OncoFacts Lung Cancer - Annual Meeting 2010 Overview (Crizotinib, paclitaxel-carboplatin, figitumumab, Mapatumumab, paclitaxel-carboplatin, paclitaxel-carboplatin-mapatumumab, NOV-002, NSCLC, CALGB 30406, gemcitabine-carboplatin)

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Description: Abstract 3 and LBA7502
Crizotinib is a small molecule EML4/ALK and MET inhibitor that was evaluated in a phase II trial that enrolled 82 patients pre-selected by the presence of the EML4/ALK fusion oncogene as determined by florescent in situ hybridization (FISH). This fusion oncogene is present in 4% - 5% of patients with non-small cell lung cancer (NSCLC). It occurs primarily in never smokers with adenocarcinoma and is exclusive of the epidermal growth factor receptor (EGFR) mutations. Most of the patients had received 1-2 prior systemic therapies. Eighty-seven percent derived clinical benefit from crizotinib, and almost all patients experienced tumor shrinkage. Progression-free survival (PFS) at 6 months was 72%. There were no grade 3-4 adverse events.

ARQ 197-209, a small molecule c-MET inhibitor. Over expression of c-MET is known to convey poor prognosis and resistance to EGFR tyrosine kinase inhibitors (TKIs). This was a randomized phase II trial in which previously treated patients with NSCLC who had not been exposed to anti-EGFR TKIs were randomized to erlotinib-ARQ197 (E-A) versus erlotinib-placebo (E-P). Crossover upon progressive disease was allowed for the E-P arm. One hundred sixty-seven patients were randomized. Only 20% were never smokers. There were some imbalances in histology, EGFR mutations, and KRAS mutations. The greatest benefit from erlotinib-ARQ 197 in PFS prolongation was seen in patients with adenocarcinoma who were EGFR wild-type (WT) and KRAS-mutant. In non-squamous NSCLC, the PFS for E-A was 18.9 weeks compared to 9.7 weeks for E-P. There are many other c-MET inhibitors under investigation, and there is evidence of synergism between c-MET inhibitors, EGFR, and mTOR inhibitors.

Abstract 7500
A randomized phase III trial comparing paclitaxel-carboplatin alone or in combination with the insulin growth factor (IGF)–1R monoclonal antibody figitumumab was reported by an international group. In phase II trials, this combination looked very effective in squamous cell carcinoma with overall response rate (ORR) of 65% and the adverse event profile was satisfactory. Accrual was permanently suspended at 681 patients after interim analysis of the first 225 events revealed that the results favored paclitaxel-carboplatin alone and that there were very serious adverse events including dehydration, hyperglycemia, hemoptysis, and 3.5% treatment related deaths in the paclitaxel-carboplatin-figitum​umab arm. Low pre-treatment body mass index and low creatinine clearance predicted for early death. In addition, OS was 8.5 months with paclitaxel-carboplatin-figitum​umab and 10.3 months with paclitaxel-carboplatin alone.

Abstracts LBA7501, LBA7007, and LBA7002
Mapatumumab, a TRAIL-R1 agonist monoclonal antibody that targets death receptor 4 was studied in a randomized phase II trial comparing paclitaxel-carboplatin versus paclitaxel-carboplatin-mapatum​umab (either 10mg/kg or 30mg/kg). This agent had not shown any single-agent activity in NSCLC in previous trials. In this trial, there were no significant increases in ORR, PFS, or OS in the mapatumumab arms. This agent will not be pursued further in NSCLC.

Another novel agent, NOV-002 is a formulation of disodium glutathione disulfide (GSSG), which is a component of the glutathione (GSH)/GSSG redox pathway vital to regulation of cell signaling proteins. Phase I-II and randomized phase II trials showed positive results in NSCLC when NOV-002 was combined with platinum-based regimens. However, this large phase III trial of paclitaxel-carboplatin versus paclitaxel-carboplatin-NOV-002 failed to demonstrate any improvement in ORR, PFS, or OS with the addition of NOV-002 to paclitaxel-carboplatin.

Finally, the phase III SPEAR trial randomized patients with relapsed small cell lung cancer (SCLC) to picoplatin versus best supportive care (BSC) in patients progressing within 6 months of prior platinum therapy. There was no significant improvement in OS, PFS, or TTP with picoplatin compared to BSC. However, among the patients who failed prior platinum or relapsed within 45 days of platinum, there did appear to be an improvement in survival.

Abstract 2
Management of the older patient with advanced NSCLC is an increasingly common challenge with the median age of diagnosis in the US at 70 years. Several studies over the past 20 years have suggested that single-agent therapy is better than BSC and at least as good as some doublets. Other studies indicate that fit elderly patients derive as much benefit from doublet therapy as do younger patients. The French IFCT randomized advanced NSCLC patients age 70-89 to weekly paclitaxel + monthly carboplatin (PC) versus single-agent gemcitabine or vinorelbine, and 451 patients were randomized. At the second planned interim analysis, accrual to the trial was stopped with median OS for PC of 10.4 months versus 6.2 months for gemcitabine or vinorelbine (P = .00004) and PFS of 6.1 months for PC versus 3.0 months for gemcitabine or vinorelbine (P<.000001). The overall response rate (ORR) was 29% for PC and 11% for gemcitabine or vinorelbine. One-year OS was increased from 27% to 45% with PC. Multivariate analysis demonstrated that the following factors predicted for improved survival: doublet therapy, Eastern Cooperative Oncology Group (ECOG) 0-1, non-smoking, adenocarcinoma, high level of performance of activities of daily living, and weight loss <5%.

