Virtual Library

Abstract not provided

Abstract not provided

Abstract not provided

Abstract not provided

Background:
Atezolizumab (atezo) prevents binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Primary analysis of the Phase III OAK study in previously treated NSCLC showed superior survival with atezo vs docetaxel (doc) in the ITT population (mOS, 13.8 vs 9.6 months; HR, 0.73) and in pts expressing ≥1% PD-L1 on TC or IC (TC1/2/3 or IC1/2/3; mOS, 15.7 vs 10.3; HR, 0.74). Here we present further subgroup analyses.

Methods:
OAK evaluated atezo vs doc in PD-L1 unselected NSCLC pts who had failed prior platinum-containing chemotherapy. Pts were stratified by PD-L1 expression, prior chemotherapy regimens and histology and randomized 1:1 to atezo (1200 mg) or doc (75 mg/m[2]) IV q3w. PD-L1 expression by IHC and mRNA was centrally evaluated by VENTANA SP142 IHC assay and Fluidigm, respectively. Data cutoff, July 7, 2016.

Results:
In the first 850 of 1225 randomized pts (primary study population), OS was improved with atezo vs doc regardless of histology, and this benefit was seen across PD-L1 subgroups within each histology (Table). Similar OS was seen regardless of PD-L1 expression as assessed by mRNA and IHC. ORR was 14.4% vs 15.2% in non-squamous (non-sq) pts and 11.6% vs 8.2% (atezo vs doc) in squamous (sq) pts. Improved OS was seen with atezo vs doc across subgroups, including pts with treated baseline brain metastases (n = 85; mOS, 20.1 vs 11.9 mo; HR, 0.54; 95% CI, 0.63, 0.89) and never smokers (n = 156; mOS, 16.3 vs 12.6 mo; HR, 0.71; 95% CI, 0.47, 1.08). Further secondary endpoints and exploratory biomarker analyses for these subgroups and by age and EGFR/KRAS status will be presented.

Conclusions:
OAK demonstrated clinically relevant improvements with atezo in the ITT population, including in both histology subgroups, regardless of PD-L1 expression (measured by IHC or tumor gene expression), and among other subgroups, including never smokers and pts with baseline brain metastases.rnTable: 89PDrn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

rn	OS
	Atezo		Doc		HR[a] 95% CI
	n	Median, mo	n	Median, mo
Non-sq population
TC3 or IC3	49	22.5	47	8.7	0.35 (0.21, 0.61)
TC2/3 or IC2/3	89	18.7	99	11.3	0.61 (0.42, 0.88)
TC1/2/3 or IC1/2/3	171	17.6	162	11.3	0.72 (0.55, 0.95)
TC0 and IC0	140	14.0	150	11.2	0.75 (0.57, 1.00)
All non-sq	313	15.6	315	11.2	0.73 (0.60, 0.89)
Sq population
TC3 or IC3	23	17.5	18	11.6	0.57 (0.27, 1.20)
TC2/3 or IC2/3	40	10.4	37	9.7	0.76 (0.45, 1.29)
TC1/2/3 or IC1/2/3	70	9.9	60	8.7	0.71 (0.48, 1.06)
TC0 and IC0	40	7.6	49	7.1	0.82 (0.51, 1.32)
All sq	112	8.9	110	7.7	0.73 (0.54, 0.98)

rnaUnstratified HRs.rnTC, tumor cell; IC, tumor-infiltrating immune cell.rn

Clinical trial identification:
NCT02008227

Legal entity responsible for the study:
F. Hoffmann-La Roche Ltd/Genentech Inc., a member of the Roche Group

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

Disclosure:
S.M. Gadgeel: Speaker\'s bureau from Astra-Zeneca, Genentech/Roche and Advisory Boards from Astra-Zeneca, Ariad, Pfizer, Bristol Myers- Squibb and Genentech/Roche. A. Rittmeyer: Grants as an advisor or speaker by Astra Zeneca, BMS, Boehringer Ingelheim, Eli Lilly, Pfizer and Roche Genentech. F. Barlesi: Honarium from Roche. T. Hida: Corporate-sponsored research from Chugai Pharmaceutical. P. He: Employee of Roche/Genentech, and has stocks for Roche and Amgen. Her husband has stocks for Allergan and Gilead. M. Ballinger: Genentech/Roche employee and has Roche stock. D.R. Gandara: Consultant for Genentech and clinical trial grant from Genentech. J. von Pawel: Adboard with fees paid to the institution from AbbVie, Pfizer, Bristol Myers Squibb, and Novartis. All other authors have declared no conflicts of interest.

