New Molecular Targets Define Treatment in Non–Small Cell Lung Cancers

Two abstracts presented at the Clinical Science Symposium “Emerging New Targets and New Drugs in Non–Small Cell Lung Cancer” demonstrate new avenues for therapy. Alice Tsang Shaw, MD, PhD, of Massachusetts General Hospital Cancer Center, presented updated results of the first clinical validation of ROS1 as a therapeutic target in cancer on behalf of her colleagues (Abstract 7508). The investigators examined the effi cacy and safety of standard oral crizotinib (250 mg twice daily) in advanced non–small cell lung cancers harboring ROS1 gene rearrangements as determined by a break-apart fl uorescence in situ hybridization assay.

Fifteen patients were enrolled at three study sites, and 14 were evaluable for response; the median age of these patients was 54, all but one of the patients were nonsmokers, 80% had received one or more prior therapies, all had adenocarcinomas, and none had ALK rearrangements. The pharmacokinetic profile of crizotinib in this group of patients was similar to that observed in patients with ALK-positive non–small cell lung cancer.

To date, the overall response rate is 57.1% (eight of 14 patients), with seven partial responses and one complete response; four patients have stable disease (Figure). Median duration of treatment is underestimated at 26 weeks, as the treatment of 12 patients is still ongoing. The disease control rate (complete or partial response plus stable disease) at 8 weeks was 79%.

Treatment-related adverse effects were for the most part mild; four patients experienced grade 3 events, which included neutropenia, hypophosphatemia, increased aspartate aminotransferase, and increased alkaline phosphatase.

Dr. Shaw concluded that chromosomal rearrangements of the ROS1-receptor tyrosine kinase gene define a new molecular subset of patients with non–small cell lung cancer for whom crizotinib therapy may be highly effective. This phase I dose-expansion study is continuing enrollment, and the use of crizotinib will be evaluated in other cancers with ROS1 rearrangements, including glioblastoma multiforme and cholangiocarcinoma.

In his discussion, Gregory J. Riely, MD, PhD, of Memorial Sloan-Kettering Cancer Center, stated that Dr. Shaw’s data reflect the current process to develop cancer therapies: fi nd a target (ROS1 rearrangements), find a drug (crizotinib), and fi nd the patients (break-apart fl uorescence in situ hybridization); moreover, Dr. Shaw’s data are compelling regarding the efficacy of crizotinib in this patient population. Dr. Riely also noted that the molecular analysis of lung cancers is becoming more complex as new targets are identified.

Julie R. Brahmer, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, presented updated results for a novel agent, BMS-936558, which is a fully human monoclonal antibody that functions as a checkpoint inhibitor, blocking the programmed death-1 (PD-1) coinhibitory receptor expressed by activated T-cells (Abstract 7509). BMS-936558 has no known Fc function and high affi nity for PD-1, blocking the binding of both PD ligands 1 and 2.

In a phase I study, BMS-936558 was administered intravenously every 2 weeks to patients with various solid tumors, including non–small cell lung cancer, at doses of 0.1 to 10 mg/kg during doseescalation and/or cohort expansion.

Of the 296 patients treated through February 2012, 122 patients with non–small cell lung cancer were evaluable for safety and 76 patients with non–small cell cancer were evaluable for clinical activity. The median age was 65, 61% were male, 39% had squamous carcinomas, and 60% had nonsquamous histology. The patient population was heavily pretreated; 94% had received platinumbased chemotherapy, and 34% had received a tyrosine kinase inhibitor.

A maximum tolerated dose was not identifi ed. There was no apparent relationship between drug dose and the frequency of adverse events in either the treated patients or the non–small cell lung cancer subgroup. Treatment with BMS-936558 was well-tolerated, with grade 3 or 4 adverse events occurring in only 14% of the total population and 8% of the patients with non–small cell cancer. The most frequently occurring adverse events—fatigue, rash, diarrhea, and pruritus—are consistent with the immunogenic activity of BMS-936558. There were three drug-related deaths due to pneumonitis. Fifteen patients were discontinued from treatment due to toxicity.

Clinical activity was observed at all dose levels; the overall response rate for patients with non–small cell cancer was 18%; progression-free survival at 24 weeks was 26%. Although BMS-936558 was active in tumors of all histologic types, a trend for increased overall response and stable disease was observed in tumors with squamous histology.

Dr. Brahmer concluded that BMS- 936558 can be administered safely in an outpatient setting to heavily pretreated patients with advanced non–small cell lung cancer and that durable clinical benefit was observed regardless of tumor histology.

In his discussion, Giuseppe Giaccone, MD, PhD, of the National Cancer Institute, noted that BMS-936588 appears to be better tolerated than ipilimumab, although severe pneumonitis is of concern. The potential for BMS-936558 to be more effective against squamous carcinoma was of special interest to Dr. Giaccone, since effective targeted agents for this tumor type are currently unavailable.