By: Mara Jeffress, Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health
Head and neck cancer patients tend to receive chemotherapy doublets with or without the only approved targeted agent, the EGFR antibody Erbitux® (cetuximab, Bristol-Myers Squibb/Lilly/Merck Serono) as first-line therapy. Up to 90% of squamous cell carcinoma of the head and neck (SCCHN) patients have a tumor with EGFR aberrations, and according to Kantar Health’s CancerMPact® Treatment Architecture United States, in 2013 38% of chemotherapy-naïve SCCHN patients received Erbitux as part of their first-line therapy for advanced disease. Erbitux may also be used in second-line, with approximately one-fifth of patients receiving Erbitux monotherapy and another one-fifth receiving Erbitux in combination with chemotherapy.
The use of Erbitux in multiple lines belies the large unmet need for relapsed or refractory patients, whose median overall survival ranges from three to six months (Machiels, Abstract LBA29, ESMO 2014). In addition, less than half of patients who receive a first-line therapy go on to receive a second line of therapy.1 Several other EGFR-directed agents have been tested in SCCHN, including Vectibix® (panitumumab, Amgen), zalutumumab (Genmab), Iressa® (gefitinib, AstraZeneca), and Tykerb® (lapatinib, GlaxoSmithKline). All have failed to improve survival in Phase III trials. Gilotrif® (Giotrif® in Europe, afatinib, Boehringer Ingelheim), an oral small molecule that inhibits EGFR, HER2 and HER4, is currently approved in non-small cell lung cancer (NSCLC) and is vying for a spot in SCCHN.
The LUX-Head & Neck 1 trial of Gilotrif in 474 second-line SCCHN patients who had progressed on platinum treatment advanced the field at this year’s European Society for Medical Oncology (ESMO) meeting2 by being the first positive trial of a novel targeted agent since the pivotal Erbitux EXTREME trial.3 The LUX-Head & Neck 1 trial stratified patients 2:1 to receive either Gilotrif (40 mg daily, oral) or methotrexate (40 mg/m2, IV weekly), and patients were stratified by ECOG status (0 vs. 1) and prior EGFR inhibitor use. Median progression-free survival (PFS) was significantly improved in the Gilotrif arm (2.6 vs. 1.7 months, HR=0.80, p=0.030), as was overall response rate (ORR; 10.2 vs. 5.6%) and disease control rate (DCR; 49.1 vs. 38.5%). There was no significant difference in overall survival (median OS 6.8 vs. 6.0 months, HR=0.96, p=0.7). Patient-reported outcomes and quality-of-life measures favored Gilotrif. In addition, Gilotrif was less toxic with fewer dose reductions (32% vs. 42%), discontinuations (7% vs. 16%) and fatal events (0.6% vs. 3%). As expected, adverse events characteristic of EGFR inhibitors were higher in the Gilotrif arm (all grade rash 74% vs. 8%; Grade 3/4 rash 10% vs. 0%; all grade diarrhea 72% vs. 12%; Grade 3/4 diarrhea 10% vs. 2%). In the methotrexate arm stomatitis (39% vs. 43%), fatigue (25% vs. 32%) and neutropenia (<1% vs. 19%) were higher.
Subgroup analysis from LUX-Head & Neck 1 suggests that patients who are HPV p16-negative and who have not received prior Erbitux are more likely to respond to Gilotrif, and prior Erbitux in 60% of the enrolled patients may have negatively biased the trial. How much better would the efficacy outcomes have been if patients had been preselected to be HPV-negative? With such a high number of patients being treated with Erbitux in front-line, would it have been possible to quickly enroll such a trial? Perhaps, as was suggested by the discussant, Dr. Seiwert, there are other biomarkers that might help refine which patients benefit the most from Gilotrif?
The suggestion that prior treatment with Erbitux negatively biased overall survival outcomes in this trial may be a biologically sound rationale, but it is clinically irrelevant since Erbitux is an approved drug used in a large proportion of patients with advanced disease. This outcome may speak to acquired resistance to EGFR inhibition, which is an inherent risk to developing a drug with a similar mechanism of action in the relapsed/refractory setting. That PFS was significantly improved despite the majority of patients having received prior Erbitux suggests they were not completely resistant, that Gilotrif remains active in Erbitux-resistant clones, or that the mechanisms of action of these two drugs (monoclonal antibody vs. tyrosine kinase inhibitor) differ sufficiently to confer response when used in sequence.
Similar outcomes have been observed with other EGFR inhibitors studied in the platinum-pretreated advanced SCCHN setting: Zalutumumab significantly improved PFS but not overall survival compared with best supportive care,4 and Iressa improved response rate but not PFS or overall survival when compared with methotrexate.5 The lack of overall survival benefit in LUX-Head & Neck 1 is concerning since there are so few effective options in this disease; one would expect that an active agent could have an impact on overall survival. The FDA may take a similar stance, requiring an overall survival benefit for approval, although other regulatory authorities (such as the European Medicines Agency) may be more willing to approve a drug with a PFS benefit alone.
If approved, Gilotrif will compete directly with Erbitux in platinum-pretreated patients in the U.S., although ex-U.S. it will be largely unchallenged due to lack of approval of Erbitux in second-line. In the U.S., Erbitux will have nearly a decade head start over Gilotrif, although Gilotrif could have the advantage of being the first marketed drug to show a PFS benefit in a randomized trial in this setting (Erbitux was approved in the U.S. based on a single-arm study). A comparison of the available data suggests that Gilotrif has similar efficacy in second-line as Erbitux; in 103 platinum-resistant second-line patients, Erbitux demonstrated a 2.3-month time to progression and a 12.6% response rate.6 With physicians being so familiar with Erbitux, would they be willing to switch to Gilotrif given the available data? The fact that Gilotrif is an oral agent will help it differentiate itself. However, given the higher co-pays required for oral agents in the United States, patients’ pocketbooks may disagree. At this time, no head-to-head trials of Erbitux vs. Gilotrif are planned.
The LUX-Head & Neck 1 trial results are the first to report as part of the larger LUX-Head & Neck program, which includes a companion trial of similar design conducted in Asian patients (LUX-Head & Neck 3), as well as two studies evaluating Gilotrif as post-remission therapy in locally advanced SCCHN (LUX-Head & Neck 2 and 4). It’s encouraging that PFS was improved in this first trial to report, and confirmation of activity in these other trials could go a long way to establish the degree of clinical benefit that Gilotrif confers in SCCHN and form a foundation upon which it may become adopted into clinical practice for this disease.
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