Background:
R (anti-VEGFR2) and P (anti-PD-1) are active in previously treated advanced NSCLC. Median progression-free survival (PFS) reported in KEYNOTE-001 (previously treated; PD-L1 all comers) was 3.0 months (95%CI, 2.2-4.0) and ORR was 18%. This is the first study to combine R with P.

Methods:
Ongoing, multi-cohort, phase 1a/b trial enrolled pts with confirmed NSCLC with prior progression on systemic therapy, measurable disease, ECOG PS 0-1 and baseline tumor tissue. PD-L1 was classified strongly positive (tumor proportion score [TPS] ≥50%), weakly positive (TPS=1-49%), or negative (TPS <1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. Primary objective- assess safety and tolerability of R + P; preliminary efficacy will be examined.

Results:
As of 21-Nov-2016, 27 pts with previously treated advanced NSCLC received R at 10 mg/kg on Day 1 with P 200 mg on Day 1 q3W. Median age was 65, 78% male, 96% had a history of smoking, 78% had adenocarcinoma and 15% had squamous-cell carcinoma. Sixteen (59%) pts received ≥2 and 4 (15%) received ≥3 prior treatment regimens for their disease. Median duration of treatment was 7.0 mo (IQR 3.0-12.4) and 8.3 mo (IQR 3.3-12.4) for R and P, respectively. Treatment related adverse events (TRAEs) occurred in 25 (93%) pts, most commonly hypertension (26%) and asthenia (19%). Five (19%) pts experienced grade 3 TRAEs (adrenal insufficiency, delirium, hypertension [n = 2], hyponatremia, infusion related reaction, proteinuria, and respiratory failure). No grade 4-5 TRAEs occurred. ORR was 30% with a median time to response of 2.1 mo. Duration of response has not been reached. Responses occurred in PD-L1 unknown (n = 1), negative (n = 2), and strong positive (n = 5) groups as well as both histologies. Median PFS was 9.7 mo (95% CI 4.6-11.5) and overall survival rate at 6 mo was 84.9%. Disease control rate was 85%. Ten (37%) pts remain on study treatment, including all responders.

Conclusions:
R + P demonstrated encouraging antitumor activity independent of PD-L1 and histology. The safety profile was consistent with monotherapy treatment for each drug, with no additive toxicities. The study was amended and is now enrolling pts with treatment naïve advanced NSCLC.

Clinical trial identification:
NCT02443324 JVDF

Legal entity responsible for the study:
Eli Lilly and Company, Indianapolis, IN

Funding:
Eli Lilly and Company, Indianapolis, IN

Disclosure:
R.S. Herbst: Personal fees from Eli Lilly, outside the submitted work. E. Calvo: Institutional research funding: multiple- available upon request; Travel expenses: Lilly, PsiOxus, Novartis; Consultant: Novartis, GSK, Astellas, Genentech, Lilly, Nanobiotich, Pfizer; SB: Novartis. N. Isambert: Honoraria: Pfizer, Novartis; Consulting/Advisory: Merck Serono. J. Bendell: Institutional research funding: From multiple and available upon request, including Lilly and Merck. P. Cassier: Personal fees from Roche/Genentech, Novartis, Astra-Zeneca, Amgen, Plexxikon; non-financial support from Roche/Genentech, Merck Sharp Dohme, Astra-Zeneca, Plexxikon; and grants from Merck Sharp Dohme and Astra-Zeneca, outside the submitted work. J. Jin, G. Mi, J. Rege: Employee and stock holder at Eli Lilly and Company. L. Paz-Ares: Consultant/Advisory role: Roche, Lilly, Novartis, MSD, BMS, Amgen, Clovis, AZ, BI, Pfizer. All other authors have declared no conflicts of interest.

Background:
Immune checkpoint inhibitors are active for patients with stage IV NSCLC who have progressed following platinum-based chemotherapy. We evaluated responses to chemotherapy in patients with NSCLC who had progressed on a checkpoint inhibitor.

