Author of

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  MO18 - NSCLC - Targeted Therapies IV (ID 116)

  • Event: WCLC 2013
  • Type: Mini Oral Abstract Session
  • Track: Medical Oncology
  • Presentations: 1
  • Moderators:L. Horn, J. Wolf
  • Coordinates: 10/29/2013, 16:15 - 17:45, Bayside Auditorium B, Level 1

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    MO18.03 - Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial (ID 2356)

    16:25 - 16:30  |  Author(s): A. Gupta
    • Abstract
    • Presentation
    • Slides

    Background
    Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian S, et al. New Engl J Med. 2012;366:2443-54). We present long-term safety and efficacy outcomes from a phase 1 study of nivolumab, a fully human IgG4 PD-1 receptor blocking monoclonal antibody, in patients with advanced NSCLC.

    Methods
    NSCLC patients enrolled between 2008–2012 received nivolumab 1, 3, and 10 mg/kg IV Q2W on either dose escalation or subsequent expansion cohorts. Tumors were assessed (RECIST 1.0) after each 4-dose cycle. Protocol was amended (Jan. 23, 2012) to explore nivolumab’s potential to deliver prolonged overall survival (OS) for the initial and expansion cohorts and the overall population.

    Results
    129 pretreated NSCLC patients (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) were treated as of March 2013. Responses (CR/PR) occurred in 22 patients (17%) and were durable (estimated median response duration, 74.0 weeks [6.1+, 133.9+]), and ongoing in 55% (12/22) of patients. The highest objective response rate (ORR) was at 3 mg/kg (24%) across NSCLC histologies. Responses were rapid; 50% of patients (11/22) demonstrated response at first tumor assessment (8 weeks). Among 12 responders who discontinued therapy for reasons other than disease progression, 3 responded for ≥24 weeks post therapy discontinuation, and all 3 had not progressed at the time of this analysis. An additional 6 of the 122 patients (5%) demonstrated unconventional “immune-related” responses (based on target lesions), but were not included among responders. Survival benefit was demonstrated by 1-year and 2-year landmark OS rates (42% and 14%; Table). Median OS was 9.6 months across doses and 14.9 months at 3 mg/kg across histologies. Median OS across doses was similar for squamous/non-squamous patients. Any grade drug-related select adverse events (AEs) occurred in 41% (53/129) of patients (grade 3/4 select AEs, 5% [6/129]); most common being skin (16%), gastrointestinal (12%), and pulmonary (7%). Any grade drug-related pneumonitis occurred in 6% (8/129) of patients (grade 3/4 pneumonitis, 2% [3/129]), resulting in 2 deaths early in the trial, leading to increased emphasis on management algorithms. Characteristics and management of nivolumab-related pneumonitis will be summarized.

    Cohort	Dose, mg/kg	ORR[a] no. of patients/total no. of patients (%) [95% CI]	Estimated median response duration, wk (range)	Median OS,[b] mo (95% CI)	OS rate, % (95% CI); patients at risk, n
    					1 y		2 y
    NSCLC (n=129)[c]	All doses	22/129 (17.1) [11.0, 24.7]	74.0 (6.1+, 133.9+)	9.6 (7.8, 12.4)	42 (33, 51); 43		14 (4, 24); 5
    	1	1/33 (3.0) [0.1, 15.8]	63.9 (63.9, 63.9)	9.2 (5.6, 11.1)
    	3	9/37 (24.3) [11.8, 41.2]	NR (16.1+, 133.9+)	14.9 (9.5, NE)
    	10	12/59 (20.3) [11.0, 32.8]	83.1 (6.1+, 117.1+)	9.2 (5.2, 12.4)
    Initial cohort (n=19)	All doses			9.6 (4.5, 19.8)	42 (20, 64); 8		26 (7, 46); 5
    Expansion cohort (n=110)	All doses			9.9 (7.8, 12.5)	42 (32, 51); 35
    Squamous (n=54)	All doses	9/54 (16.7) [7.9, 29.3]	NR (16.1, 133.9+)	9.2 (7.3, 12.5)	39 (25, 53); 16
    	1	0/15	0	8.0 (2.6, 13.3)
    	3	4/18 (22.2) [6.4, 47.6]	NR (16.1, 133.9+)	9.5 (6.7, NE)
    	10	5/21 (23.8) [8.2, 47.2]	83.1 (16.1, 117+)	10.5 (7.8, 12.5)
    Non-squamous (n=74)	All doses	13/74 (17.6) [9.7, 28.2]	63.9 (6.1+, 74.0+)	10.1 (7.2, 13.7)	43 (31, 54); 26
    	1	1/18 (5.6) [0.1, 27.3]	63.9 (63.9, 63.9)	9.9 (5.6, 22.7)
    	3	5/19 (26.3) [9.1, 51.2]	74.0 (24.3, 74.0+)	18.2 (10.3, 18.2)
    	10	7/37 (18.9) [8.0, 35.2]	NR (6.1+, 65.7+)	7.4 (4.6, 12.4)
    [a]ORR = ([CR + PR] ÷ n) × 100.[b]OS estimates after 1 year reflect censoring and shorter follow-up for patients enrolling later in the study.[c]Non-squamous (n=74), squamous (n=54), and unknown histology (n=1) NE = not estimable; NR = not reached.

    Conclusion
    In advanced NSCLC patients, nivolumab produced durable responses and survival benefit (1-year OS rate, 42%), with a long-term safety profile acceptable for the outpatient setting, supporting ongoing development in phase 3 trials with survival endpoints. Additional follow-up on patient survival will be presented at the time of the meeting.

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