Background

1L standard-of-care treatment (tx) for ES-SCLC is platinum (carboplatin or cisplatin) + etoposide. Despite high response rates, outcomes remain poor. IMpower133, a global Ph1/3, double-blind, randomized, placebo (PBO)-controlled trial evaluated efficacy and safety of adding atezolizumab (atezo; anti–PD-L1) or PBO to 1L tx (NCT02763579).

Methods

Patient (pts) without prior tx for ES-SCLC were enrolled. PD-L1 testing was not required. Randomization was 1:1 to four 21-day cycles of carboplatin (AUC 5 mg/mL/min IV, Day 1) + etoposide (100 mg/m² IV, Days 1–3) with either atezo (1200 mg IV, Day 1) or PBO, then maintenance atezo or PBO until PD, unacceptable toxicity or loss of clinical benefit. During maintenance tx, prophylactic cranial irradiation (PCI) was allowed per protocol; definitive thoracic radiation (TR) was not. Co-primary endpoints were OS and investigator-assessed PFS. Blood tumor mutation burden (bTMB) was an exploratory subgroup analysis using prespecified cutoffs (≥16 vs < 16 and ≥10 vs < 10 mutations/Mb).

Results

Adding atezo to carboplatin + etoposide provided a significant improvement in OS and PFS in 1L ES-SCLC (Table; WCLC 2018:PL02.07). Survival benefits were consistent across key subgroups and prespecified bTMB cutoffs. 44 pts (22 in each arm) received PCI, and 7 pts (3 in atezo arm, 4 in PBO) received TR. Gr 3–4 tx-related adverse events (AE) occurred in 56.6% vs 56.1% of pts in atezo vs PBO arms, respectively; serious tx-related AEs occurred in 22.7% vs 18.9% of pts, respectively. CNS-related AE rates in patients who had PCI are shown in the table.Table: LBA1

Conclusions

Adding atezo to carboplatin + etoposide provided a significant improvement in survival in 1L ES-SCLC in all-comers. No unexpected safety signals emerged, including in pts who had PCI or TR. Atezo + carboplatin + etoposide may represent a new standard regimen for pts with untreated ES-SCLC.

Editorial acknowledgement

Support for third-party writing assistance for this manuscript, furnished by Rachel Johnson, Ph.D, of Health Interactions, was provided by Genentech, Inc.

Clinical trial identification

NCT02763579.

Legal entity responsible for the study

F. Hoffmann-La Roche/Genentech, Inc., a member of the Roche Group.

Funding

F. Hoffmann-La Roche/Genentech, Inc., a member of the Roche Group.

Disclosure

T.S.K. Mok: Grants: AZ, Roche/Genentech, BMS, BI, Novartis, MSD, Pfizer, Clovis Oncology, SFJ Pharmaceuticals, Taiho, Eisai, Takeda, Xcovery; Personal fees: AZ, Roche/Genentech, Eli Lilly, BMS, BI, Novartis, MSD, Pfizer, Merck Serono, Clovis Oncology, Vertex, SFJ Pharmaceuticals, ACEA Biosciences, Oncogenex, Celgene, Ignyta Inc, Taiho, Fishawack Facilitate Ltd, Takeda, Janssen, Hutchison ChiMed, OrigiMed, Hengrui Therapeutics, Sanofi-Aventis R&D, Yuhan Corporation; Stock: Hutchison ChiMed and Sanomics; Non-financial support: geneDecode. M. Reck: Personal fees: Roche, Lilly, AZ, Abbvie, BI, BMS, Celgene, MSD, Merck, Novartis, Pfizer. L. Horn: Consultancy: AbbVie, AstraZeneca, Merck, Incyte, Xcovery, Genentech, EMD Serono. S. Lam: Employment: Genentech/Roche. D.S. Shames: Employment: Roche/Genentech; Stock: Roche; Patent pending: Genentech Inc. J. Liu: Employment: Roche (China) Holding Ltd. F. Kabbinavar: Employment: Genentech; Stock: Genentech. W. Lin, A. Sandler: Employment: Roche/Genentech; Stock: Roche. S.V. Liu: Grants: AZ, Bayer, Clovis, Corvus, Genentech, Lilly, Merck, Molecular Partners, Esanex, Pfizer, OncoMed, Blueprint, Lycera, Threshold; Personal fees: AZ, BMS, Celgene, Genentech, Lilly, Pfizer, Taiho, Takeda, Regeneron, Heron.

Background

The highly selective central nervous system (CNS)-active ALK inhibitor ALC showed superior efficacy vs CRZ in treatment-naïve ALK+ NSCLC in the global phase III ALEX study. At an updated data cut off, the PFS HR was 0.43 (95% CI 0.32–0.58), median PFS 34.8 months ALC, 10.9 months CRZ. We present results from the phase III ALESIA study of first-line ALC vs CRZ in Asian pts with advanced ALK+ NSCLC (NCT02838420).

Methods

Pts had ALK+ stage IIIB/IV NSCLC (by central IHC testing) and ECOG PS 0–2. Asymptomatic CNS metastases were allowed. Pts were randomised 2:1 to receive the global ALC dose 600mg BID or CRZ 250mg BID. Regular tumour/CNS imaging was done. Primary objective: consistent PFS benefit as seen in ALEX. Primary endpoint: PFS by investigator (INV). Secondary endpoints included: PFS by independent review committee (IRC), time to CNS progression, ORR, DOR, OS, CNS ORR, CNS DOR, QoL and safety.