Methods:
Eligible patients were adults with NSCLC who received salvage chemotherapy following PD-1/PD-L1 inhibitors (cases) versus no PD-1/PD-L1 inhibitors (controls). CT-imaging was done within 4 weeks of initiation of salvage chemotherapy and every 6 weeks thereafter. Revised RECIST guidelines were used to define response. Clinical and imaging data were abstracted from review of electronic medical records. Multivariate logistic regression analysis was used to calculate probability of response.

Results:
355 patients’ charts were reviewed and 82 patients met eligibility criteria. Among evaluable patients, 46 were males versus 36 females. 67 patients were classified as cases versus 15 controls. 56 patients received nivolumab, 7 pembrolizumab and 4 atezolizumab. 63 (77%) patients had adenocarcinoma, 18 (22%) squamous cell carcinoma and 1 (1%) large cell carcinoma. The mean number of chemotherapy regimens prior to salvage chemotherapy was 2.37 (95% CI: 2.10-2.64) in cases versus 1.93 (95% CI: 1.32-2.54) in controls. Salvage drugs used included docetaxel (62%), pemetrexed (20%), gemcitabine (12%) and paclitaxel (6%). 18 (27%) cases had partial response to chemotherapy versus 1 (7%) controls. 15 (22%) cases had progressive disease versus 6 (40%) controls. 34 (51%) cases had stable disease versus 8 (53%) controls. The odds ratio for achieving a partial response was 0.30 (95% CI: 0.18 to 0.50, p = 0.000). In multiple logistic regression model, age, gender, number of prior chemotherapy regimens, tumor histology, smoking status, different salvage chemotherapy regimens were not associated with the likelihood of achieving a partial response.

Conclusions:
The odds of achieving a partial response to salvage chemotherapy were significantly higher in patients with prior exposure to PD-1/PD-L1 inhibitors. This observed difference however warrants confirmation in larger cohorts. Ongoing investigations include the duration of response as well as evaluation of toxicity.

Clinical trial identification:


Legal entity responsible for the study:
N/A

Funding:
N/A

Disclosure:
All authors have declared no conflicts of interest.

Abstract not provided

Background:
In the Phase III LL3 and LL6 trials, first-line afatinib significantly improved PFS and ORR versus platinum-doublet chemotherapy in pts with EGFRm+ NSCLC. In the Phase IIb LL7 trial, afatinib significantly improved PFS, time to treatment failure, and ORR versus gefitinib in this setting. Here we present post-hoc analyses of afatinib LTRs (treated with afatinib ≥3 years) in LL3/6/7.

Methods:
Treatment-naïve pts with stage IIIB/IV EGFRm+ NSCLC who were randomized to 40 mg/day afatinib in LL3/6/7 were included.

Results:
24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated pts in LL3, LL6 and LL7 were LTRs; 6, 9 and 14 LTRs were still on treatment at the time of analysis. In LL7, 4% of gefitinib-treated pts were LTRs. Baseline characteristics were generally consistent with the overall study populations, with the exception of greater proportions of women (LL3/6 only; 92/78% vs 64% in the overall populations) and Del19+ pts (63–79% vs 49–58% overall) among LTRs. The table shows treatment duration and outcomes. The median OS values for LL3/6 were >30 months longer than those reported in the overall populations. ORRs ranged from 70.8% in LL3 to 89.5% in LL7. Frequency and duration of subsequent therapy was similar to the overall population. Frequency of afatinib dose reduction due to TRAEs was broadly consistent with the overall populations; final afatinib doses of 20/30/40/50 mg were observed in 50/25/21/4% in LL3, 13/22/61/4% in LL6, and 32/21/47/0% in LL7.

