Vanessa Tassell

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).

BACKGROUND. Comprehensive genomic profiling of a patient’s cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprise-wide, unselected cancer patient population has yet to be reported. METHODS. We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested. RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (&gt;20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR , associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a “cancer-agnostic” approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS. Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale. FUNDING. This work was supported by DFCI, BWH, and the National Cancer Institute (5R33CA155554 and 5K23CA157631).

7514 Background: The anaplastic lymphoma kinase (ALK) fusion gene is a key oncogenic driver in a subset of NSCLC patients (pts). Crizotinib is a potent, selective, ATP-competitive, small molecule ALK inhibitor. Pts with ALK-rearranged NSCLC had a high response rate to crizotinib in a prior expanded cohort study. Methods: This ongoing study included pts from 57 sites in 12 countries with ALK-rearranged NSCLC (by centralized FISH test) who progressed after ≥1 chemotherapy for recurrent/advanced/metastatic disease (including treated brain metastases). Pts received oral crizotinib 250 mg BID continuously in 3-week cycles. Disease response was evaluated by RECIST 1.1 every 6 weeks and safety/patient-reported outcomes (PRO; by EORTC QLQ-C30/QLQ-LC13 v3) were evaluated every 3 weeks. Results: Currently, 136 pts are evaluable for safety, 109 for PRO, and 76 for tumor response. Median age was 52 years, 94% had adenocarcinoma, 68% had never smoked, and 53% were female. Most pts (93%) had ≥2 prior chemotherapy regimens (range 1–11). Pts received a median 9 weeks of treatment (range 1–13 cycles started) and 88% remain on therapy. On a waterfall plot of tumor measurements in evaluable pts, 63 of 76 pts (83%) had target lesion shrinkage (41 pts had ≥30% shrinkage). Seven patients experienced objective progression by RECIST. The most frequent treatment-related AEs were nausea (46%), vision disorder (45%), vomiting (39%), and diarrhea (29%), mostly Grade 1/2. Treatment-related Grade 3/4 AEs were reported in 15% of pts (mostly increased ALT, dyspnea, and neutropenia). Two of the 9 deaths on-study were considered treatment-related (pneumonitis, unknown cause). Most pts had completed 4 PRO assessments by this review, with clinically significant (≥10 points) improvements in pain, cough, dyspnea and fatigue seen as early as cycle 2. Only a clinically significant increase in constipation was reported by patients over the course of therapy. Overall, quality of life was maintained. Conclusions: Data from a second global clinical study suggest crizotinib was safe and well-tolerated with preliminary evidence of improved symptoms and clinically meaningful antitumor activity in pts with pre-treated ALK-rearranged NSCLC.

PURPOSE: Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. PATIENTS AND METHODS: Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). RESULTS: A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. CONCLUSION: The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.