Person: Clark, Jeffrey
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Clark
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Jeffrey
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Clark, Jeffrey
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Publication Antitumor Activity of Crizotinib in Lung Cancers Harboring a MET Exon 14 Alteration(Springer Science and Business Media LLC, 2020-01) Camidge, D. Ross; Solomon, Benjamin J.; Li, Sherry; Drilon, Alexander; Clark, Jeffrey; Weiss, Jared; Ou, Sai-Hong Ignatius; Otterson, Gregory; Villacruz, Liza; Riely, Gregory; Suk Heist, Rebecca; Awad, Mark; Shapiro, Geoffrey; Satouchi, Miyako; Hida, Toyoaki; Hayashi, Hidetoshi; Murphy, Danielle; Wang, Sherry; Usari, Tiziana; Palk, Paul; Wilner, Keith; Solomon, BenjaminMET exon 14 alterations are oncogenic drivers of non-small cell lung cancers (NSCLCs).1 These alterations are associated with increased MET activity and preclinical sensitivity to MET inhibition.2 Crizotinib is a multikinase inhibitor with potent activity against MET.3 The antitumor activity and safety of crizotinib were assessed in 69 patients with advanced NSCLCs harboring MET exon 14 alterations in an expansion cohort of a phase 1 study of crizotinib (NCT00585195). The confirmed objective response rate was 32% (95% confidence interval [CI], 21–45) among 65 response-evaluable patients. Objective responses were observed independent of the molecular heterogeneity that characterizes these cancers and did not vary by MET exon 14 alteration splice site region and mutation type, concurrent increased MET copy number, or the detection of a MET exon 14 alteration in ctDNA. The median duration of response was 9.1 months (95% CI, 6.4–12.7). The median progression-free survival was 7.3 months (95% CI, 5.4–9.1). MET exon 14 alteration defines a molecular subgroup of NSCLCs for which MET inhibition with crizotinib is active. These results address an unmet need for targeted therapy in patients with MET exon 14-altered lung cancers and adds to an expanding list of genomically-driven therapies for oncogenic subsets of NSCLC.Publication METAmplification Identifies a Small and Aggressive Subgroup of Esophagogastric Adenocarcinoma With Evidence of Responsiveness to Crizotinib(American Society of Clinical Oncology (ASCO), 2011) Lennerz, J. K.; Kwak, E. L.; Ackerman, Allison Kalben; Michael, M.; Fox, S. B.; Bergethon, K.; Lauwers, Gregory Y.; Christensen, J. G.; Wilner, K. D.; Haber, Daniel; Salgia, R.; Bang, Y.-J.; Clark, Jeffrey; Solomon, B. J.; Iafrate, AnthonyPurpose: Amplification of the MET proto-oncogene in gastroesophageal cancer (GEC) may constitute a molecular marker for targeted therapy. We examined a GEC cohort with follow-up and reported the clinical response of four additional patients with MET-amplified tumors to the small molecule inhibitor crizotinib as part of an expanded phase I cohort study. Patients and Methods: From 2007 to 2009, patients with GEC were genetically screened as a consecutive series of 489 tumors (stages 0, I, and II, 39%; III, 25%; IV, 36%; n = 222 esophageal, including n = 21 squamous carcinomas). MET, EGFR, and HER2 amplification status was assessed by using fluorescence in situ hybridization. Results: Ten (2%) of 489 patients screened harbored MET amplification; 23 (4.7%) harbored EGFR amplification; 45 (8.9%) harbored HER2 amplification; and 411 (84%) were wild type for all three genes (ie, negative). MET-amplified tumors were typically high-grade adenocarcinomas that presented at advanced stages (5%; n = 4 of 80). EGFR-amplified tumors showed the highest fraction of squamous cell carcinoma (17%; n = 4 of 23). HER2, MET, and EGFR amplification were, with one exception (MET and EGFR positive), mutually exclusive events. Survival analysis in patients with stages III and IV disease showed substantially shorter median survival in MET/EGFR-amplified groups, with a rank order for all groups by median survival (from most to least aggressive): MET (7.1 months; P < .001) less than EGFR (11.2 months; P = .16) less than HER2 (16.9 months; P = .89) when compared with the negative group (16.2 months). Two of four patients with MET-amplified tumors treated with crizotinib experienced tumor shrinkage (−30% and −16%) and experienced progression after 3.7 and 3.5 months. Conclusion: MET amplification defines a small and aggressive subset of GEC with indications of transient sensitivity to the targeted MET inhibitor crizotinib (PF-02341066).Publication A Safety and Survival Analysis of Neoadjuvant Bevacizumab with Standard Chemoradiation in a Phase I/II Study Compared with Standard Chemoradiation in Locally Advanced Rectal Cancer(Alphamed Press, 2010) Willett, C. G.; Duda, Dan; Ancukiewicz, Marek; Shah, M.; Czito, B. G.; Bentley, R.; Poleski, M.; Fujita, H.; Lauwers, Gregory Y.; Carroll, M.; Tyler, D.; Mantyh, C.; Shellito, Paul; Chung, Daniel; Clark, Jeffrey; Jain, RakeshIntroduction. Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. Materials and Methods. Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. Results. Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. Conclusions. Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.Publication A Multicenter Retrospective Study on Clinical Characteristics, Treatment Patterns, and Outcome in Elderly Patients with Hepatocellular Carcinoma(AlphaMed Press, 2011) Kozyreva, Olga N.; Chi, Dorcas; Clark, Jeffrey; Wang, Hejing; Theall, Kathy P.; Ryan, David; Zhu, AndrewBackground. There is a paucity of information on the clinical presentation and outcome of elderly hepatocellular carcinoma (HCC) patients. We performed a multicenter retrospective comparative study to assess the impact of age on potential differences in clinical characteristics, treatment patterns, and outcome in HCC patients. Methods. We retrospectively analyzed HCC patients treated at two U.S. tertiary institutions from 1998 to 2008. Demographics, tumor parameters, etiology and severity of cirrhosis, treatment, and survival from diagnosis were collected and analyzed. After exclusion of transplanted patients, survival analyses were performed using the Kaplan-Meier method with log-rank tests and Cox proportional hazards models. Results. Three hundred thirty-five HCC patients were divided into two groups: “elderly” (95 patients, age ≥70 years) and “younger” (240 patients, aged <70 years). The male/female (M/F) ratio was 5.8:1 and 1.7:1 in the younger and elderly groups, respectively (p < .0001). Hepatitis C virus (HCV) infection rate was 48.3% in younger and 21.1% in elderly patients (p < .0001); Child class B and C cirrhosis accounted for 35.8% in younger and 25.3% in elderly patients (p = .063). Compared with younger patients, the elderly received transplant less frequently (19.6% versus 5.3%, p = .0002) and were more likely to receive supportive care only (22.9% versus 36.8%, p = .01). No significant differences between the two age groups were seen in tumor parameters or other treatments received. Overall (p = .47) and HCC-specific survival rates (p = .38) were similar in both age groups. Conclusions. Characteristics that distinguish elderly from younger HCC patients include lower M/F ratio, worse performance status, lower rate of HCV infection, and less advanced underlying cirrhosis. Elderly patients were less likely to have a liver transplant and more likely to receive supportive care only. However, overall and HCC-specific survival were similar between the two groups.Publication Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine(WILEY-VCH Verlag, 2010) Dias-Santagata, Dora; Akhavanfard, Sara; David, Serena S; Vernovsky, Kathy; Kuhlmann, Georgiana; Boisvert, Susan L; Stubbs, Hannah; McDermott, Ultan; Settleman, Jeffrey; Kwak, Eunice Lee; Clark, Jeffrey; Isakoff, Steven; Sequist, Lecia; Engelman, Jeffrey A; Lynch, Thomas J; Haber, Daniel; Louis, David; Ellisen, Leif; Borger, Darrell; Iafrate, AnthonyTargeted cancer therapy requires the rapid and accurate identification of genetic abnormalities predictive of therapeutic response. We sought to develop a high-throughput genotyping platform that would allow prospective patient selection to the best available therapies, and that could readily and inexpensively be adopted by most clinical laboratories. We developed a highly sensitive multiplexed clinical assay that performs very well with nucleic acid derived from formalin fixation and paraffin embedding (FFPE) tissue, and tests for 120 previously described mutations in 13 cancer genes. Genetic profiling of 250 primary tumours was consistent with the documented oncogene mutational spectrum and identified rare events in some