Background

Hyperprogressive disease (HPD), characterised by a rapid increase in tumour growth rate, has been recently reported in patients (pts) treated (tx) with CPI monotherapy and requires evaluation of pre-tx tumour growth rates. HPD is rare and has been associated with older age (>65 y; Champiat, CCR 2017), EGFR mutation (Kurzrock, Kato 2018) and poor OS. In the Phase III OAK study in 2L/3L NSCLC (n = 850), ITT OS was superior for atezo vs doc (mOS, 13.8 vs 9.6 mo; HR, 0.73). Here we examine fast progression (FP) as a surrogate for HPD, its relation to CPI vs chemo and association with efficacy according to pre-tx factors expected to be prognostic for FP, including early failure of the preceding tx.

Methods

FP was defined as ≥ 50% increase in the SLD (per investigator) from baseline to first assessment (6 weeks) or death due to PD per investigator within 12 weeks without a post-tx scan. Baseline factors of pts with FP were compared for atezo vs doc to identify associations with a specific tx. OS was evaluated according to selected baseline factors, including early prior tx failure, LDH ≥225 units/L, SLD ≥80 mm and ≥3 metastatic sites.

Results

The proportion of pts meeting FP criteria was similar between atezo and doc arms (n = 44 [10.4%] vs n = 41 [9.6%], respectively). Baseline factors for FP pts were similar across arms except for more males, non-smokers and fewer pts with early prior tx failure among atezo FP pts. Improved OS with atezo vs doc was seen in pts with early prior tx progression (median, 8.9 vs 6.2 mo), high LDH (median, 11 vs 8.9 mo), high SLD (median, 9.4 vs 6.9 mo), and ≥3 metastatic sites (median, 11.7 vs 8.6 mo).

Conclusions

The proportions of FP pts in atezo and doc arms were similar, suggesting that rapid post-baseline progression is not specific to anti–PD-L1 tx. A consistent benefit of tx with atezo vs doc was seen across subgroups defined by baseline factors associated with aggressive disease.Table: LBA1

Patient characteristics by FP status (ITT, N = 850)

Editorial acknowledgement

Chris Lum, PhD of Health Interactions, Inc.

Clinical trial identification

NCT02008227.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

D.R. Gandara: Consulting/advisory role: Genentech, AZ, Merck; Supported/contracted research/grant: Genentech; Support of parent study and funding of editorial support: F.Hoffmann-La Roche. M. Reck: Consulting/advisory role, speakers bureau: F. Hoffmann-La Roche, Lilly, BI, AstraZeneca, MSD, BMS, Merck, Novartis, Pfizer, Celgene; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. S. Morris: Employee and stock: Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. A. Cardona: Employee: Roche; Support of parent study and funding of editorial support: F. Hoffman-La Roche. D. Mendus: Employee: Genentech/Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. M. Ballinger: Employee: Genentech/Roche; Stock: Roche; Support of parent study and funding of editorial support: F. Hoffmann-La Roche. A. Rittmeyer: Speakers bureau: Lilly, BMS, MSD, Roche/Genentech; Consulting/advisory role: Lilly, BMS, Boehringer Ingelheim, AstraZeneca, MSD, Pfizer, Roche/Genentech, AbbVie; Support of parent study and funding of editorial support: F. Hoffmann-La Roche.

Background

Preclinical data show that antibiotics (ATB) and proton pump inhibitors (PPI) may modulate the microbiome. Recent data from retrospective analyses suggest reduced benefit of immune checkpoint inhibitors (ICI) in patients treated with ATB. Here we explore ATB and PPI use in NSCLC patients who received atezolizumab or chemotherapy.

Methods

This retrospective analysis was performed with pooled data from the phase III OAK (NCT02008227) and phase II POPLAR (NCT01903993) studies. In both studies, patients with previously treated metastatic NSCLC were randomized to receive either atezolizumab or docetaxel. All patients from these studies were included in the analysis (n = 1512, 757 in the atezolizumab and 755 in the docetaxel group). The primary objective of this study was to assess the impact of ATB or PPI use within 30 days before and after beginning treatment on overall survival (OS). Hazard ratios (HR) were estimated using univariate and multivariate cox regression models adjusting for baseline variables, such as treatment arm, histology, ECOG number of metastatic sites and age.

