When one reviews the excitement that has been generated over the last several years in regards to the advancement of therapy for NSCLC, it becomes painfully apparent that patients with adenocarcinoma have reaped the greatest benefits, and patients with squamous cell lung cancer have been more or less left out in the cold. The addition of Avastin to doublet chemotherapy prolongs life for patients with non-squamous cell lung cancer, while patients with squamous cell lung cancers have an increased risk of life-threatening bleeding from the lungs. Although Tarceva can prolong survival for patients with advanced NSCLC of all histolologies that has grown after chemotherapy, patients with the greatest chance of benefit in the first-line or salvage setting (those with activating EGFR mutations) almost exclusively have adenocarcinoma. Alimta, a “traditional” chemotherapy drug with a much lower toxicity profile than most chemotherapy agents, was shown to be active in non-squamous cell lung cancers, and to have virtually no activity in squamous NSCLC. This caused Alimta to lose its indication for NSCLC of squamous cell histology. Recently, a new mutation has been identified for NSCLC, the EML4-ALK translocation. This translocation, much like the EGFR activating mutations, drives cancer cell function in a dependent fashion, and inhibition with a novel c-met and ALK inhibitor is showing promise in early clinical data. Again, this mutation occurs in patients with non-squamous cell lung cancers, more commonly in lifetime never smokers. So where is the drug for squamous cell lung cancer? Although squamous cell NSCLC is decreasing in frequency as adenocarcinoma of the lung becomes more common, squamous cell tumors are far from rare.

Figitumumab, also known as CP-751,871, is a monoclonal antibody inhibiting the insulin-like growth factor receptor. The results of a phase II study presented at ASCO 2008 were reviewed in a previous post. In this phase II trial figitumumab was tested in combination with carboplatin and paclitaxel for patients with previously-untreated NSCLC. Of particular note in that study, 13 of 18 patients with squamous cell lung cancer had a response to the treatment, yielding a response rate of 72% (compared to 42% response rate with carboplatin and paclitaxel alone). In an update at ASCO 2009, an additional 56 patients with non-adenocarcinoma NSCLC treated with the triplet combination were reported to have a response rate of at least 53%. Toxicity in the phase II study included those expected with carboplatin and paclitaxel (neutropenia, fatigue, decreased appetite), as well as hyperglycemia (high blood sugar levels). The hyperglycemia is thought to be a class effect of these drugs. Here, hopefully, was our targeted agent for squamous NSCLC. Based upon the hopeful response rates above, Pfizer launched several phase III trials in NSCLC. These included a phase III study of figitumumab with carboplatin and paclitaxel for previously-untreated non-adenocarcinoma NSCLC; a first-line phase III study of figitumumab with cisplatin and gemcitabine for patients with previously-untreated “all-histology” NSCLC; and a phase III trial of Tarceva with or without figitumumab for relapsed non-adenocarcinoma. It was then disappointing news to hear that Pfizer has suspended accrual to the phase III study with carboplatin and paclitaxel due to an increase in toxicity (termed serious adverse events, which includes severe toxicities that result in hospitalization, life-threatening events, and deaths). Not much information is currently available, and this information is obtained from a bare-bones report on Reuters, as the Pfizer website does not have the press release listed. The phase III study with cisplatin and gemcitabine has not yet begun recruiting patients, while the salvage therapy trial with erlotinib is ongoing. We will look forward to hearing more specific information, and to see whether the toxicities seen will affect the other trials or the future of this agent in NSCLC. I fear that we will still be looking for the White Knight for squamous NSCLC.