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- Enriqueta Felip (Barcelona, ES)
- Pieter E. Postmus (Leiden, NL)
Session DOI
LBA48_PR - CTONG 1103：Erlotinib versus Gemcitabine plus Cisplatin as Neo-adjuvant Treatment for Stage IIIA –N2 EGFR-mutation Non-small-cell lung cancer (EMERGING): a Randomised Study
- Wen-Zhao Zhong (Guangzhou, CN)
Abstract
Background
Cisplatin-based doublet chemotherapy as neoadjuvant treatment for IIIA-N2 non-small cell lung cancer (NSCLC) give patients 5% survival benefit. EGFR-TKIs have been proved to prolong PFS of advanced EGFR-mutant NSCLC. CTONG1104 trial shown adjuvant gefitinib could improve 10 months (disease free survival) DFS than chemotherapy in N1/N2 resected NSCLC. It raises the possibility that EGFR-TKIs may play a beneficial role in the neoadjuvant setting. We conducted this randomized trial to compare the efficacy of erlotinib (E) and gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant treatment.
Methods
Eligible patients with N2 disease were randomly assigned in 1:1 ratio to E group for 42 days as neoadjuvant therapy and then for 12 months after surgery or GC group for 2 cycles neoadjuvant chemotherapy and 2 cycles after complete resection. The primary endpoint is objective response rate (ORR). secondary endpoints included downstaging rates of pathological lymph nodes, pathological complete response (pCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability.
Results
A total of 386 patients from 17 centers were screened, 72 were randomized and included in the intention-to-treat population. The ORR for neoadjuvant E versus GC was 54.1% (95% CI, 37.2% to 70.9%) vs 34.3% (95% CI, 17.7% to 50.8%) (OR 2.26; 95% CI, 0·87–5.84; p=0·092). After neoadjuvant therapy, 31 patients (83·8%) in the E group and 24 (68·6%) in the GC group underwent surgery. Overall, lymph node downstaging occurred in 13% in the E and 4·2% in the GC group. The major pathological response (MPR) occurred in 3 of 28 patients (10.7%) in the E and no MPR (0/22) in the GC group. Median PFS was significantly longer with E (21·5 months; 95% CI, 19·3–23·6) versus GC (11·9 months; 95% CI, 9·1–14·7; HR 0·42; 95% CI, 0·23–0·76; p=0·003), whereas OS data was immature. The incidence of grade 3/4 toxicities was lower in the E group (0%) than that in the GC group (29·4%). No unexpected AEs were found.
Conclusions
Neoadjuvant/adjuvant erlotinib improved ORR, and significantly prolonged PFS compared with GC chemotherapy in patients with stage IIIA-N2 EGFR mutation NSCLC.
Clinical trial identification
NCT01407822
Editorial Acknowledgement
No
LBA49 - Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC)
- Tina Cascone (Houston, US)
Abstract
Background
Neoadjuvant N induces a 45% major pathologic response (MPR) in resected NSCLCs. We report preliminary results of NEOSTAR (NCT03158129) - a phase 2 trial evaluating neoadjuvant N or NI in resectable NSCLC pts.
Methods
Pts with stage I-IIIA (single N2) resectable NSCLC (AJCC 7th), ECOG PS 0-1, were randomized 1:1 to N (3 mg/kg IV Q2 weeks, on D1, 15, 29) or NI (N plus I, 1 mg/kg IV on D1) followed by surgery (n=22/arm). Primary endpoint is MPR (≤10% viable tumor cells at surgery), hypothesized to be higher than MPR to induction chemotherapy historical controls. Immune infiltrates were assessed by flow cytometry on checkpoint inhibitor (CPI)-treated tumors and compared to untreated resected samples (ICON set).