Conclusions:
In the LL3/6/7 studies, 10–12% of afatinib-treated pts were LTRs (treated ≥3 years). Among these pts, greater proportions of women (LL3/6 only) and Del19+ NSCLC were observed. In LTRs, afatinib conferred a long-term survival benefit of ∼5 years and was well tolerated. Long-term treatment was independent of tolerability-guided dose adjustment, or the presence of brain metastases at time of enrolment, and had no detrimental impact on subsequent treatment.rnTable: 92PDrn

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn rnrn

Characteristic	LL3 (n = 24)	LL6 (n = 23)	LL7 (n = 19)
Median follow-up for OS, months	64.6	57.0	42.1
Median duration of treatment, months (range)	50 (41–73)	56 (37–68)	42 (37–50)
Median PFS (central review), months	37.5	30.6	27.6
Median OS, months	63.2	55.3	40.8
Overall response rate (CR+PR), n (%)	17 (70.8)	18 (78.3)	17 (89.5)
CR, n (%)	1 (4.2)	3 (13.0)	1 (5.3)
PR, n (%)	16 (66.7)	15 (65.2)	16 (84.2)
SD, n (%)	5 (20.8)	2 (8.7)	2 (10.5)
NN, n (%)	2 (8.3)	3 (13.0)	–
Median duration of response, months	34.5	28.3	19.4

rnCR, complete response; NN, not-PR/not-SD; PR, partial response; SD, stable diseasern

Clinical trial identification:
LUX-Lung 3: EudraCT No: 2008-005615-18 LUX-Lung 6: clinicaltrials.gov ref: NCT01121393 LUX-Lung 7: EudraCT No: 2011-001814-33

Legal entity responsible for the study:
Boehringer Ingelheim

Funding:
Boehringer Ingelheim

Disclosure:
M. Schuler: Advisory boards: AstraZeneca, Boehringer Ingelheim, Celgene, Eli Lilly, Novartis; Corporate-sponsored research: Boehringer Ingelheim, Bristol-Myers Squibb, Novartis; Honoraria: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Novartis, Roche, MSD, Alexion; Patents: University Duisburg-Essen. L. Paz-Ares: Honoraria from Pfizer, Bristol-Myer Squibb, MSD, Novartis, Roche, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, AstraZeneca, and Amgen. L.V. Sequist: Participated on advisory boards for Boehringer Ingelheim, AstraZeneca, Novartis, Clovis Oncology, Genentech, Merrimack, Ariad, and Bristol-Myers Squibb. S.L. Geater: Participated in advisory boards for Novartis and Boehringer Ingelheim, and has also received honoraria from Roche, AstraZeneca, Boehringer Ingelheim, and Novartis. A. Märten: Employee of Boehringer Ingelheim. J. Fan: Boehringer Ingelheim Pharmaceuticals Inc. employee. K. Park: Participated on advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, MSD, Novartis, and Roche. J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, and AZ. All other authors have declared no conflicts of interest.

Background:
A, an irreversible ErbB family blocker, and G, a reversible EGFR TKI, are approved for 1st-line treatment (tx) of advanced EGFRm+ NSCLC. In LL7, A (40 mg/d) significantly improved PFS (HR 0.73 [95% CI 0.57–0.95], p = 0.017), ORR (70 vs 56%, p = 0.008) and time to tx failure (TTF; HR 0.73 [0.58–0.92], p = 0.007) vs G (250 mg/d) in this setting; the primary OS analyses (data cut-off 8 Apr 16) showed a non-significant difference in OS between A and G (median 27.9 vs 24.5 mos; HR 0.86 [0.66–1.12], p = 0.258) that was consistent across subgroups. Here, we present updated OS data.

Methods:
LL7 assessed A vs G in tx-naïve pts with EGFRm+ (Del19/L858R) stage IIIb/IV NSCLC. Co-primary endpoints were PFS, TTF and OS. Other endpoints: ORR and AEs.

