Lung cancer
A prospective study of carboplatin and paclitaxel for advanced thymic carcinoma
- Author(s)：
- Akira Ono
- Affiliation(s)：
- Shizuoka Cancer Center, Japan
Background: Thymic carcinoma (TC) is a rare malignant tumor originated within the thymus gland and is associated with a poor prognosis, differing from thymoma which is the most common type of thymic malignant neoplasm. No results of clinical trials focusing on TC have been reported. This single-arm study evaluated carboplatin and paclitaxel (CbP) in previously untreated patients (pts) with advanced TC. Methods: Chemotherapy-naïve pts with Masaoka's stage III to IVb, ECOG PS 0 to 1, and more than 20 years old were eligible. The study treatment consisted of carboplatin (AUC 6) and paclitaxel (200 mg/m2) every 3 weeks for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) by extramural assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. All pts were followed-up until 24 months (mo) after last enrollment. Results: From May 2008 to November 2010, 40 pts were enrolled from 21 centers. Of 39 evaluable for analysis, the median age was 62 years (range, 36-84); 23/16 males/females; 3/10/26 with Masaoka's stage III/IVa/IVb; 9/11/19 with squamous cell carcinoma/poorly differentiated neuroendocrine carcinoma/other types. The median number of cycles was 6. There was 1/13 complete/partial responses with an ORR of 36% (95% CI, 21-53%; P = 0.031). The median PFS was 7.52 mo (6.18 - 12.32 mo) while OS did not reach the median value. The 1-year and 2-year survival rates were 85% (69-93%) and 71% (54-83%), respectively. Major adverse event was grade 3-4 neutropenia in 34 pts (87%). Two cases (5%) of grade 3 febrile neutropenia, neuropathy, and arthralgia were observed, respectively. There was no treatment-related death. Conclusions: CbP showed higher efficacy in advanced TC. Our results established that CbP, one of the standard treatments for non-small cell lung cancer, also serves as a key chemotherapy regimen for TC.
Phase II Study of Docetaxel and CBDCA Plus Bevacizumab for Non-squamous NSCLC
- Author(s)：
- Kozo Yoshimori1） ，Yuichi Takiguchi2） Koichi Minato3）， Hiroaki Okamoto4） Hidehiko Kuribayashi5），Masahiro Ando6）, Masato Shingyoji7）, Akihiko Gemma8）
- Affiliation(s)：
- 1）Department of respiratory medicine, Anti-tuberculosis Association Fukujuji Hosp., 2）Medical Oncology, Chiba Univ. Hosp., 3）Gunma Prefectural Cancer Center, 4）Yokohama Municipal Citizen's Hosp., 5）Nippon Medical School Chiba Hokusoh Hosp., 6）Tsuboi Cancer Center Hosp., 7）Chiba Cancer Center, 8）Nippon Medical School
Background: Some clinical studies suggested a possible advantage of bevacizumab combined with taxanes. Although carboplatin is slightly inferior to cisplatin in terms of survival, addition of bevacizumab to carboplatin may overcome this disadvantage. The aim of this study was to clarify the efficacy and safety of combination chemotherapy consisting of bevacizumab, docetaxel and carboplatin in the 1st line chemotherapy for non-squamous non-small cell lung cancer.
Patients and methods: Patients who are untreatable with thoracic curative radiotherapy, with stage IIIB/IV non-squamous non-small cell lung cancer, age ranging from 20 to 74 years, PS 0 or 1, adequate organ functions, measurable lesions, and written informed consents were eligible. Combination chemotherapy consisting of bevacizumab (15 mg/kg), docetaxel (60 mg/m2) and carboplatin (AUC=6) on day 1 was administered every 3 weeks up to 6 cycles (induction phase). Unless PD, bevacizumab maintenance therapy was performed until PD (maintenance phase). The primary endpoint was median PFS to prove its superiority to the previous standard combination chemotherapy consisting of docetaxel and cisplatin with its historical median PFS of 4.6 months. With α=0.05 and β=0.20, calculated minimum sample size was 37, and the final determined sample size was 40.