Results
As of 9/6/2018, 33 pts were randomized, 17 to N, 16 to NI: mean age 65, 67% males, 21% never smokers, stage I n=10, II n=15, III n=8, 58% adenocarcinomas. 30 pts completed neoadjuvant therapy (2 ongoing, 1 G3 hypoxia [N]) & 26 had surgery (5 unresectable [2 N, 3 NI], 2 pending). Overall MPR rate was 26% (8/31). MPR rate to N and NI were 25% (4/16) and 27% (4/15), respectively. Median % of viable tumor cells was lower in tumors resected post NI vs. N (28% vs. 65%, p=0.32). There were 5 pathologic CRs (2 N, 3 NI). Radiographic ORR by RECIST v1.1 was 19% (5 PR [N], 1 CR [NI]). 19% of pts had PD (6/31, 3 N, 3 NI). Surgical complications included 1 bronchopleural fistula (BPF). Treatment-related AEs included G5 death due to BPF post steroid-treated pneumonitis (n=1, N); G3 pneumonia (n=1, N), hypoxia (n=1, N); G2 cough (n=3, NI), rash (n=1, N), fatigue (n=1, N). CPIs increased proliferative (Ki67+) & activated (ICOS+) effector CD8+ & CD4+ TILs in treated vs. untreated tumors (p<0.0001). CD27+CD28+ effector memory CD8+ TILs were higher in N vs. NI (49% vs. 33%, p=0.06). Ki67+CD103+ tissue resident effector CD8+ (98% vs. 65%, p=0.1) & CD4+ (99% vs. 40%, p=0.03) TILs and Tregs (97% vs. 47%, p=0.06) were higher in NI vs. N.
Conclusions
Neoadjuvant CPI is overall safe and induces a 26% MPR rate, with a trend towards less viable tumor after NI. Preliminary results suggest neoadjuvant CPIs induce higher TIL proliferation and activation vs. untreated tumors. NI may induce higher proliferation of different T cell subsets vs. N, which may lead to distinct antitumor immune responses.
Clinical trial identification
NCT03158129
Invited Discussant LBA48_PR and LBA49
- Suresh S. Ramalingam (Atlanta, US)
1664O - A randomized non-comparative phase II study of anti–PD-L1 ATEZOLIZUMAB or chemotherapy as second-line therapy in patients with small cell lung cancer: Results from the IFCT-1603 Trial
- Jean-Louis Pujol (Montpellier, FR)
Abstract
Background
This randomized Phase II trial sought to evaluate the activity of the engineered PD-L1 antibody ATEZOLIZUMAB (ATZ), as systemic therapy of small cell lung cancer (SCLC) progressing after first line platinum – ETOPOSIDE based chemotherapy (CT).
Methods
Patients (pts) were randomly assigned 2:1 to ATZ, 1200 mg IV, every three weeks until progression or unacceptable toxicity, or conventional CT up to six cycles: i.e. second-line oral or IV TOPOTECAN or re-induction of CARBOPLATIN – ETOPOSIDE doublet (investigator choice based on center policy). Main eligibility criteria were performance status (PS) 0-2 and measurable disease (RECIST 1.1). We performed no selection on PD-L1 tissue expression. Patients receiving corticosteroid therapy, pts with autoimmune disease history and these with brain metastases were excluded. The primary endpoint was objective response rate (ORR) at 6 weeks (confirmation needed at 12 weeks).
Results
A total of 73 patients were randomized (ATZ n = 49; CT n = 24) between 03/2017 and 12/2017. One patient in the ATZ group did not receive any treatment. In the ATZ group, 83.7 % of the pts had PS 0-1, 79.6% had an extensive disease and 67.3 % had a sensitive relapse (progression after 90 days since the last dose of first line CT). At six weeks, in the ATZ group and eligible pts (n = 43), ORR was observed in 1 pt (2.3%, CI [0.0; 6.8]) and 8 other pts (18.6%, CI [7.0; 30.2]) had a stable disease. In the CT group and eligible pts (n = 21), 9.5% of the pts achieved an ORR and 52.4% had a stable disease. Progression-free survival were 1.4 months, CI [1.2; 1.5] in the ATZ group and 4.2 months CI [1.5; 5.9] in the CT group. At the time of reporting, 5 pts still benefit from a stable disease in the ATZ group versus none in the CT group. Two pts (4.2%) in the ATZ group experienced a grade 3 fatigue. Two pts developed grade 1 dysthyroidism.
Conclusions
IFCT-1603 trial did not show any efficacy or safety signals for single drug ATEZOLIZUMAB used as treatment in relapsed SCLC. Follow-up data will be updated and search for PD-L1 tissue expression and mutational tumor burden will be presented.
Clinical trial identification
NCT03059667.
Legal entity responsible for the study
IFCT (French Cooperative Thoracic Intergroup).
Funding
Roche.
Editorial Acknowledgement
N/A
Disclosure
L. Greillier: Grants, personal fees and non-financial support: Roche, outside the submitted work. C. Audigier Valette: Roche. D. Moro-Sibilot: Advisory board: Roche, Pfizer, AstraZeneca, BMS, MSD, Lilly, Boehringer, Abbvie, Takeda; Corporate-sponsored research: Boehringer Ingelheim, Abbvie. V. Gounant: AstraZeneca, Roche, Boehringer Ingelheim, BMS, Pfizer, Abbvie, MSD. P-J. Souquet: Grant, personnal fees, congress, board: Roche. All other authors have declared no conflicts of interest.