Results:
Data cut-off for the updated OS analysis was 12 Dec 16. Median follow-up for OS was 49.2 mos. 73/77% (A/G) of pts had ≥1 subsequent systemic anti-cancer tx after discontinuation of A/G. 48/56% (A/G) received a subsequent EGFR TKI; 31 (19%)/26 (16%) pts (A/G) received a 3[rd]-gen EGFR TKI. Updated median OS was 27.9 vs 24.5 mos with A vs G (HR 0.85 [0.66–1.09], p = 0.1950). Landmark 24-mo and 30-mo OS with A vs G was 61 vs 51% and 48 vs 40%, respectively; 48-mo OS was 28% with A vs 20% with G. In patients treated with A, ≥30-mo survival rates were generally similar across countries of origin and mean average dose received. Similar OS trends were observed with A vs G in pts with Del19 (30.7 vs 26.4 mos; HR 0.82 [0.59–1.15]) and L858R (25.0 vs 21.2 mos; HR 0.89 [0.61–1.31]) mutations. There was a trend towards improved OS with A vs G in pts who received a 3[rd]-gen EGFR TKI (NE vs 48.3 mos; HR 0.49 [0.20–1.19]). In patients treated with A, consistent OS outcomes were observed across age groups (median, mos: 28.9 [<60 years]; 30.1 [<65 years]; 28.9 [<75 years]; 27.9 [≥75 years]). Updated PFS, TTF and ORR (at primary OS data cut-off, 8 Apr 16) were similar to the primary analyses, and all were significantly improved with A vs G; the AE profile of A and G was virtually unchanged since the primary analysis.

Conclusions:
In this updated OS analysis, there was no significant difference in OS with A vs G. A trend favouring A, generally consistent across subgroups, was observed.

Clinical trial identification:
Clinical Trials.gov Identifier: NCT01466660

Legal entity responsible for the study:
Boehringer Ingelheim

Funding:
Boehringer Ingelheim

Disclosure:
K. Park: Participated on advisory boards for Astellas, AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Hanmi, Merck & Co., Inc., Novartis, and Roche. J.C-H. Yang: Ad board and honoraria: BI, Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono pharmaceutical Daiichi, Sankyo, AZ. T. Mok: Receipt of grants/research supports: AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS. Receipt of honoraria or consultation fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, AVEO & Biodesix, Prime Oncology, Amgen. Participation in a company sponsored speaker’s bureau: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, Novartis, BMS, PrIME Oncology. Stock shareholder: Sanomics Limited. K. O\'Byrne: Ad board, speaker bureau, travel to international conferences and honoraria: AZ, BMS, Roche-Genentech, MSD, Pfizer, BI. Ad board and speaker bureau: Novartis. 3 Patents: 1 on novel drugs, 2 on biomarkers, IP held by Queensland University of Technology. V. Hirsh: Has received advisory board honoraria from Boehringer Ingelheim, AstraZeneca, Roche, Merck, Eli Lilly, Pfizer, Amgen, and Bristol-Myers Squibb. M. Boyer: Ad board: BMS, Merck Sharpe and Dohme, Pfizer Board of Directors: IASLC Research: Pfizer, Genentech, BI, AZ, Novartis, Merck Sharpe and Dohme, Clovis Honoraria: Merck Sharpe and Dohme, BI, BMS, AZ. J. Fan: Boehringer Ingelheim employee. All other authors have declared no conflicts of interest.

Background:
The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) complements standard adverse event (AE) reporting in oncology trials. We assessed patient-reported symptomatic AEs in individuals receiving osimertinib 80mg once daily or chemotherapy for advanced non-small cell lung cancer (NSCLC) in the AURA3 trial, using the PRO-CTCAE.

Methods:
AURA3 (NCT02151981) was a multinational, open-label, randomized phase III trial involving 419 patients.1 As part of exploratory analyses, individuals for whom validated local language versions were available (in English, German, Japanese or Spanish) were asked to complete the PRO-CTCAE by e-device, weekly for 18 weeks and then every 3 weeks.

Results:
In total, 161 patients (38%; 102 osimertinib, 59 chemotherapy) provided data for PRO-CTCAE analysis (mean age: 64 years; 63% women). The number of patients providing PRO-CTCAE data fluctuated between different items and time points, and decreased over the study period. Of patients on osimertinib providing information on acne/pimples, 37%, 38%, 32% and 29% reported having acne/pimples at baseline, 4 weeks, 12 weeks and 24 weeks, respectively, compared with 30%, 19%, 14% and 12% on chemotherapy. Most cases (>90%) were mild. Reported rates of diarrhoea changed little over time post-baseline and were higher with osimertinib than with chemotherapy (32% vs 36% at baseline, 47% vs 28% at 4 weeks, 53% vs 33% at 12 weeks, 45% vs 21% at 24 weeks). Most cases were mild or moderate. Fatigue (64% vs 72% at baseline, 72% vs 89% at 4 weeks, 55% vs 89% at 12 weeks, 60% vs 79% at 24 weeks) and decrease in appetite (54% vs 53% at baseline, 42% vs 75% at 4 weeks, 35% vs 69% at 12 weeks, 33% vs 46% at 24 weeks) were reported less commonly with osimertinib than with chemotherapy. Most cases were mild.

