Lessons from randomized phase III studies with active cancer immunotherapies – Outcomes from the 2006 Meeting of the Cancer Vaccine Consortium (CVC)

L, Finke; Wentworth, Kerry; Blumenstein, Brent A.; Rudolph, Natalie S.; Levitsky, Hyam I.; Hoos, Axel

doi:10.1016/j.vaccine.2007.06.067

Cited by 115 publications

(77 citation statements)

References 34 publications

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“…Delayed action -late benefit model Earlier discussions of the reason for delayed separation of survival curves in immunotherapy trials have focused on the fact that the development of a clinically effective immune response may take time and that, therefore, the benefit of the treatment will not be evident until late, sometimes only after several months of treatment [9]. This model gains some support from patients with metastatic disease undergoing immunotherapy, who initially display progression but then later respond to therapy [15][16][17].…”

Section: Possible Reasons For Delayed Divergence Of Survival Curves Imentioning

confidence: 99%

“…natural, multisubtype, interferon-alpha (nIFN-alpha) [9,18]. In the study adjuvant nIFN-alpha was given for 6 months, preceded by 2 cycles of dacarbazine to patients with melanoma in different stages.…”

Section: Example Of Late Curve Divergencementioning

confidence: 99%

“…In recent years, it has been recognized that survival curves of treated patients and controls obtained from successful immunotherapy trials commonly display late divergence [1][2][3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…The phenomenon has usually been interpreted as a delayed effect of the treatment, being in contrast to the immediate effect and early curve divergence seen in chemotherapy [9,12]. For instance, treatment with the immunotherapeutic drug ipilimumab resulted in effects that were not graphically observable until several months after initiation of treatment, resulting in late divergence of the survival curves [1].…”

Section: Introductionmentioning

confidence: 99%

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Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

Thorén

Anderson

Strannegård

2013

Cancer Immunol Immunother

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Late divergence of survival curves of treated patients and controls is commonly seen in successful cancer immunotherapy trials. Although late survival curve divergence may be caused by a delayed action of therapy, it may also be related to early effects of the treatment.We suggest that late survival divergence most often reflects a specific benefit of therapy for patients who suffer from a more slowly progressing disease. The occurrence of delayed survival curve divergence has important implications for the statistical analysis of immunotherapy trials. Thus, it leads to non-proportional hazard ratios that make commonly used statistical tests, e.g. the logrank test, suboptimal. It is therefore suggested that the statistical analysis of immunotherapy trials primarily should be based on a test that compares the survival curves at or after a pre-specified, fixed, late time point. PrécisLate survival curve divergence in immunotherapy trials has important implications for the statistical analysis and is commonly misinterpreted to be a consequence of delayed therapeutic effects.3

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Section: Possible Reasons For Delayed Divergence Of Survival Curves Imentioning

confidence: 99%

Section: Example Of Late Curve Divergencementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

Thorén

Anderson

Strannegård

2013

Cancer Immunol Immunother

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“…Unlikely with cytotoxic agents, which showed constant proportional progression events during whole follow-up time, Kaplan-Meier survival curves of ICBAs showed initial non-separation, delayed separation after specific time point and long tail without event. The delayed separation of Kaplan-Meier survival curves associated with ICBAs reduces the statistical power to differentiate between the arms [9]. Clinical trials showing delayed response and durable response can be distinguished from other randomized trials that assume a proportional hazard, that is, that no events occur before the separation of curves in both arms and that the hazard is constant over time [8,10].…”

mentioning

confidence: 99%

Optimal design and endpoint of clinical trials using immune checkpoint blocking agents

Keam

Jung

Nam

2016

Expert Review of Anticancer Therapy

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Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression

et al. 2016

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IMPORTANCE Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression. OBJECTIVE To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC). DESIGN, SETTING, AND PARTICIPANTS Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression. INTERVENTIONS Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks. MAIN OUTCOMES AND MEASURES Safety and efficacy of nivolumab treatment. RESULTS Of 168 patients (median [range] age, 61 [37–81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for ≤ 6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8–5.5) and 2.6 (95% CI, 1.5–3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression). CONCLUSIONS AND RELEVANCE In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression.

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Lessons from randomized phase III studies with active cancer immunotherapies – Outcomes from the 2006 Meeting of the Cancer Vaccine Consortium (CVC)

Cited by 115 publications

References 34 publications

Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

Late divergence of survival curves in cancer immunotherapy trials: interpretation and implications

Optimal design and endpoint of clinical trials using immune checkpoint blocking agents

Safety and Efficacy of Nivolumab in Patients With Metastatic Renal Cell Carcinoma Treated Beyond Progression

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