Feasibility of preemptive biomarker profiling for personalised early clinical drug development at a Comprehensive Cancer Center.

PURPOSE: Multiple investigational drugs are currently explored in cancer patient populations defined by specific biomarkers. This demands a new process of patient selection for clinical trials. PATIENTS AND METHODS: Starting January 1, 2012, preemptive biomarker profiling was offered at the West German Cancer Center to all patients with advanced non-small-cell lung (NSCLC) or colorectal cancer (CRC), who met generic study inclusion criteria. Tumour specimens were subjected to prespecified profiling algorithms to detect 'actionable biomarkers' by amplicon sequencing, in situ hybridisation and immunohistochemistry. The clinical course was closely monitored to offer trial participation whenever applicable. RESULTS: Within 12 months, 267 patients (188 NSCLC, 79 CRC) were profiled. Estimated additional cost for biomarker profiling was 219615.51 EUR excluding histopathology workup and administration. The most prevalent biomarkers in pulmonary adenocarcinoma were KRAS mutations (29%), loss of PTEN expression (18%), EGFR mutations (9%), HER2 amplification (5%) and BRAF mutations (3%), while the prevalence of ALK translocations and PIK3CA mutations was extremely low. In pulmonary squamous cell carcinoma FGFR1 amplifications were found in 15%, PTEN expression was lost in 20% and DDR2 was mutated in a single case. KRAS mutations (41%) predominated in CRC, followed by loss of PTEN expression (16%), PIK3CA (5%) and BRAF (5%) mutations. So far 13 patients (5%) have entered biomarker-stratified clinical trials. Therapeutic decisions for approved drugs were guided in another 45 patients (17%). CONCLUSION: Preemptive biomarker profiling can be implemented into the diagnostic algorithm of a large Comprehensive Cancer Center. Substantial investments in diagnostics and administration are required.

Phase II trial of carcinoembryonic antigen radioimmunotherapy with 131I-labetuzumab after salvage resection of colorectal metastases in the liver: five-year safety and efficacy results.

PURPOSE: Although complete resection (R0) of liver metastases (LM) remains the treatment of choice for colorectal cancer (CRC) patients amenable to curative therapy, only approximately one third survive for 5 years. The objective of this phase II study was to evaluate the safety and efficacy of radioimmunotherapy (RAIT) after salvage resection of LM. PATIENTS AND METHODS: Twenty-three patients who underwent surgery for LM of CRC received a dose of 40 to 60 mCi/m2 of 131I-labetuzumab, which is a humanized monoclonal antibody against carcinoembryonic antigen. Safety (n = 23), disease-free survival (DFS; n = 19), and overall survival (OS; n = 19) were determined. RESULTS: With a median follow-up of 64 months, the median OS time from the first liver resection for RAIT patients was 68.0 months (95% CI, 46.0 months to infinity), and the median DFS time was 18.0 months (95% CI, 11.0 to 31.0 months). The 5-year survival rate was 51.3%. RAIT benefited patients independently of bilobar involvement, size and number of LM, and resection margins. The major adverse effect was transient myelosuppression, resulting mostly in grade < or = 3 neutropenia and/or thrombocytopenia. CONCLUSION: Because both the median OS and 5-year survival rates seem to be improved with adjuvant RAIT after complete LM resection in CRC, compared with historical and contemporaneous controls not receiving RAIT, these results justify further evaluation of this modality in a multicenter, randomized trial.

Radioimmunotherapy of small-volume disease of metastatic colorectal cancer.

BACKGROUND: Whereas radioimmunotherapy (RIT) has shown disappointing results in bulky, solid tumors, preclinical results in small-volume disease and in an adjuvant setting are promising. In a previous Phase I study, the authors had encouraging results with the iodine-131 ((131)I)-labeled humanized anti-carcinoembryonic antigen (anti-CEA) antibody (MAb) hMN-14 in small-volume disease of colorectal cancer. The aim of this study was to evaluate, in a subsequent Phase II trial, the therapeutic efficacy of this (131)I-labeled humanized anti-CEA antibody in colorectal cancer patients with small-volume disease or in an adjuvant setting. METHODS: Thirty colorectal cancer patients, with small-volume metastatic disease (n = 21; all lesions less-than-or-equal 3.0 cm, and chemorefractory to 5-fluorouracil and folinic acid) or in an adjuvant setting (n = 9), 4-6 weeks after surgical resection of liver metastases with curative intention, were studied. The patients were given a single injection of (131)I-hMN-14 immunoglobulin G at a 60 mCi/m(2) dose level, which was shown to be the maximum tolerated dose in the previous Phase I study. Follow-up was obtained at 3-month intervals for as long as 36 months. RESULTS: At a mean blood-based red marrow dose of 1.8 +/- 0.8 Gy, myelotoxicity was the only toxicity observed, but only 1 of 28 assessable patients developed transient Grade 4 thrombocytopenia. Of the 21 patients with radiologically documented lesions, 19 were assessable. Three experienced partial remission and eight showed minor responses up to 15 months in duration (corresponding to an objective response rate of 16% and an overall response rate of 58%; the mean duration of response was 9 months). At the time this article was written, seven of nine patients in the adjuvant setting had remained free of disease for up to 36 months (one patient relapsed after 6 months and another after 30 months), whereas the relapse rate in a historical control group receiving chemotherapy was 67% over the same time period. Five patients with radiologically documented lesions, having experienced at least disease stabilization as a consequence of RIT, were retreated at the same 60-mCi/m(2) dose level at 8-16 months after the first therapy. No evidence of increased toxicity was observed (no hematologic toxicity was higher than Grade 3). Two of four assessable retreated patients experienced partial remissions; one of these four again experienced disease stabilization as a consequence of the second radioantibody therapy injection. CONCLUSIONS: These data suggest that RIT is a safe and effective form of therapy for small-volume colorectal cancer and has potential as treatment for colorectal cancer in an adjuvant setting. Toxicity is restricted to mild and transient leuko- and thrombocytopenia. Retreatment seems to be a feasible option. A prospective randomized comparison with standard chemotherapy is indicated.