Conclusions:
Self-reported data from patients with NSCLC treated with osimertinib or chemotherapy showed changes over time in AE rates from start of treatment and differences in prevalence of patient-reported AEs (PRO-CTCAEs) with osimertinib versus chemotherapy.

Clinical trial identification:
NCT02151981

Legal entity responsible for the study:
AstraZeneca

Funding:
AstraZeneca

Disclosure:
M. Sebastian: Honoraria: Novartis, BMS, Roche, Lilly, Boehringer-Ingelheim, Pierre-Fabre, Pfizer, MSD, AstraZeneca. Consultant: Novartis, BMS, Roche, Lilly, Boehringer-Ingelheim, Pfizer, MSD, AstraZeneca, Celgene. V. Papadimitrakopoulou: Advisory: Eli Lilly&Co, Genentech, Janssen Global Sevices, Bristol-Myers Squibb, ARIAD, AstraZeneca Pharmaceuticals, Novartis, Merck Corporate-sponsored. Research: Novartis, AstraZeneca, Genentech, Merck, Janssen, ACEA, Bristol-Myers Squibb. A. Walding: AstraZeneca employee and shareholder. S. Ghiorghiu: AstraZeneca employee and shareholder. A. Ryden: AstraZeneca employee and shareholder. K. Rudell: Former AstraZeneca employee and shareholder. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
Single MET inhibition has controversial effects in MET addicted tumors. Proviral integration site for Moloney murine leukemia virus-1 (PIM1) is activated upon MET inhibition in MET addicted cells. PIM1 drives the expression of receptor tyrosine kinases (RTKs). SHP2, a non-receptor protein tyrosine phosphatase, is central in RTKs signaling and in Src activation. We have shown that the overexpression of RTKs like AXL and the transmembrane protein CUB domain-containing protein-1 (CDCP1) as well as Src activation, are mechanisms of intrinsic resistance to EGFR inhibition in EGFR mutant lung cancer. We are now testing whether RTKs, SHP2 or CDCP1 expression and activation are driven by PIM1 or Src and cause resistance to MET inhibitors in MET addicted tumors.

Methods:
We studied the inhibitory effect of the class I MET inhibitors tepotinib and savolitinib, the pan-PIM inhibitor AZD1208, and the Src inhibitor dasatinib in five MET addicted cell lines: 2 MET amplified lung cancer cells (EBC1 and H1993), 2 MET exon 14 mutant cells (Hs746T and H596) and a glioma cell line that carries the still not well recognized MET exon 7–8 splicing variant (E98). We assessed the effect of combined MET and PIM or MET and Src inhibition in cell viability and protein immunoblotting.

Results:
All the cell lines were sensitive to single MET inhibition (except H596) and resistant to single AZD1208 or dasatinib. The combination of savolitinib or tepotinib with AZD1208 was synergistic in the EBC1 cell line and slightly synergistic or additive in the H1993, Hs746T and E98 cell lines. The combination of savolitinib or tepotinib with dasatinib was highly synergistic in all four cell lines. The treatment of EBC1 cells with tepotinib monotherapy was not able to inhibit AXL activation while it induced the activation of SHP2 and CDCP1. AXL, CDCP1 and SHP2 expression or activation were downregulated when tepotinib was combined with dasatinib.

Conclusions:
Co-targeting PIM or Src with MET can be more effective than MET inhibition alone in MET addicted cell lines. Overexpression and activation of RTKs, CDCP1 and SHP2 can be mechanisms of resistance to single MET inhibition. The investigation of combinatorial strategies in MET addicted tumors, merits further investigation.

Clinical trial identification:


Legal entity responsible for the study:
IGTP – Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain

Funding:
Fundació Obra Social “La Caixa”

Disclosure:
All authors have declared no conflicts of interest.

Background:
Preclinical models suggest that MAPK pathway is implicated in the immune-resistance of tumors and MEK-inhibition can increase the CD8+ T-cell infiltration and the efficacy of PD-1/PD-L1 blockade.

