28 CHAPTER 2 clinical benefit rate of 27%). The median progression-free survival and overall survival were 3 months (95% confidence interval 2–4 months) and 10 months (95% confidence interval 7–13 months), respectively (Figure. 2). To put this in perspective, a large database of 854 patients who were participating in phase I studies and were treated with molecularly targeted agents indicated a median progression-free survival and overall survival of 2 and 8 months, respectively17. Figure 2. Response and survival plots. a. Waterfall plot of the best percentage change in the sum of target lesions compared to baseline tumour measurements according to ‘Response Evaluation Criteria in Solid Tumours’ (RECIST) 1.1, for all patients with ≥1 response evaluation and with a known change in the sum of target lesions (n = 166 patients). Patients with unequivocal disease progression at the first evaluation (on the basis of non-target lesions or non-RECIST measurements only) and patients who went off-study before their response could be evaluated are not included in this graph (n = 49 patients). b. Kaplan–Meier curve for estimated progression-free survival. c. Kaplan–Meier curve for estimated overall survival, with 95% confidence interval (dashed lines). One hundred and forty-one patients (66%) did not experience a clinical benefit, either because of progressive disease (n = 117 patients) or because they went off-study before they could be classified as having experienced a clinical benefit or not (n = 24 patients). Reasons for early withdrawal from the study without obtaining radiologic or clinical diagnosis of progressive disease included death (n = 9 patients), adverse events (n = 5 patients), patient preference (n = 3 patients) or were unknown (n = 7 patients). Adverse events were consistent with those observed in standard of care (Extended Data Table 4). Overall, ten patients discontinued treatment owing to toxicity. Two suspected unexpected severe adverse reactions were reported: bacterial peritonitis in a patient with ovarian carcinoma and sinus thrombosis in a patient with breast cancer. To date, two cohorts have completed accrual: the first is a tumour-type-agnostic cohort of patients with microsatellite-instable (MSI) tumours treated with nivolumab. In total, 30 patients with 8 types of tumour were enrolled in this cohort. As of 3 May 2019, one patient (3%) had a complete response. Eleven patients (37%) had a partial response, and seven patients (23%) had stable disease at ≥16 weeks. Four patients (13%) had progressive disease as a best overall response, and seven patients (23%) went off study before evaluability was reached (that is, after fewer than two cycles of nivolumab treatment and/or with insufficient response evalu-
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