Results

A total of 169 (22.3%) patients in the atezolizumab and 202 (26.8%) patients in the docetaxel group received ATB. PPI was used in 234 (30.9%) patients in the atezolizumab group and 260 (34.4%) patients in the docetaxel group. The univariate analysis showed that ATB use was associated with shorter OS (HR 1.21 [95%CI 1.05-1.39]), as was PPI use (HR 1.29 [95% CI 1.13-1.48]). This impact remained significant at multivariate analysis in the overall population. While univariate analysis of interactions between ATB or PPI use and treatment showed a shorter OS in the atezolizumab treated population (HR 1.32 [95%CI 1.06-1.63] and HR 1.45 [95% CI 1.20-1.75], resp.), the multivariate analysis did not confirm the relationship to be statistically significant.

Conclusions

Together with previous published data, this retrospective analysis suggest that ATB or PPI use 30 days before and after beginning treatment in patients with metastatic NSCLC may be associated with lower efficacy of ICI. Future research on cancer immunotherapy should elucidate the effects of concomitant medications and the role of microbiome.

Clinical trial identification

NCT0190399; NCT02008227.

Legal entity responsible for the study

F. Hoffmann- La Roche.

Funding

Funding support provided by the imCORE Network on behalf of F.Hoffmann- La Roche.

Disclosure

M. Chalabi, M. Kok: Advisory board: Bristol-Myers Squibb; Research funding to institute: Roche-Genentech, Bristol-Myers Squibb. A. Cardona, A.M. Dhawahir Scala: Full time employee: Hoffmann-La Roche. D. Nagarkar: Full time employee and stocks: Genentech. M. Albert: Full time employee: Genentech. T.B. Powles: Honoraria: BMS, Roche, AZ, Exelexis, MSD, Pfizer, Novartis, Ipsen, Esai, Astellas, Seattle Genetics, Incyte; Research funding: BMS, Roche, AZ, MSD, Pfizer. All other authors have declared no conflicts of interest.

Background

In the global, open-label, phase 2/3 study KEYNOTE-010, pembro 10 mg/kg or 2 mg/kg Q3W improved OS vs docetaxel in pts with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1% (coprimary analyses) at median follow-up of 13.1 mo. We present long-term results overall, in pts who completed 35 cycles (∼2 y) of pembro, and in pts who received a second course of pembro.

Methods

Pts aged >18 y with previously treated advanced NSCLC with PD-L1 TPS ≥1% were randomized 1:1:1 to pembro 10 mg/kg or 2 mg/kg Q3W, or docetaxel 75 mg/m² Q3W. Pts received pembro for 35 cycles, until disease progression/intolerable toxicity. Response was assessed every 9 wk (RECIST 1.1 by independent central review), and survival every 2 mo posttreatment. There was no difference between pembro doses in the primary analysis, thus doses were pooled in this analysis.

Results

As of March 16, 2018, median (range) follow-up was 42.6 (35.2–53.2) mo overall (N = 1033). Pembro improved OS vs docetaxel in pts with PD-L1 TPS ≥50% (HR, 0.53; 95% CI, 0.42–0.66; P < 0.00001) and TPS ≥1% (HR, 0.69; 95% CI, 0.60–0.80; P < 0.00001). In pts with PD-L1 TPS ≥50%, median (95% CI) OS was 16.9 (12.3–21.4) mo with pembro vs 8.2 (6.4–9.8) mo with docetaxel; 36-mo OS rates were 35% vs 13%, respectively. Similar to the primary analysis, 16% of pembro pts and 36% of docetaxel pts had grade 3–5 treatment-related AEs. 79 of 690 pembro pts received 35 treatment cycles (∼2 y). 36-mo OS rate among these 79 pts was 99% and 75 (95%) had PR/CR as best response; 72 pts (91%) remained alive. 48 pts (64%) had an ongoing response; median duration of response was not reached (range, 4–46+ mo). 25 of 79 pts (32%) had PD (investigator review) after stopping 35 cycles of pembro. 14 pts received second course pembro, 5 of whom completed 17 cycles; 6 (43%) had PR, 5 (36%) had SD, and 11 (79%) remained alive.

Conclusions

At 43-mo follow-up, pembro continued to prolong OS vs docetaxel in pts with previously treated, PD-L1–expressing advanced NSCLC, with manageable long-term safety. Most pts who completed 35 cycles (∼2 y) of pembro had durable response. The majority of pts with PD by investigator review who received second course pembro had either PR or SD and remained alive.