cancer types. The assay is currently being used for clinical testing of tumour samples and contributing to cancer patient management. This work therefore establishes a platform for real-time targeted genotyping that can be widely adopted. We expect that efforts like this one will play an increasingly important role in cancer management.Publication Long Term Survivors with Metastatic Pancreatic Adenocarcinoma Treated with Gemcitabine: A Retrospective Analysis(BioMed Central, 2009) Goulart, Bernardo HL; Clark, Jeffrey; Lauwers, Gregory Y.; Ryan, David; Grenon, Nina; Muzikansky, Alona; Zhu, AndrewBackground: Metastatic pancreatic adenocarcinoma has a short median overall survival (OS) of 5–6 months. However, a subgroup of patients survives more than 1 year. We analyzed the survival outcomes of this subgroup and evaluated clinical and pathological factors that might affect survival durations. Methods: We identified 20 patients with metastatic or recurrent pancreatic adenocarcinoma who received single-agent gemcitabine and had an OS longer than 1 year. Baseline data available after the diagnosis of metastatic or recurrent disease was categorized as: 1) clinical/demographic data (age, gender, ECOG PS, number and location of metastatic sites); 2) Laboratory data (Hematocrit, hemoglobin, glucose, LDH, renal and liver function and CA19-9); 3) Pathologic data (margins, nodal status and grade); 4) Outcomes data (OS, Time to Treatment Failure (TTF), and 2 year-OS). The lowest CA19-9 levels during treatment with gemcitabine were also recorded. We performed a univariate analysis with OS as the outcome variable. Results: Baseline logarithm of CA19-9 and total bilirubin had a significant impact on OS (HR = 1.32 and 1.31, respectively). Median OS and TTF on gemcitabine were 26.9 (95% CI = 18 to 32) and 11.5 (95% CI = 9.0 to 14.3) months, respectively. Two-year OS was 56.4%, with 7 patients alive at the time of analysis. Conclusion: A subgroup of patients with metastatic pancreatic cancer has prolonged survival after treatment with gemcitabine. Only bilirubin and CA 19-9 levels were predictive of longer survival in this population. Further analysis of potential prognostic and predictive markers of response to treatment and survival are needed.Publication Liquid Versus Tissue Biopsy for Detecting Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers(Springer Science and Business Media LLC, 2019-09) Leshchiner, Ignaty; Elagina, Liudmila; Goyal, Lipika; Siravegna, Giulia; Livitz, Dimitri; Hanna, Megan; Wong, Alicia; Fece de la Cruz, Ferran; Giantonio, Bruce; Roeland, Eric; Ryan, David P.; Aguet, François; Hazar-Rethinam, Mehlika; Dias-Santagata, Dora; Bardelli, Alberto; Parida, Laxmi; Juric, Dejan; Getz, Gad; Corcoran, Ryan B.; Parikh, Aparna; Levovitz, Chaya; Rhrissorrakrai, Kahn; Martin, Elizabeth; Van Seventer, Emily; Slowik, Kara; Ultro, Filippo; Pinto, Christopher; Danysh, Brian; Fetter, Isobel; Shahzade, Heather; Nadres, Brandon; Allen, Jill; Blaszkowsky, Lawrence; Clark, Jeffrey; Murphy, Janet; Nipp, Ryan; Weekes, Colin; Kwan, Eunice; Faris, Jason; Wo, Jennifer; Dey-Guha, Ipsita; Ting, David; Zhu, Andrew; Hong, Theodore; Golub, Todd; Iafrate, John; Adalsteinsson, ViktorDuring cancer therapy, tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique resistance mechanisms in an individual patient1-3. Prior case reports and small case series have suggested that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance4-8. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger scale prospective cohorts of patients following progression on targeted therapy. Here, in a prospective cohort of 42 patients with molecularly-defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of post-progression cfDNA versus tumor biopsy revealed that cfDNA more frequently identified clinically-relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not found in the matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cfDNA, tumor biopsies, and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity, and that the emergence of multiple resistance alterations in an individual patient may represent the “rule” rather than the “exception.” These findings have profound therapeutic implications and highlight the potential advantages of cfDNA over tissue biopsy in the setting of acquired resistance.