Results

Median follow-up: 16.2 months ALC, 15.0 months CRZ. At the primary data cut off (May 31, 2018), ALC significantly reduced the risk of progression/death (INV PFS) vs CRZ: HR 0.22 (95% CI 0.13–0.38), p < 0.0001; median PFS not estimable (NE) ALC, 11.1 months CRZ. Secondary endpoints (Table) supported the primary data.Table: LBA2

OS data are immature: HR 0.28 (95% CI 0.12–0.68), p = 0.0027, event rate ALC 6.4%, CRZ 21.0%; median OS NE both arms. ALC pts reported delayed time to worsening of lung cancer symptoms (HR 0.67 [95% CI 0.38–1.18]) and QoL (HR 0.48 [95% CI 0.23–1.04]), compared with CRZ pts. Despite longer treatment duration (14.7 months ALC, 12.6 months CRZ), fewer ALC pts had grade 3–5 AEs (29% vs 48% CRZ), serious AEs (15% vs 26%) or AEs leading to treatment discontinuation (7% vs 10%).

Conclusions

Results confirm the clinical benefit of ALC in pts with advanced ALK+ NSCLC including greater improvement in QoL and demonstrate consistency with the ALEX study.

Clinical trial identification

NCT02838420.

Legal entity responsible for the study

F. Hoffmann-La Roche.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

C. Zhou: Honoraria: Eli Lily, Roches, BI, Hengrui. L. Bu, C. Wang, L. Yang: Roche employee. P.N. Morcos: Stock ownership in Roche. E. Mitry: Roche employee and stock ownership. All other authors have declared no conflicts of interest.

Background

Pts with newly diagnosed advanced OC are treated with cytoreductive surgery and platinum-based chemotherapy. Most relapse within the first 3 years and have further chemotherapy, but once relapsed are largely not curable. SOLO1 (NCT01844986) is the first Phase III trial to evaluate PARP inhibitor (olaparib [Lynparza®]) maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced OC with a BRCAm.

Methods

SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm, had received platinum-based chemotherapy and were in clinical complete or partial response. Pts were randomized 2:1 to olaparib tablets 300 mg bd or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1).

Results

Of 391 randomized pts, 260 received olaparib and 130 placebo (one pt did not receive placebo). Median follow-up was 41 months. Baseline characteristics were well balanced. Primary PFS analysis showed a significant 70% reduction in the risk of progression or death with olaparib versus placebo (Table). PFS sensitivity analyses, second PFS and time to first subsequent therapy or death support the primary analysis. Overall survival data are immature.Table: LBA3

Adverse events were mostly low grade. The most common grade ≥3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no change from baseline in health-related quality of life scores with olaparib.

Conclusions

Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years.

Editorial acknowledgement

Gillian Keating, MBChB, from Mudskipper Business Ltd, funded by AstraZeneca and Merck & Co., Inc.

Clinical trial identification

NCT01844986, 26 August 2013.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Friedlander: Personal fees for advisory boards: AZ and MSD. K. Moore: Consultancy: Tesaro, Genentech Roche, Clovis, Immunogen, VBL Therapeutics, Janssen (honorarium, ad board), AstraZeneca - honorarium, ad board (for agents not involved in the SOLO-1 study). N. Colombo: Honoraria: Genentech, Astra Zeneca, PharmaMar; Consulting or advisory role: Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD, Tesaro; Research Funding AstraZeneca. G. Scambia: Fees for advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro. A. Oaknin: Fees for advisory board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro; Travel/accommodation: Roche, AstraZeneca, PharmaMar. A. Floquet: Fees for advisory board: Astra Zeneca, Roche, Tesaro; Support travel: Roche. A. Leary: Ad boards: Clovis, AstraZeneca, Gamamabs, Pfizer, Gridstone; Travel costs: AstraZeneca; Preclinical research support: Merus, Gamamabs, Sanofi. G.S. Sonke: Institutional research support: AstraZeneca, Merck, Novartis, Roche. C. Gourley: Fees for advisory role: Roche, AstraZeneca, Tesaro, Nucana, Clovis, Foundation One; Lecture fees: AstraZeneca; Research funding (to my institution): Novartis, Aprea, AstraZeneca, Nucana, Tesaro. S. Banerjee: Research Funding AstraZeneca; Advisory boards: AstraZeneca, Tesaro, Clovis. A.M. Oza: Steering committees for trials: AstraZeneca, Clovis, Tesaro (all non-compensated); Honoraria: Intas Pharma. A. González-Martín: Grants as speaker/advisory board participants (last 36 months): AstraZeneca, Tesaro, Roche, Clovis, Pharmamar. C. Aghajanian: Consultancy: Tesaro, Cerulean, Bayer, VentiRx (honorarium, ad board); Mateon Therapeutics (honorarium steering committee meetings); Clovis (honorarium ad boards and steering committee meeting). W. Bradley: Fee for advisory role: Celsion E.S. Lowe, R. Bloomfield: Employee and stockholder: AstraZeneca. P. Disilvestro: Consulting fees: AstraZeneca and Tesaro (over last 2 years). All other authors have declared no conflicts of interest.