Combination exhibits ‘impressive’ activity in HPV-negative head and neck cancer
The combination of ficlatuzumab and cetuximab extended PFS for patients with pan-refractory recurrent or metastatic head and neck squamous cell carcinoma, according to randomized phase 2 study results.
The benefit appeared confined to individuals with HPV-negative disease, and a phase 3 trial to further evaluate the regimen in that population is planned.
“HPV-negative disease is one aera of head and neck cancer where we haven’t made much progress,” investigator Barbara Burtness, MD, chief translational research officer for Yale Cancer Center and Smilow Cancer Hospital, as well as associate cancer center director for translational research at Yale Cancer Center, told Healio. “These cancers respond to chemotherapy and EGFR inhibitors, but the duration of response has not been great.
“There has been a breakthrough with the introduction of immune checkpoint inhibitors, but the majority of patients progress on those as well,” added Burtness, a Healio | HemOnc Today Editorial Board Member. “When we move into late lines of therapy, not many agents have shown promise. That’s one of the reasons people are so excited about this study.”
Background
Cetuximab (Erbitux, Eli Lilly), a monoclonal antibody that inhibits EGFR, is approved for treatment of patients with recurrent or metastatic HNSCC that progressed on platinum-based therapy.
However, many patients develop primary or acquired resistance to cetuximab. This limits the agent’s potential utility in this setting, according to study background.
Aberrant activation of the hepatocyte growth factor (HGF)/cMet pathway is an established resistance mechanism. cMet and HGF are overexpressed in approximately 70% to 80% of patients with HPV-negative HNSCC.
“Preclinical data and biomarker studies suggested you can see upregulation of cMet after EGFR targeting,” Burtness said. “It’s not necessarily mutated or amplified in most cases, but its expression is increased, so the possibility you could target this alone or in combination with EGFR inhibition was exciting.”
Ficlatuzumab (AV-299, Aveo Oncology) is a humanized IgG1 monoclonal antibody that targets HGF.
A phase 1 study showed the ficlatuzumab-cetuximab combination appeared safe and exhibited efficacy in a cohort of patients with cetuximab-resistant recurrent/metastatic HNSCC. Researchers reported a 17% objective response rate and 5.4-month median PFS.
Methods
Burtness and colleagues — including lead author Julie E. Bauman, MD, MPH, director of George Washington University Cancer Center — conducted a multicenter, noncomparative phase 2 study to further assess ficlatuzumab alone or with cetuximab as treatment of recurrent or metastatic HNSCC.
Investigators enrolled 60 patients between 2018 and 2020. Eligibility criteria included known HPV status, cetuximab resistance — defined as progression within 6 months of exposure in the definitive or recurrent/metastatic setting — and resistance to platinum and anti-PD-1 monoclonal antibody therapy.
Researchers assigned 27 patients to ficlatuzumab monotherapy administered at 20 mg/kg via IV every 2 weeks. The other 33 received ficlatuzumab at the same dose, plus cetuximab dosed at 500 mg/m2 every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or consent withdrawal.
PFS served as the primary endpoint. Protocol established statistical significance if the lower bound of the 90% CI excluded the historical control of 2 months.
Secondary endpoints included objective response rate, association of HPV status and cMet overexpression with efficacy, and toxicity.
Efficacy results
Researchers reported median PFS of 1.8 months and median OS of 6.4 months among the 26 patients treated in the monotherapy group.
In the combination group, six (19%) of 32 patients treated responded to therapy. Two achieved complete response and four achieved partial response, with median response duration of 46 weeks (range, 17 weeks to not reached).
Median PFS in the combination group reached statistical significance (3.7 months; lower bound 90% CI, 2.3 months; P = .04), and results showed median OS of 7.4 months.
“Our hypothesis had been that cMet expression would go up in response to EGFR inhibition among patients with HPV-negative disease,” Burtness said. “It looks like that was true, as all of the benefit with the combination was confined to HPV-negative patients.”
Six of 16 (38%) patients with HPV-negative disease responded to the combination, compared with none of the 16 patients with HPV-positive disease (P = .02).
Bauman called the response rate in the HPV-negative group “gratifying,” noting in a press release that the expected response rate in this heavily pretreated group would be about 5%.
Patients with HPV-negative disease achieved longer median PFS with the combination than those with HPV-positive disease (4.1 months vs. 2.3 months; P = .03).
Patients classified as cMet-positive exhibited a significantly reduced risk for progression compared with those classified as cMet-negative (HR = 0.3; 95% CI, 0.1-0.9).
Toxicity results
Adverse events reported among patients assigned ficlatuzumab monotherapy included hypoalbuminemia (66%), edema (25%) and acneiform rash (12%).
Adverse events reported among patients assigned the combination included acneiform rash (82%), hypoalbuminemia (76%) and edema (44%).
Researchers reported 25 infections among the 32 patients treated with the combination, with four of those infections attributed to protocol treatment.
Three patients — two assigned ficlatuzumab monotherapy and one assigned the combination — developed pneumonitis.
Two treatment-related deaths occurred — one death due to pneumonitis in the monotherapy group and one sudden death not otherwise specified in the combination group.
Next steps and implications
The findings support further development of this combination, researchers concluded.
“Even when you look at the overall PFS results — including the HPV-positive, cMet-low group — they’re still better than some of the prior studies of best supportive care or [investigator’s] choice of second-line therapies,” Burtness told Healio. “When you focus on the HPV-negative group, I think the 38% response rate, durable complete responses and an impressive duration of response in a very heavily pretreated population grabbed everybody’s attention.”
Bauman is working with a group of investigators to design a randomized phase 3 trial to compare the ficlatuzumab-cetuximab combination with standard therapy for patients with advanced HPV-negative HNSCC.
For more information:
Barbara Burtness, MD, can be reached at barbara.burtness@yale.edu.
Perspective
Back to Top
Ficlatuzumab inhibits cMet by targeting HGF. Preclinical models show the cMet expression in head and neck cancers and potential contribution to cetuximab resistance. This study investigated the activity of ficlatuzumab as a single agent or in combination with cetuximab in relapsed or metastatic HNSCC patients refractory to prior systemic treatments.
The efficacy of single-agent treatments in the heavily pretreated R/M HNSCC patients is limited, and ficlatuzumab did not show effectiveness as a single agent. The combination of ficlatuzumab and cetuximab showed encouraging response rates, with a 19% ORR, including two complete responses. Researchers reported no unexpected adverse events.
Although several studies are re-addressing the role of cetuximab in relapsed or metastatic HNSCC, the results of these studies are mostly from small phase 2 trials. Although results from the early phase 2 trials could be encouraging, translation to phase 3 trials for the clinical benefit may be challenging, as observed in INTERLINK-1. Although the monalizumab (Innate Pharma) and cetuximab combination showed promise in a phase 2 trial, the larger phase 3 INTERLINK-1 study did not show benefit.
However, designing a phase 3 trial could be challenging for patients with platinum/immune checkpoint inhibitor/cetuximab-refractory HNSCC given no effective standard-of-care treatment exists. Therefore, the importance of biomarker-driven studies in this patient population becomes more relevant.
Collapse