Nicolas Sommer

Phase IB study of vemurafenib in combination with irinotecan and cetuximab in patients with metastatic colorectal cancer with BRAFV600E mutation

In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression. SIGNIFICANCE Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352-65. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1293.

Patient and physician preferences for anticancer drugs for the treatment of metastatic colorectal cancer: A discrete-choice experiment

Objective Many publications describe preferences for colorectal cancer (CRC) screening; however, few studies elicited preferences for anticancer-drug treatment for metastatic CRC (mCRC). This study was designed to elicit preferences and risk tolerance among patients and oncologists in the USA for anticancer drugs to treat mCRC. Materials and methods Patients aged 18 years or older with a self-reported diagnosis of mCRC and board-certified (or equivalent) oncologists who had treated patients with mCRC were recruited by two survey research companies from existing online patient panels in the USA. Additional oncologists were recruited from a list of US physicians. Patients and oncologists completed a discrete-choice experiment (DCE) survey. DCEs offer a systematic method of eliciting preferences and quantifying both the relative importance of treatment attributes and the tradeoffs respondents are willing to make among benefits and risks. Treatment attributes in the DCE were progression-free survival (PFS) and risks of severe papulopustular rash, serious hemorrhage, cardiopulmonary arrest, and gastrointestinal perforation. Patients’ and physicians’ maximum levels of acceptable treatment-related risks for two prespecified increases in efficacy were estimated. Results A total of 127 patients and 150 oncologists completed the survey. Relative preferences for the treatment attributes in the study were mostly consistent with the expectation that better clinical outcomes were preferred over worse clinical outcomes. Risk tolerance varied between patients and physicians. On average, physicians were willing to tolerate higher risks than patients, although these differences were mostly not statistically significant. Post hoc latent-class analyses revealed that some patients and physicians were unwilling to forgo any efficacy to avoid toxicities, while others were willing to make such tradeoffs. Conclusion Differences in preferences between patients and physicians suggest that there is the potential for improvement in patients’ well-being. Initiating or enhancing discussions about patient tolerance for toxicities, such as skin rash and gastrointestinal perforations, may help prescribe treatments that entail more appropriate benefit–risk tradeoffs.

Overall survival in patients with glioblastoma before and after bevacizumab approval

Abstract Objective: Glioblastoma (GBM) is an aggressive disease with limited therapeutic options. While bevacizumab was approved in 2009 for the treatment of patients with progressive GBM, its impact on overall survival (OS) remains unclear. Using US population-based cancer registry data (SEER), this study compared OS of patients diagnosed with GBM before and after bevacizumab approval. Methods: Adult patients from SEER with a GBM diagnosis were divided into two cohorts: patients diagnosed in 2006–2008 (pre-bevacizumab cohort, n = 6,120) and patients diagnosed in 2010–2012 (post-bevacizumab cohort, n = 6,753). Patients were included irrespective of the treatments received. OS post-diagnosis was compared between the study cohorts utilizing Kaplan-Meier analyses and multivariate Cox proportional hazards regression. Results: Among 12,873 patients with GBM, the median age was 62 years, 41% were women, 31% underwent gross total resection, and 75% received radiation therapy. Survival was stable within the 2006–2008 period (median survival = 9 months for each year), but increased after year 2009 (median survival = 10 and 11 months for years 2010/2011 and 2012, respectively). The adjusted hazard of death was significantly lower in the post-bevacizumab approval cohort (hazard ratio = 0.91, p < .01). Conclusions: The results of this large population-based study suggested an improvement in OS among patients with a GBM diagnosis in 2010–2012 compared to 2006–2008. While the cause of this improvement cannot be proven in a retrospective analysis, the timing of the survival increase coincides with the approval of bevacizumab for the treatment of patients with progressive GBM, indicating a possible benefit of bevacizumab in this population.

Real-world Direct Health Care Costs for Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab-containing Regimens in First-line or First-line Through Second-line Therapy

Micro‐Abstract Cost considerations could factor into the choice of metastatic colorectal cancer (mCRC) treatment. The present real‐world observational study of 2352 mCRC patients in the United States found that the per‐patient monthly health care costs for first‐line (1L) or 1L through second‐line therapy were substantially greater for patients treated with 1L cetuximab‐containing versus bevacizumab‐containing regimens. Such cost implications could be meaningful in real‐world clinical practice. Background The present study examined real‐world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first‐line (1L) bevacizumab (BEV)‐ or cetuximab (CET)‐containing regimen in 1L or 1L‐through‐second‐line (1L‐2L) therapy. Patients and Methods Using a large US insurance claims database, patients with mCRC initiating 1L BEV‐ or 1L CET‐containing regimen from January 1, 2008 to September 30, 2014 were identified. The per‐patient per‐month (PPPM) all‐cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic‐containing regimen, 1L‐2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV‐ versus 1L CET‐containing regimen. Results A total of 6095 patients initiating a 1L BEV‐ and 453 initiating a 1L CET‐containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV‐ and 134 initiating a 1L CET‐containing regimen were evaluated for 1L‐2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were

Treatment Patterns and Outcomes in Patients with KRAS Wild-Type Metastatic Colorectal Cancer Treated in First Line with Bevacizumab- or Cetuximab-Containing Regimens

3135 (95% confidence interval [CI],

Real-world cancer regimen costs for metastatic colorectal cancer patients treated with biologics in first- through second-line.

1174‐

Abstract A36: Circulating cell-free DNA as a marker for response and resistance to BRAF and EGFR inhibition in BRAF-mutated metastatic colorectal cancer

5040; P < .001) greater on average than 1L BEV. In 1L‐2L therapy, 1L BEV‐2L CET had adjusted PPPM costs that were

Characteristics of long- versus short-surviving patients (Pts): An analysis of the ARIES Observational Cohort Study (OCS) of bevacizumab (BV)-treated pts with metastatic colorectal cancer (mCRC).

1402 (95% CI,

521PINTERIM SAFETY RESULTS FROM STEAM: A RANDOMIZED PHASE 2 TRIAL OF SEQUENTIAL AND CONCURRENT FOLFOXIRI–BEVACIZUMAB (BEV) VS FOLFOX–BEV FOR THE FIRST-LINE (1L) TREATMENT (TX) OF PATIENTS (PTS) WITH METASTATIC COLORECTAL CANCER (MCRC)

1365‐

520POVERALL SURVIVAL ACCORDING TO PATIENT SUBGROUPS: RESULTS FROM A POOLED ANALYSIS OF 5 OBSERVATIONAL OR PHASE IV STUDIES OF BEVACIZUMAB IN METASTATIC COLORECTAL CANCER

1442; P = .010) greater than those for 1L BEV‐2L BEV, and 1L CET‐2L BEV had adjusted PPPM costs that were