However, additional studies are required to further optimize the dosing regimen and treatment duration of immunotherapeutic agents. Although survival is the gold standard endpoint for fully establishing efficacy for anti-cancer agents, early tumor shrinkage could offer an appealing surrogate of survival Mouse monoclonal to IgG1 Isotype Control.This can be used as a mouse IgG1 isotype control in flow cytometry and other applications in the context of dose selection. melanoma and renal cell carcinoma (RCC), while higher ORRs were observed in non-small cell lung cancer (NSCLC) at 3?mg/kg and 10?mg/kg versus 1?mg/kg. Peripheral receptor occupancy was saturated at doses??0.3?mg/kg. In D-R/E-R analyses, a positive dose-dependent objective response trend was observed for each tumor type, but appeared to plateau at nivolumab doses of??1?mg/kg for melanoma and RCC, and at??3?mg/kg for NSCLC. Although there was no apparent relationship between tumor shrinkage rate and exposure, WZ4003 tumor progression rate appeared to decrease with increasing exposure up to a dose of 3?mg/kg Q2W for NSCLC. Conclusions Nivolumab monotherapy at 3?mg/kg Q2W provides unified dosing across tumor types. This dose and schedule has been validated in several phase II/III studies in which overall survival was an endpoint. Integrating D-R/E-R relationships with efficacy data and a safety profile that is unique to I-O therapy is a rational approach for dose selection of these agents. Electronic supplementary material The online version of this article (doi:10.1186/s40425-016-0177-2) contains supplementary material, which is available to authorized users. +?for the represent baseline tumor size, tumor shrinkage rate constant, and linear tumor progression rate for the and adverse event, WZ4003 colorectal cancer, discontinuation, metastatic castration-resistant prostate cancer, melanoma, non-small cell lung cancer, every 2?weeks Open in a separate window Fig. 2 Integrated dose-response for treatment-related grade 3 AEs and AEs leading to discontinuation. AEs?=?adverse events There was no apparent relationship between the incidence of select AEs and the dose of nivolumab. Integrated D-R for safety was assessed with respect to the cumulative time-to-event distribution of grade??3 treatment-related AEs and AEs leading to discontinuation across all tumor types in the dose-ranging phase Ib study (Fig.?2). The probability of AEs leading to discontinuation appeared to be lower in doses??1?mg/kg compared with the 3 and 10?mg/kg doses. The probabilities of both grade??3 treatment-related AEs and those leading to discontinuation were similar between 3 and 10?mg/kg doses. In addition, relative dose intensity across dose levels appeared to be? ?90?% for all dose levels. The average dose intensity per patient was 1.0, 2.9, and 9.8?mg/kg/2?weeks for 1.0, 3.0, and 10.0?mg/kg dose levels, respectively. Overall, with no established MTD, similar dose intensity, nature, and frequency of AEs across dose levels, and manageable safety profile of nivolumab, 10?mg/kg Q2W was considered safe and tolerable. In the 69 evaluated patients with melanoma, peripheral PD-1 RO was saturated at??0.3?mg/kg doses after 8?weeks (Fig.?3a). The E-R relationship for RO is shown in Fig.?3b. Peripheral RO is saturated at a lesser concentration with dosages matching to??0.3?mg/kg. Furthermore, there were minimal increases in turned on T cells in peripheral bloodstream, with no proof WZ4003 D-R. The peripheral pharmacodynamics data didn’t differentiate activity by dosage level. However, it ought to be observed that the partnership between peripheral and intra-tumoral PD-1 RO and T-cell proliferation is not established and could have limited worth in understanding D-R romantic relationships. Open in another screen Fig. 3 Peripheral a PD-1 occupancy and b receptor occupancy (RO) of sufferers treated with nivolumab. MEL?=?melanoma; PD-1?=?designed deathC1; pts?=?sufferers ORRs were similar over the evaluated dosage runs for RCC and melanoma. Nevertheless, higher ORRs had been noticed for NSCLC at WZ4003 3 (24.3?%) and 10?mg/kg (20.3?%) than at 1?mg/kg Q2W (3?%) (Desk?2). The PFSR 24 was larger at 3 numerically?mg/kg for melanoma and NSCLC than in other dosages tested (melanoma: 0.1, 0.3, 1, and 10?mg/kg; WZ4003 NSCLC: 1 and 10?mg/kg). For RCC, ORRs had been very similar for 1 and 10?mg/kg, and PFSR 24 was higher at 10 numerically?mg/kg than in 1?mg/kg (Desk?2). Desk 2 PFSR and ORR 24 prices by dosage in sufferers with melanoma, NSCLC, and RCC treated.