1380P - PK/PD analysis of pembrolizumab, nivolumab and atezolizumab in NSCLC patients: The PIONeeR trial

Background

Exposure-response relationships with immune checkpoint inhibitors are unclear. The PIONeeR trial (NCT03833440) aims to predict response/resistance to anti-PD1/L1 drugs in patients with advanced NSCLC. Here we present preliminary data from the PK/PD analysis of atezolizumab, nivolumab and pembrolizumab.

Methods

A total of 456 patients (median age: 63 years (range: 56-70), F/M: 35/65, ECOG 0 (41%) or 1 (59%)) were treated with standard atezolizumab (n= 53), nivolumab (n= 51) and pembrolizumab (n= 352). Patients were given single-agent treatment (39%) or concomitant chemotherapy (60%). PD-L1 status was available in 368 patients and was negative in 38%. Atezolizumab and nivolumab were given only as 2^d line, whereas pembrolizumab was given as 1^st line (81% patients) or 2^nd line (19%). Pharmacokinetics (PK) sampling (Cmin, Cmax) was performed longitudinally, drugs assayed by LC-MS/MS and PK parameters at baseline were calculated using a pop-PK approach and time-varying clearance models. Time-to-event analysis was performed using parametric models. We searched for PK parameters associated with events. Multiple parametric distributions helped to determine the best model to capture the baseline hazard. Logistic models were specifically applied to assess association with overall response rate (ORR) and PFS.

Results

Median trough levels at cycle-1 were 67 (55-81) mg/L, 20 (13-27) mg/L and 12 (9-16) mg/L for atezolizumab, nivolumab and pembrolizumab, respectively. Median PFS was 6.90, 12.7 and 19 months for the 1^st, 2^nd and 3^rd tertiles (lowest-highest) of pembrolizumab Cmin at cycle 1 (p<0.001, log-rank test). Accordingly, baseline clearance (CL) of pembrolizumab was strongly associated with both ORR and PFS. With nivolumab, a similar trend towards longer PFS was observed in patients with higher Cmin but was not statistically significant (PFS: 1.51, 2.4, and 4.83 months for the 1^st, 2^nd, and 3^rd tertiles, respectively). Conversely, no such trend was observed with atezolizumab (PFS: 4.96, 5.19, and 5.36 months, respectively).

Conclusions

First-cycle trough levels and CL are strong and independent predictors of PFS with pembrolizumab in NSCLC patients. A similar trend was observed with nivolumab, but not with atezolizumab.

Clinical trial identification

NCT03833440.

Editorial acknowledgement

Legal entity responsible for the study

AMIDEX.

Funding

AstraZeneca.

Disclosure

J. Ciccolini: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Pierre Fabre, Daiichi Sankyo, Servier, GSK, Gilead; Other, Institutional, Research Funding: Merck Serono. S. Hominal: Financial Interests, Personal, Invited Speaker: Amgen, Pfizer; Financial Interests, Personal, Advisory Board: BMS. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, LILLY, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, Janssen, GSK, Eisai, Ipsen, AstraZeneca, AbbVie, AnHeart Therapeutics, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, Boehringer Ingelheim, Takeda, Illumina, Pfizer, Medscape; Financial Interests, Personal, Advisory Board, Advisory board: NOVOCURE; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Steering Committee Member: Roche, Sophia Genetics, PharmaMar, AnHeart Therapeutics; Financial Interests, Personal, Other, DMSB: ROCHE; Financial Interests, Institutional, Local PI: AstraZeneca, Amgen, Roche, AbbVie, Apollomics, AnHeart Therapeutics, Innate Pharma, Boehringer Ingelheim, Arrivent Biopharma, Daiichi Sankyo, Bayer; Financial Interests, Steering Committee Member: Lilly. L. Greillier: Financial Interests, Personal, Advisory Board: AbbVie, AstraZeneca, BMS, MSD, Novartis, Sanofi, Takeda, Roche; Financial Interests, Personal, Invited Speaker: Lilly, Pfizer; Financial Interests, Institutional, Local PI: AstraZeneca, AbbVie, BMS, MSD, Novartis, Takeda, Pfizer, PharmaMar; Financial Interests, Institutional, Coordinating PI: Sanofi; Financial Interests, Personal, Local PI: Roche. F. Barlesi: Financial Interests, Institutional, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi Aventis, Seattle Genetics, Takeda, AbbVie, ACEA, Amgen, Eisai, Ignyta; Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd., Innate Pharma, Mirati. All other authors have declared no conflicts of interest.