Editorial acknowledgement

Medical writing and editorial assistance was provided by C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Clinical trial identification

NCT01905657.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

R.S. Herbst: Consulting role: Eli Lilly, Genentech/Roche, Merck, NextCure, Novartis, Pfizer; Research support: AstraZeneca, Eli Lilly, Merck. E.B. Garon: Funding to institution: Merck & Co., Inc., AstraZeneca, Eli Lilly, Genentech, Bristol-Myers Squibb, Pfizer, Novartis, Mirati. B. Chul Cho: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim; Research funding: Bayer, AstraZeneca, Yuhan, Novartis; Consultant or advisor: AstraZeneca, Roche, Boehringer Ingelheim; Speakers’ bureau: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis. J.L. Pérez Gracia: Grants: Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Lilly; Advisor, speakers’ bureau: Bristol-Myers Squibb, Roche. J-Y. Han: Honoraria: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme; Research funding: Roche; Consultant or advisor: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Eli Lilly. M. Majem: Consultant or advisor: AstraZeneca, Roche, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis. M. Forster: Research grants: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Merck; Honoraria for advisory and consultancy roles: Achilles, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Merck, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche. I. Monnet: Congress invitations: Roche, AstraZeneca. S. Novello: Funding to institution: Merck Sharp & Dohme; Speakers bureau: Eli Lilly, Takeda, Roche, AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim. M.A. Gubens: Research grant to institution: Merck & Co., Inc.; Personal fees for consulting: AbbVie, Ariad, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera, Clovis, Genentech-Roche, Mersana, Nektar, Novartis, Pfizer. A. Samkari, E. Jensen, G.M. Lubiniecki: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. P. Baas: Consulting role: Genentech/Roche, Merck, Bristol-Myers Squibb, Pfizer; Research support: Bristol-Myers Squibb, Roche, Merck. All other authors have declared no conflicts of interest.

Background

In IMpower133 (NCT02763579), 1L treatment (tx) with atezo + CP/ET for ES-SCLC provided a significant improvement in survival v placebo (PBO) + CP/ET and no unexpected safety signals. PROs were assessed to inform the overall tx benefit of adding atezo to CP/ET.

Methods

Patients (pts) were randomised to atezo + CP/ET (1200 mg + AUC 5/100 mg/m²) (N = 201) or PBO + CP/ET (N = 202) IV q3w x 12 wks, then maintenance atezo or PBO q3w until progression/intolerable toxicity/clinical benefit loss. Descriptive analyses of EORTC QLQ-C30 and QLQ-LC13 scales (score range 0–100) included change from baseline (BL), cumulative distribution function curves of change at wk 12 and time to deterioration (TTD). A ≥ 10-point change from BL was prespecified as clinically meaningful.

Results

Completion rates were ≥85% at BL and ≥70% to wk 75 in both arms; BL PRO scores were comparable. At wks 27 and 54, 108 and 34 pts remained on study and eligible to complete assessments, respectively. Pts in both arms reported early, notable lung cancer (LC) symptom palliation (Table) with numeric trends of greater improvement with atezo + CP/ET. Higher proportions of atezo + CP/ET pts reported LC symptom relief at wk 12 v PBO + CP/ET. No apparent differences in TTD of cough or chest pain were seen; a numeric delay in TTD of dyspnoea favoured atezo + CP/ET (HR 0.75; 95% CI 0.55–1.02). Atezo + CP/ET pts reported improved physical function above BL until wk 51 and clinically meaningful health-related quality of life (HRQoL) improvements that persisted at most visits through wk 54. Changes in tx-related symptoms (diarrhoea, nausea/vomiting) were similar across arms.Table: 49O

Conclusions

Atezo + CP/ET tx provided a significant improvement in survival as well as immediate and tangible improvements in pt-reported LC symptoms. PROs indicating sustained function and improved HRQoL with minimal impact from tx toxicities further support the positive benefit:risk of atezo + CP/ET in 1L ES-SCLC.

Editorial acknowledgement

Support for third-party writing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.

Clinical trial identification

NCT02763579, May 5, 2016.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd/Genentech, Inc.

Funding

F. Hoffmann-La Roche Ltd/Genentech, Inc.

Disclosure

R. Califano: Honoraria for consultancy, speaker bureau and advisory board: Roche. S.V. Liu: Research grant (institution): AZ, Bayer, Blueprint, Clovis, Corvus, Esanex, Genentech, Lilly, Lycera, Merck, Molecular Partners, OncoMed, Pfizer, Threshold; Consultant: AZ, BMS, Celgene, Genentech, Heron, Lilly, Pfizer, Regeneron, Taiho (DSMB), Takeda. L. Horn: Consultancy: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. C. Quach, F. Kabbinavar, S. Lam: Employment and stock: Roche/Genentech. W. Yu: Employment: Genentech. A. Mansfield: Honoraria for participation in advisory boards (institution): Genentech, AbbVie, BMS; Grants: Novartis, Verily. All other authors have declared no conflicts of interest.