Abstract 7503
Pasi Janne reported the results of CALGB 30406, a randomized phase II trial of erlotinib alone or in combination with paclitaxel-carboplatin (PC) for 6 cycles followed by erlotinib alone in never or light smokers with adenocarcinoma of the lung, and 188 patients were accrued. Seventy-six percent were never smokers. Thirty-nine percent had EGFR mutations. Overall there were no significant differences in PFS or OS between the 2 treatment groups. However, there were marked differences in PFS and OS (P = .01) between the EGFR WT and the EGFR mutated populations treated with erlotinib. The study questioned the role for erlotinib-chemotherapy combinations in patients with EGFR mutations.

Abstracts 7506 and 7507
Two maintenance trials were presented. Chandra Belani presented a multicenter study in which patients with non-progressive NSCLC following 4 cycles of gemcitabine-carboplatin were randomized to maintenance gemcitabine or BSC. This study showed no improvement in PFS or OS with gemcitabine compared to BSC (hazard ratio [HR] = 0.97). However, it should be noted that in this trial 64% of the patients were performance status-2 and 57% were older than 65. Performance status >2 and male gender predicted for poor survival.

In the second maintenance trial the IFCT randomized NSCLC patients (834) who had complete response (CR), partial response (PR), or stable disease (464) after 4 cycles of cisplatin-gemcitabine to gemcitabine, erlotinib, or observation with all patients to receive pemetrexed upon progression. Thirty-eight percent were non-smokers. Fifty-percent were ECOG 0, 45% ECOG 1, and only 5% were ECOG 2. By independent review, PFS was significantly improved by gemcitabine at 3.8 months (HR = 0.51) and also by erlotinib at 2.9 months (HR = 0.83) compared to observation at 1.9 months. Patients with CR/PR from induction and those who went on to receive pemetrexed achieved the best PFS. Overall survival results are not available as yet.

Abstract LBA7511
Mark Socinski presented the results of a phase III trial comparing weekly nab-paclitaxel + Q 3 week carboplatin with Q 3 week paclitaxel-carboplatin in 1038 patients with advanced NSCLC. Forty-three percent had squamous cell carcinoma and 49% had adenocarcinoma. The ORR was the primary endpoint. Dose intensity was higher for nab-paclitaxel-carboplatin versus paclitaxel-carboplatin. The ORR was higher for nab-paclitaxel-carboplatin at 33% compared to 25% for paclitaxel-carboplatin. In squamous cell carcinoma, the ORR was 41% for nab-paclitaxel-carboplatin versus 24% for paclitaxel carboplatin (P<.001). Nab- paclitaxel-carboplatin was also better tolerated than paclitaxel-carboplatin with less neutropenia, febrile neutropenia, anemia, and thrombocytopenia. Progression-free survival and OS data are immature at this time.

1. Bang Y, Kwak EL, Shaw AT. Clinical activity of the oral ALK inhibitor PF-02341066 in ALK-positive patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract 3.

2. Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract LBA7502.

3. Jassem J, Langer CJ, Karp DD, et al. Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract 7500.

4. Von Pawel J, Harvey JH, Spigel DR, et al. A randomized phase II trial of mapatumumab, a TRAIL-R1 agonist monoclonal antibody, in combination with carboplatin and paclitaxel in patients with advanced NSCLC. J Clin Oncol. 2010;28(15s). Abstract LBA7501.

5. Fidias P, Ciuleanu TA, Gladkov O, et al. A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carboplatin (C) versus paclitaxel and carboplatin alone for the treatment of advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract LBA7007.

6. Ciuleanu T, Samarzjia M, Demidchik Y, et al. Randomized phase III study (SPEAR) of picoplatin plus best supportive care (BSC) or BSC alone in patients (pts) with SCLC refractory or progressive within 6 months after first-line platinum-based chemotherapy. J Clin Oncol. 2010;28(15s). Abstract LBA7002.

7. Quoix EA, Oster J, Westeel V, et al. Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract 2.

8. Janne PA, Wang XF, Socinski MA, et al. Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406. J Clin Oncol. 2010;28(15s). Abstract 7503.

9. Belani CP, Waterhous DM, Ghazal H, et al. Phase III study of maintenance gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract 7506.

10. Perol M, Chouaid C, Milleron BJ, et al. Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III study. J Clin Oncol. 2010;28(15s). Abstract 7507.

11. Socinski MA, Bondarenko IN, Karaseva NA, et al. Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28(15s). Abstract LBA7511.
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