A phase 1/2 trial of a monoclonal antibody targeting fucosyl GM1 in relapsed/refractory small cell lung cancer (SCLC): Safety and preliminary efficacy
Q.S-C. Chu1, B. Markman2, N. Leighl3, L. Krug4, C. Rudin5, D. Lathers6, P. Basciano4, P.M. Fracasso7, G. Kollia8, P. Phillips9, G. Kolaitis10, D. Williams6, J. Jackson6, N. Ready11
Background: Fucosyl-GM1 (Fuc-GM1), a ganglioside with abundant yet restricted expression on the cell surface of SCLCs, is a potential target for therapeutic approaches. Here we present preliminary results from a Phase 1/2 study of BMS-986012, a first-in-class fully human IgG1 monoclonal antibody with enhanced ADCC that specifically binds to Fuc-GM1, for the treatment of SCLC.
Methods: Patients (pts) with relapsed/refractory SCLC after at least one line of prior therapy were enrolled. BMS-986012 was administered IV at flat doses of 70, 160, 400, and 1000 mg every 3 weeks (wk) during dose escalation. Pharmacokinetics (PK) and anti-drug antibodies (ADA) were assessed during cycle 1.
Results: Twenty-nine pts were treated across all doses. Median age was 63 yr (range: 26–81); 55% were female; 95% had a smoking history. Pts had received up to five lines of prior therapy; 52% had one prior line; 48% had 2 or more two prior lines. Nine pts were platinum refractory (≤3 mo from end of first line therapy to progression). No dose limiting toxicities or treatment-related grade 4 or 5 adverse events occurred. Treatment-related adverse events occurring in >10% of pts were pruritus, decreased appetite, and rash. Preliminary PK analysis suggests a linear dose-exposure relationship (Table). No ADAs were detected.
One confirmed complete response (CR; duration 53 wk; 70 mg dose level) and one confirmed partial response (PR; duration 17 wk; 400 mg dose level) were observed. Stable disease (SD) was reported in 4 pts. The CR and 2 SD occurred among the 9 platinum refractory pts.
Conclusions: BMS-986012 demonstrates a manageable safety profile and resulted in objective responses in relapsed SCLC, including platinum refractory pts. Preliminary PK analysis showed dose-proportional and linear increase in exposure with moderate to high variability. Dose expansion is currently enrolling at 400 and 1000 mg.
Clinical trial identification: NCT02247349
Legal entity responsible for the study: Sponsored by Bristol-Myers Squibb
Funding: Sponsored by Bristol-Myers Squibb
Disclosure: Q.S-C. Chu: Personal fees from BMS and Lilly (advisory boards), Novartis (advisory board and consultancy), and Astra Zeneca, Merck (advisory and consultancy). Grants and personal fees from BI (Research Grant and advisory board).
L. Krug: Grants from Bristol-Myers Squibb, during the conduct of the study; other from Bristol-Myers Squibb, outside the submitted work. C. Rudin: Personal fees from Bristol Myers Squibb, Celgene, Novartis, Medivation, and Merck, outside the submitted work. D. Lathers: Employee & Shareholder at BMS. P. Basciano: Personal fees from Bristol-Meyers Squibb, outside the submitted work as a Study Sponsor. P.M.
Fracasso: Employee of BMS. P. Phillips: Employee of Bristol-Myers Squibb. N. Ready: Personal fees from Bristol Myers Squibb, Celgene, Novartis, Medivation, and Merck, outside the submitted work. All other authors have declared no conflicts of interest.
Phase I/II study of induction chemotherapy using carboplatin plus irinotecan and sequential thoracic radiotherapy (TRT) for elderly patients with limited-stage small-cell lung cancer (LD-SCLC): The final results of TORG 0604
Background: The role of irinotecan for elderly patients with LD-SCLC has been unclear, and the timing of TRT combined with chemotherapy has not been fully evaluated.
Methods: Patients aged > 70 years with untreated, measurable, LD-SCLC, performance status (PS) 0-2, and adequate organ function were eligible. Treatment consisted of induction with carboplatin on day 1 and irinotecan on days 1 and 8, every 21 days for 4 cycles, and sequential TRT (54Gy in 27 fractions). Carboplatin doses were based on AUC of 4 and 5 (levels 1 and 2, respectively), with a fixed irinotecan dose (50 mg/m2). Primary objectives of the phase II study were efficacy, adverse events, and feasibility.
Results: Forty-one patients were enrolled (median age75 years [range 70-86 years); males 31; PS 0/1/2, n = 22/18/1]. The number of patients with carboplatin dose-limiting toxicities at levels-1 (n = 6) and -2 (n = 6) were 1(grade 3 hypertension) and 2 (grade 4 thrombocytopenia), respectively. The phase II trial was expanded to 29 additional patients receiving the level 1 carboplatin dose. The median number of chemotherapy cycles was 4 (range 1-4), and the median radiation dose was 54Gy (range 36-60). Toxicities were generally mild. There were 5 complete and 30 partial responses (response rate 90%).With a median follow-up of 80.4 months (n = 41), the median progression-free and overall survival times were 12.5 and 27.5 months, respectively.
Conclusions: Induction chemotherapy of carboplatin plus irinotecan and sequential
TRT was well tolerated and effective for elderly patients with LD-SCLC. Additional
confirmatory studies are warranted.
Legal entity responsible for the study: Thoracic Oncology Reserch Group (TORG)
Funding: Nippon Kayaku, Taiho, Lilly, Sanofi, Chugai, Astra Zeneca, Daiichi Sankyo,
Disclosure: All authors have declared no conflicts of interest.
入组条件为70岁以上未接受过治疗、有可测量病灶、PS评分0-2分、有足够脏器功能的局限期小细胞肺癌患者。治疗为第一天卡铂化疗，第一天及第八天伊立替康化疗，每21天重复治疗4个周期，之后序贯进行胸部放疗（54Gy，分27次）。卡铂剂量为AUC 4和5（分别为1级和2级），伊立替康剂量固定为50mg/m2 。II期研究的主要目标位疗效、不良反应及可行性分析。