-small cell lung cancer

Dr. Geiger is part of a global team of researchers studying the safety and efficacy of amivantamab as monotherapy and in combination with different agents and in multiple settings for treating advanced HNSCC.

“What we’ve seen in other cancer-directed therapies is when you block one part of cell signaling, it can amplify other parts of the cell signaling cascade, so if you block EGFR, at some point, MET may become overactivated,” explains Dr. Geiger. “By blocking EGFR and MET simultaneously, amivantamab addresses the proliferation of the cancer itself by blocking MET, one of the major resistance mechanisms for EGFR blockade.”

Study design

Cohort 1 of the OrigAMI-4 study investigated the safety and efficacy of subcutaneous amivantamab for patients with HNSCC unrelated to human papillomavirus who experienced disease progression on chemotherapy and a checkpoint inhibitor.

Eighty-six patients received 1,600 mg of amivantamab on cycle 1, day 1 and 2,500 mg after that. CT scans or MRIs were conducted at screening, at six weeks after cycle 1, day 1 and then every six weeks afterwards for a period of one year.

The primary endpoint was overall response rate.

Study outcomes

In this heavily pretreated population, the overall response rate was 45%, with 75% of patients receiving a clinical benefit (response or stable disease).

In the patients who responded, the median time to response was 6.4 weeks, and median duration of response was 7.2 months. Median progression-free survival was 6.8 months, which is an improvement on historical standards for recurrent HNSCC where the median overall survival in typically three to six months. Dr. Geiger notes that long-term follow-up is needed for more meaningful data about patient outcomes.

Adverse events were in line with previous studies of amivantamab. Ninety-two percent of patients experienced at least one treatment-related side effect (45% having grade 1 or 2 and 47% having grade ≥3), such as stomatitis, rash or peripheral edema.

The most common side effect was an acne-form rash. “Because of the dual blockade of amivantamab, this rash can be pretty severe,” explains Dr. Geiger. “Lung cancer studies of the medication have informed the prophylactic regimen for skin toxicity, which we’ve adopted as our standard of care for this and similar drugs in development.

Also, using the subcutaneous version of this medication instead of IV has reduced infusion-related toxicities and is more convenient for patients because there’s less time in clinic.”

Dr. Geiger notes that although this is a small, single-arm study, the results are promising and that with further randomized studies, amivantamab has the potential to represent a new standard of care. Many questions remain, such as whether this therapy could be moved earlier in the treatment sequence or be combined with other agents to increase efficacy.

What’s next

A segment of cohort 1 patients in OrigAMI-4 is still receiving treatment, and additional cohorts (including newly diagnosed patients who will receive amivantamab in the neoadjuvant setting) have recently begun accruing. Further results will be forthcoming as the study progresses and patients continue to enroll.

Cleveland Clinic Cancer Institute is also looking into participating in the OrigAMI-5 study evaluating whether adding the medication to carboplatin and pembrolizumab in the frontline setting would improve upon the current standard of care.

Dr. Geiger cautions that if patients have already started on cetuximab they would be ineligible for amivantamab since it attacks a similar target. “If the patient’s disease is progressing rapidly, treating with standard of care is usually appropriate,” she says. “However, if time allows, early referrals to an academic cancer center like Cleveland Clinic Cancer Institute may help inform decision-making around treatment sequence and clinical trial options.”