MILAN – The combination of pemetrexed and cisplatin failed to extend overall survival of recurrent or metastatic squamous cell carcinoma of the head and neck significantly in a pivotal phase III trial.
The primary end point of median overall survival was 7.3 months with pemetrexed injection (Alimta) plus cisplatin, and 6.3 months with cisplatin plus placebo. The 1-month difference was not statistically significant (hazard ratio, 0.87; P = .082), Dr. Susan G. Urba said at the annual congress of the European Society for Medical Oncology.
Median progression-free survival also was similar at 3.6 months in the experimental arm vs. 2.8 months in the control arm (HR, 0.88; P = .166), as was response rate (12% vs. 8%; P = .061).
The data were disappointing enough for pemetrexed maker Eli Lilly & Co. to subsequently announce it is forgoing plans to submit marketing authorization applications for pemetrexed in squamous cell carcinoma of the head and neck with the Food and Drug Administration and the European Medicines Agency.
Pemetrexed has shown single-agent activity in head and neck cancer. It is FDA approved for several indications in nonsquamous non–small cell lung cancer and malignant pleural mesothelioma.
The 795-patient trial, described as the largest trial conducted to date in this setting, did provide some good news.
A planned subgroup analysis showed that patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, which represented 87% of the total population, derived a survival advantage with pemetrexed plus cisplatin, said Dr. Urba of the cancer center at the University of Michigan in Ann Arbor.
In this subpopulation, median overall survival significantly increased from 6.7 months with cisplatin alone to 8.4 months with combination therapy (P = .026). Response rate also improved from 9% to 14%, respectively (P = .033).
Patients with oropharyngeal cancers, who accounted for 24% of the study population, also experienced an overall survival advantage with pemetrexed plus cisplatin, compared with cisplatin alone (9.9 months vs. 6.1 months; P = .002), she said.
A further analysis among good-performance-status patients suggested that those with prior platinum therapy may also benefit from combination therapy.
When asked during a discussion of the paper whether the combination therapy should be introduced into clinical practice, Dr. Urba responded, “If I was in my clinic at home and had a good-performance-status patient, would I consider using this regimen? Yes, I would.
“I think we certainly see that it was well tolerated for a group of patients who can tolerate double combination chemotherapy. And I also think that in this group of patients with head and neck cancer ... even response rate and shrinking tumors for some period of time [are] very important because it can really impact quality of life.”
In all, 41% of pemetrexed/cisplatin patients and 22% of controls experienced at least one serious potentially drug-related grade 3 or 4 adverse event, with bone marrow toxicity, febrile neutropenia, and fatigue significantly more common in the experimental arm. There were 13 deaths that were possibly related to study drugs in the combination arm and 1 in the control arm. Upon review, 3 of the 13 deaths were considered not related to pemetrexed/cisplatin, Dr. Urba said.
Invited discussant Dr. Marshall Posner said the duet of pemetrexed and cisplatin is active, and the activity is consistent with other duets in this particular class of drugs.
He suggested that the target population will probably be good performance status patients, at least for now, as well as oropharynx cases and perhaps patients with prior cisplatin exposure.
“This may be most effective in the setting of postprimary platinum therapy, and may provide a different spectrum of toxicities for those patients who would be intolerant of 5-fluorouracil or taxane-induced toxicity,” said Dr. Posner, medical director of the head and neck oncology program and cancer clinical trials office at Mount Sinai Medical Center in New York City.
Investigators at 113 sites in 20 countries randomized 398 patients to pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2, both every 21 days for up to six cycles, and 397 patients to the same cisplatin regimen plus placebo. Their median age was 57 years. About 90% of patients had been previously treated for their head and neck cancer, half had received prior platinum-based therapy, and 60% had distant metastases. No prior treatment for metastatic disease was allowed.
Eli Lilly supported the study. Dr. Urba and seven coauthors reported no conflicts of interest. Two coauthors were Lilly employees with stock ownership. Dr. Posner disclosed consulting with several pharmaceutical companies, but not with Lilly.