Methods:
First, we evaluated PD-L1 mRNA expression by Real Time qPCR and its protein production, togheter with MAPK proteins in a panel of non-small cell lung cancer (NSCLC) cell lines. Then, we studied the changes in PD-L1 and major histocompatibility complex class-I (MHC-I) expression and cytokines’ production, after inhibition with selumetinib or stimulation of MAPK signalling by phorbol 12-myristate 13-acetate (PMA). In addition, we explored the effect of MEK inhibition on T-cell function by using Peripheral blood mononuclear cells (PBMC) from healthy volunteers.

Results:
A consistent correlation between PD-L1 mRNA and protein expression across cell lines suggested that expression mainly depends on trascriptional regulation, and it is regulated by MAPK signal, through the bindng of p65 to the PD-L1 promoter. Moreover, MEK inhibition resulted in an increased expression of MHC-I on cancer cells and increased mRNA expression levels of IFN gamma, IL-6, IL-1B, and TNFalpha, all molecules involved in the activation and differentiation of TCD8+ cytotoxic lymphocytes (CTL) subset. In this scenario, we also tested the effect of MEK inhibitor on activated T-lymphocytes from PBMC of healthy volunteers. After five days of treatment, RT-qPCR analysis revealed a significant increase of mRNA expression of some typical CD8+ T cell pro-inflammatory cytokines, like IL-12, TNFalpha and IFNgamma.

Conclusions:
These results further support the idea that MEK inhibitor reduces PD-L1 expression and this allows the establishment of a pro inflammatory microenvironment. On the other side, pheripheral T cells, treated with selumetinib, produce pro inflammatory cytokines typical of CTL subset, that seems more involved in immune response against cancer. In this context, MEK inhibition may represent a potential mechanism to convert otherwise resistant cancers and suggest new potential treatment combination strategies of MEK-inhibitors with anti-PD-L1 antibodies in NSCLC.

Clinical trial identification:


Legal entity responsible for the study:
University of Campania “L. Vanvitelli”

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Background:
Currently, there are no clinically useful predictors of efficacy and toxicity to pemetrexed (PMX) in advanced non-small-cell lung cancer (NSCLC). Using population pharmacokinetic (pop-PK) modelling, we explored whether total exposure to PMX predicts for progression-free and overall survival (PFS/OS) and occurrence of (severe) chemotherapy (CTx)-related adverse events (AEs).

Methods:
In a prospective observational multi-center study, patients with stage IIIB/IV NSCLC receiving first- or second-line PMX(/platinum) were enrolled. PMX (500 mg/m[2]) was administered as a 10-min intravenous infusion every 21 days. Prior to and weekly after each PMX administration, plasma sampling was performed (cycle PK). In a subgroup, blood samples were also collected at 10, 30 minutes and 1, 2, 4, 8, 24 hours after start of PMX infusion (24h PK). With pop-PK modelling total exposure (AUC) to PMX per patient was estimated. The relation between AUC during cycle 1 (AUC~1~) and OS/PFS in treatment-naïve patients was examined using Cox regression analyses and in all patients we compared the difference in mean AUC~1~ between patients with and without grade ≥3 CTx-related AEs (CTCAE 4.03) during total treatment of 4 cycles.

Results:
For 106 of the 165 patients, concentrations of PMX were quantified (24h PK, n = 15; cycle PK, n = 106). Median estimated AUC~1~ was 201 mg·h/L (interquartile range: 179–224). In treatment-naive patients (n = 95), AUC~1~ did neither univariably predict for OS/PFS, nor multivariably when adjusted for prognostic factors sex, disease stage and WHO performance score (OS, HR = 1.05, 95%CI: 1.00–1.11; PFS, HR = 1.03, 95%CI:0.98–1.08). Compared to patients without ≥ grade 3 CTx-related AEs (n = 51), patients with ≥ grade 3 CTx-related AEs (n = 55) had significantly higher AUC~1~ values (220 vs 191, p < 0.001). When seperating ≥ grade 3 CTx-related AEs into clinical and laboratory AEs, identical results were found.