Invited Discussant 1664O and 1363O
- Johan F. Vansteenkiste (Leuven, BE)
1363O - Efficacy and safety evaluation based on time from completion of radiotherapy to randomization with durvalumab or placebo in pts from PACIFIC
- Corinne Faivre-Finn (Manchester, GB)
Abstract
Background
In the Ph 3 PACIFIC study of durvalumab (durva) versus placebo (pbo) in pts with stage III, locally advanced (LA), unresectable NSCLC after concurrent chemoradiotherapy (cCRT), PFS was significantly longer with durva (stratified HR 0.52; 95% CI 0.42–0.65; P < 0.0001). This exploratory analysis characterizes outcomes based on time from completing RT to Tx.
Methods
PACIFIC (NCT02125461) was a randomized, double-blind, all-comers study of LA NSCLC pts with WHO PS 0/1 who did not progress after ≥2 cycles of platinum-based cCRT. Pts were stratified by age, sex and smoking history and randomized (2:1) to durva 10 mg/kg IV Q2W or pbo up to 12 months. Co-primary endpoints were PFS (BICR, RECIST v1.1) and OS (not available). Secondary endpoints included ORR, time to death/distant metastases (TTDM) and safety. We investigated potential associations between time to randomized Tx (<14 or ≥ 14 days) with efficacy and safety.
Results
As of Feb 13, 2017, 713 pts were randomized, 26% within 14 days of RT. Baseline characteristics between the durva and pbo arm were well balanced in both the <14 and ≥14 days groups. PFS benefit with durva compared to pbo was observed regardless of timing from RT to randomization (<14 days: median NR vs 4.8 months, HR = 0.39, 95% CI: 0.26–0.58; ≥14 days: median 14.0 vs 5.6 months, HR = 0.63, 95% CI: 0.49–0.80). In addition, TTDM (<14 days: HR = 0.33, 95% CI: 0.20–0.55; ≥14 days: HR = 0.70, 95% CI: 0.51–0.95) and ORR (<14 days: 34.2% vs 16.4%; ≥14 days: 26.5% vs 15.8%) favored durva, regardless of time to randomization. There were no reported differences in safety with durva based on time to randomization, with incidences of any-cause grade 3/4 AEs (34.2% vs 31.3%) and SAEs (30.0% vs 28.2%) comparable across subgroups. In contrast, earlier randomization in the pbo arm was associated with increased rates of grade 3/4 AEs (33.3% vs 25.9%) and SAEs (33.3% vs 19.0%). Early randomization had minimal impact on grade ≥3 pneumonitis/radiation pneumonitis with durva (4.2% vs 4.5%).
Conclusions
Durva provided clinical benefit compared to pbo, regardless of time from RT to randomization. There was no meaningful difference in safety, including high grade AEs, in durva-treated patients randomized within 2 weeks from RT versus later.
Clinical trial identification
PACIFIC [NCT02125461] released May 7, 2014.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Editorial Acknowledgement
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Andrew Gannon, MS, of Cirrus Communications, an Ashfield company (Lyndhurst, NJ, USA), and was funded by AstraZeneca.
Disclosure
C. Faivre-Finn: Research funding: AstraZeneca, MSD. D.R. Spigel: Advisor/consultant: AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech, Inc. S. Senan: Personal fees: AstraZeneca, Eli Lilly, MSD, Celgene; Research grant support: Varian Medical Systems, ViewRay, Inc. D. Raben: Consultant/advisory board member: AstraZeneca, EMD Serono, Genentech, Merck, Oncology Analytics. B. Perez: Advisory board: AstraZeneca, Bristol-Meyers Squibb outside the submitted work. A. Villegas: Speaker's bureau: AstraZeneca. R. Hui: Advisory board: AstraZeneca, MSD, Roche, Novartis, and BMS; Honoraria: AstraZeneca, MSD, Roche, Novartis. L. Paz-Ares: Scientific advice: BMS, Lilly, MSD, AstraZeneca, Roche, Pfizer, Novartis, Incyte, Merk, Boehringer. L. Poole: Contracted to work and holds a small number of shares: AstraZeneca. C. Wadsworth: Employed and holds a small number of shares: AstraZeneca. P.A. Dennis: Personal fees, full-time employment, and stock ownership: AstraZeneca. All other authors have declared no conflicts of interest.
Invited discussant 1363O
- Naiyer A. Rizvi (New York, US)