Diversity of Genetic and Epigenetic Events Leading to Malignant Transformation: Unifying Themes for the Effective Management of Solid Tumor and Hematologic Malignancies

ORLANDO, Fla. – The ASH/ASCO Joint Symposium, held today at the 52nd American Society of Hematology Annual Meeting and Exposition, focused on the understanding of the various genetic and epigenetic events that lead to malignant transformation and solid tumor/hematologic malignancies and discussed novel therapies that selectively target those events.

Anaplastic lymphoma kinase (ALK) has been identified as a direct driver of oncogenesis. Patients with ALK positive (ALK+) lung cancer are generally non-smokers and represent approximately 4% of patients with non-small cell lung cancer (NSCLC). Eunice Lee Kwak, MD, PhD of Massachusetts General Hospital, Boston, Mass., presented data on crizotinib, a potent and selective ATP competitive oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants, in ALK+ NSCLC. The phase 1 trial A808100, conducted in 113 patients with refractory NSCLC demonstrated an overall response rate of 56% (95% CI 46–66), measured at week 8; median progression-free survival (PFS) was 9.2 months.

Adverse events were mostly mild with crizotinib. Those occurring in >10% of patients were primarily gastrointestinal (GI) toxicities, which included nausea and diarrhea, visual impairment, and increased ALT. Prevalence of all-cause adverse events rapidly decreased, however, with continued crizotinib therapy. Positive phase 1 data supports PROFILE 1007, an ongoing phase 3 study evaluating the efficacy of crizotinib versus pemetrexed or docetaxel in patients with ALK+ NSCLC treated with 1 prior (platinum-based) chemotherapy.

Elizabeth Quiox, MD of the French Intergroupe Francophone de Cancérologie Thoracique looked at the efficacy of single agent vs combination (doublet) therapy in elderly patients (70–89 years old) with advanced NSCLC. Combination therapy is generally avoided in the elderly to minimize toxicity, which may result in reduced overall survival (0S). The phase 3 IFCT-0501 study investigated the efficacy of monthly carboplatin plus weekly paclitaxel versus single agent therapy. A total of 451 patients were randomized 1:1 to carboplatin + paclitaxel or to vinorelbine or gemcitabine, all patients were later progressed over to erlotinib to ensure any benefit observed from doublet therapy was due to the first line treatment.

While complete response was not observed in any patients, partial response was 10.2% for the single agent arm and 27.1% for the doublet. OS for the doublet arm had a hazard ratio (HR) 0.54 (95% CI, 0.52–0.78, P<0.0001). The main cause of death was cancer in both arms (180 deaths for single vs. 146 for doublet, P<0.05). One-year progression-free survival (PFS) was 1.8% (95% CI,  19.9–31.3) for the single agent arm versus 13.4% (95% CI, 9.3–50.9) for the doublet arm. While second-line OS was better in the doublet arm compared to the single, it was not statistically significant.

The prevalence of grade 3/4 toxicities, however, was higher in the doublet arm. Hematological toxicities included neutropenia (12.4% for single vs. 48.4% for doublet) and febrile neutropenia (2.6% for single vs. 9.4% for doublet). Non-hematological toxicities also occurred more frequently in the doublet arm, particularly GI toxicities and sensitive neuropathy. Dr. Quiox stated that “the study showed superiority of the carboplatin doublet over single agent therapy in advanced NSCLC. The doublet had a beneficial effect on survival in most of the subgroups tested. Chemotherapy regimens that minimize toxicity may offer a new paradigm in the treatment of elderly patients.”                                                                                                          

Steven O'Day, MD of the Angeles Clinic Research Institute of Los Angeles, Calif., presented data from MDX-020, a phase 3 study which compared ipilimumab or gp100 peptide vaccine monotherapy and combination therapy in HLA-A*0201 positive patients with previously treated, unresectable stage 3 or 4 melanoma. Ipilimumab is a fully human monoclonal antibody that targets the CTLA-4 receptor, which down regulates T-cell activation. MDX-020 randomized 676 patients 3:1:1 to ipilimumab + gp100, ipilimumab + placebo, or gp100 + placebo.

Study results showed that ipilimumab + gp100 improved OS compared to gp100 alone (P=0.0004), but that the addition of gp100 to ipilimumab therapy did not significantly improve OS compared to ipilimumab alone. The ipilimumab + gp100 and ipilimumab monotherapy arms demonstrated greater OS (at 1-year: 44% and 46%, respectively; at 2-years: 22% and 24%, respectively) than gp100 monotherapy. PFS was greatest for the ipilimumab monotherapy group: ipilimumab + gp100 vs. gp100, HR 0.81 (P<0.0464); ipilimumab vs. gp100, HR 0.64 (P=0.0007); ipilimumab + gp100 vs. ipilimumab, HR 1.25 (P=0.0371).

Approximately 97% of all patients experienced an adverse event. Toxicities were primarily dermatologic (40%) and GI-related (30%, 1–2% were serious and included colitis). In the ipilimumab + gp100 and ipilimumab arms 17% and 23%, respectively, were treatment related and 10% and 15% were immune-related. Dr. O'Day emphasizes however that with prompt steroid treatment, immune mediated adverse events can be greatly reduced. In summary, the addition of gp100 to ipilimumab had no influence on OS, safety, and showed lower PFS and best objective response rates.