KRAS-Variant HNSCC Outcomes May Improve With Cetuximab

Joanne B. Weidhaas, MD, PhD

Patients with head and neck cancer whose disease is associated withKRASvariant had significantly better progression-free survival (PFS) and overall survival (OS) when treated with the monoclonal antibody cetuximab (Erbitux), according to findings of a retrospective analysis of a randomized trial.

During the first year of follow-up, cetuximab-treated patients withKRASvariant had almost a 70% reduction in the hazard for death or progression as compared with aKRAS-variant subgroup whose treatment did not include cetuximab. The hazard for OS during the first 2 years was improved by 80% in patients withKRAS-variant disease treated with cetuximab versus those who did not receive the agent.

The PFS benefit dropped out after the first year and the OS benefit after the second year. The reason for the rapid loss of benefit remained unclear but could reflect a short term of exposure to the drug (8 weeks), reported Joanne B. Weidhaas, MD, PhD, during the 2016 American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston, Massachusetts.

The cetuximab benefit “may represent inherent resistance to cisplatin-radiation therapy or a weak immune response, overcome by cetuximab,” said Weidhaas, a professor of Radiation Oncology at the University of California, Los Angeles. “TheKRASvariant andp16status are both important in head and neck squamous cell carcinoma (HNSCC) in predictive response. Elevated TGFb1 levels could perhaps explain the immunosuppression and elevated toxicity that we observed.”

The findings came from a new analysis of the RTOG (now NRG) 0522 trial—a phase III randomized comparison chemoradiation with or without cetuximab for patients with HNSCC. Identification of radiation biomarkers of response has proven challenging, and availability of tissue from the RTOG 0522 patient population afforded an opportunity to continue the exploration.

The trial had a primary endpoint of PFS and secondary endpoints that included OS. The overall trial results were negative, as the addition of cetuximab failed to improve PFS or OS.

“Clearly, there were some people who responded,” said Weidhaas. “We wanted to test for theKRASvariant in this population.”

TheKRASvariant is a germline mutation in a microRNA-binding site in KRAS. The variation disrupts regulation of KRAS, occurs in a variety of tumor types, and is present in as many as 30% of patients with cancer patients, said Weidhaas. Previous studies had demonstrated an association between the variant and response to cancer therapy, including cetuximab.

In the current analysis, investigators evaluated the relationship ofKRAS-variant status to cetuximab response,p16status, and plasma levels of the immune protein TGFb1.

The trial included 891 evaluable patients, 413 of whom had samples available forKRAS-variant testing, and 376 patients had plasma samples available for TGFb1 measurement.KRASassessment showed that 17% of the patients had the variant, evenly distributed in the treatment groups and not enriched in thep16-positive subgroup.

The results showed that patients with theKRASvariant treated with cetuximab had a hazard of 0.31 for progression or death during the first year, as compared with patients who had the variant and were not treated with the antibody (95% CI, 0.10-0.94;P=.04). After year 1, however, the hazard ratio for progression or death increased to 1.76 for cetuximab-treated patients.

The OS analysis showed a similar pattern of benefit during the first 2 years of follow-up: a hazard ratio of 0.19 for cetuximab-treated patients with theKRASvariant (95% CI, 0.04-0.86;P=.03), followed thereafter by a turn in the opposite direction, resulting in a hazard ratio of 2.34 (95% CI, 0.58-9.41;P=.23).

In a multivariate analysis of the PFS data, a favorable effect of cetuximab on distant metastasis appeared to drive the benefit (HR, 0.45), as compared with locoregional failure (HR, 0.84).

Searching for an explanation for the survival benefit, investigators explored cetuximab’s effect on immunity. Specifically, they examined interaction amongKRASvariant, cetuximab, andp16, asp16-positive tumors are immunogenic at baseline. They also studied TGFb1, a known marker of immunity found in the circulation.

The results demonstrated a significant three-way interaction (P= .02). Patients who had theKRASvariant but werep16positive had much worse survival than with conventional chemotherapy and radiation therapy (HR, 2.48;P=.19). The addition of cetuximab appeared to reverse the unfavorable prognosis in that subset of patients (HR, 0.22;P= 0.14), said Weidhaas.

High levels of TGFb1 are known to inhibit radiation-induced antitumor immunity, and cetuximab has been shown to overcome TGFb1 inhibition of natural killer cells. Data from RTOG 0522 showed thatKRAS-variant patients had elevated levels of TGFb1. When treated without cetuximab,KRAS-variant patients with elevated TGFb1 appeared to have an increased incidence of grade 3/4 toxicity (OR, 2.31), although the interaction betweenKRASand TGFb1 did not achieve statistical significance.

Reference:

Weidhaas JB, Harris J, Schaue D, et al. The KRAS-variant is a biomarker of cetuximab response, potentially through altered immunity in head and neck cancer: re-analysis of NRG Oncology/RTOG 0522. Presented at: 2016 ASTRO Annual Meeting; Boston, Massachusetts, September 25-28, 2016.