Results: Forty patients enrolled and 39 patients were analyzed. They included women in 31%, patients with PS of 0 in 67%, stage IV in 92%, EGFR mutations in 13% and unknown EGFR status in 8%. The median age was 62 years. The induction phase was delivered for 4 cycles in median (range: 1-6), and 21 patients (54%) received maintenance phase with median 4 cycles (range: 2-24). Frequent toxicities ≥ grade 3 during the induction phase in completely analyzed patients (n=32) included neutropenia (50.0%), anemia (9.4%), thrombocytopenia (9.4%), febrile neutropenia (25.0%) and hypertension (37.5%). Other toxicities ≥ grade 3 were cholecystitis, increased ALP, hyperpotassemia, proteinuria, diarrhea, appetite loss, nausea, constipation, infection, stomatitis, and cancer pain in 3.1%, respectively. Interim external reviews of 35 pts revealed ORR of 74% (26/35) and median PFS of 6.4 months (95% CI: 4.8-9.9).
Conclusions: The primary endpoint was met because the lower end of the 95%CI exceeded the threshold of 4.6 months. This combination chemotherapy seems promising in terms of safety and effectiveness, warranting phase III studies.
Identification of RET and ROS tyrosine kinase fusions in lung adenocarcinomas and phase II trial of the RET inhibitor cabozantinib (XL184)
- Author(s)：
- Yoshiyuki Suehara 1), 2), Alexander Drilon 3), Maria E. Arcila 1),
Lu Wang 1), Adnan Hasanovic 1), Raya Khanin 4), Mark G. Kris 3),
Maureen F. Zakowski 1), Naiyer Rizvi 3), and Marc Ladanyi 1) - Affiliation(s)：
- 1) Department of Pathology, Memorial Sloan-Kettering Cancer Center
2) Department of Orthopedic Surgery, Juntendo University (present)
3) Departments of Medicine Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center
4) Departments of Bioinformatics Core, Memorial Sloan-Kettering Cancer Center
Background: We performed a systematic screen for novel tyrosine kinase (TK) fusions in lung adenocarcinoma (ADC) and, based on the results, initiated a phase II trial of the RET inhibitor cabozantinib (XL184). Methods: We studied 67 patients whose lung ADC lacked major known oncogene mutations to discover novel TK fusions. A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5´ to the KD and within or 3´ to the KD. Presumed novel fusion events were followed up by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The NanoString assay detected aberrant 5´ to 3´ ratios in ROS and RET in 2 cases. We identified a novel GOPC-ROS fusion and a novel KIF5B-RET fusion by 5´ RACE, RT-PCR and FISH (Clinical Cancer Research 2012 (i)). Based on our RET fusion finding and the simultaneous reports of RET fusions by several other groups, we initiated a prospective phase II trial of the RET inhibitor cabozantinib for patients with RET fusion-positive lung ADC(NCT01639508). We report preliminary data for the first three patients and have so far observed partial responses in 2 patients and stable disease in one patient (Cancer Discovery 2013 (ii)). Conclusion: RET fusions define a new subset of lung ADC with a targetable driver oncogene.
(i) Suehara Y, Arcila M, Wang L, Hasanovic A, Ang D, Ito T, Kimura Y, Drilon A, Guha U, Rusch V, Kris MG, Zakowski MF, Rizvi N, Khanin R, Ladanyi M; Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions. Clin Cancer Res. 2012 18(24):6599-608.
(ii) Drilon A, Wang L, Hasanovic A, Suehara Y, Lipson D, Stephens P, Ross J, Miller V, Ginsberg M, Zakowski MF, Kris MG, Ladanyi M, Rizvi N; Response to Cabozantinib in patients with RET fusion-positive lung adenocarcinomas. Cancer Discov. 2013 3(6):630-5.
Biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with
S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC))
- Author(s)：
- Toshiaki Takahashi, Tetsuya MItsudomi, Kazuto Nishio, Yasuo Iwamoto, Takeharu Yamanaka, Hiroshige Yoshioka, Hiroto Tada, Masahiro Yoshimura, Ichiro Yoshino, Syunichi Sugawara, Shinzo Kudo, Mitsunori Ohta, Kazuhiko Nakagawa, Yoichi Nakanishi.
- Affiliation(s)：
- West Japan Oncology Group
Background:
We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.
Methods: cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). The expression of each gene was dichotomized according to its median value of expression.
Results: The only gene with interaction P<0.05 after adjustment with sex, histology, age, stage was UMPS (uridine monophosphate synthase) (P=0.0348). UMPS catalyzes conversion of fluoro UMP from 5FU and thus high UMPS expression is implicated to enhance 5FU effect. DFS@2 % (95% CI) for UMPS high/S, UMPS high/CS, UMPS low/S, UMPS low/CS were 69 (54-80), 53 (37-66), 64 (49-76), 61 (46-73)%, respectively. However, molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively).
Conclusion: UMPS expression may define patient subset that would benefit from postoperative S-1 therapy.