Conclusions:
Total systemic exposure to PMX does not predict for PFS/OS, but is significantly associated with more frequent occurrence of severe CTx-related AEs. Although the impact of peak concentrations on efficacy remains unclear, our findings suggest that lower dosage might prevent severe toxicity with preservation of efficacy.

Clinical trial identification:


Legal entity responsible for the study:
Erasmus MC

Funding:
ZonMw

Disclosure:
J. Aerts: Member of Scientific Committee ELCC 2018; consultant/advisory role with Eli Lilly and Company. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
TKI has significantly improved survival time of NSCLC pts with sensitive mutation. However, pts present different outcome while receiving TKI treatment. We conduct a prospective multicenter clinical trial to determine whether clonality of sensitive mutation is related to the efficacy of TKI. We also evaluate the consistency of TMB between tissue and blood in this cohort.

Methods:
Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve pts with advanced NSCLC. DNA was sequenced by target-capture deep sequencing of 1021 previously annotated genes related to solid tumors. Clonal EGFR mutation was defined if EGFR mutation was in the cluster with the highest mean variated allele frequency with PyClone, and otherwise subclonal EGFR mutation. TMB of tissue (tTMB) and blood (bTMB) analysis interrogated single nucleotide variants, small insertion and deletion, with VAF ≥3% and ≥0.5%, respectively. TMB-high pts were identified with ≥9 mut/MB (upper quartile of data from geneplus).

Results:
During February to November 2017, 80 advanced NSCLC pts were enrolled from 9 centers. A total of 371 somatic variations were detected in tissues. Mutations occurred most frequently in TP53 (52%), EGFR (47%), ALK (13%), KRAS (11%). In matched plasma, 258 (70%) tumor-derived mutations were detected by pan-caner panel sequencing. A total of 41 EGFR mutations were detected in 37 pts, most of which occurred in tyrosine kinase domain (Ex19del, 42%; L858R, 37%). Most EGFR mutation were clonal in tissue and plasma, with a consistence of 85% in paired samples. In addition, bTMB was significantly correlated to tTMB (Pearson r = 0.75, p-value = 2.3e-12), with a consistence of 90%. Interestingly, high TMB was observed in a small fraction of patients (6%) with driver mutations, such as mutations in EGFR, ALK fusion, ERBB2 and PIK3CA.

Conclusions:
Deep sequencing with the pan-cancer panel can effectively detect mutations and evaluate TMB in both tissue and blood with high consistence. EGFR mutations can be clonal or subclonal in both tissue and blood. Prospective multicenter study is ongoing to determine the EGFR clonality as a predictive factor for the TKI efficacy in NSCLC (TRACELib-NSCLC).

Clinical trial identification:
NCT03059641

Legal entity responsible for the study:
Shanghai Chest Hospital

Funding:
Geneplus-Beijing Institute

Disclosure:
All authors have declared no conflicts of interest.

Background:
The role of adjuvant EGFR-TKIs in NSCLC is not well defined. Recently 2 randomized trials showed a significant disease free survival (DFS) benefit with the use of adjuvant TKIs compared to platinum-based chemotherapy in EGFR-mutant patients. Yet, older trials conducted on patients with any EGFR status did not demonstrate the same benefit. Herein, we conduct a systematic review and meta-analysis to assess the efficacy and safety of adjuvant TKIs in NSCLC patients.

Methods:
The electronic databases Medline (PubMed) and EMBASE were searched for relevant randomized trials between January 2000 and October 2017. Pooled hazard ratios (HR) for DFS and overall survival (OS), and pooled risk ratios (RR) and odds ratios (OR) for 2-year DFS and toxicity were extracted using the generic inverse variance and the Mantel-Haenszel and Peto method to perform a meta-analysis. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses assessed patients with a sensitizing EGFR mutation.

Results:
Six studies met the inclusion criteria and were included. In patients with any EGFR status, adjuvant TKIs marginally improved the DFS (5 trials, 1,860 participants, HR = 0.65, 95%CI 0.43–1.00) but not OS (4 trials, 662 participants, HR = 0.8, 95%CI 0.48–1.33). The risk of developing grade 3 or higher skin toxicity (6 trials, 1,831 participants, OR = 6.07, 95%CI 4.34–8.51) and diarrhea (6 trials, 1, 831 participants, OR = 4.05, 95%CI 2.44–6.74) was increased compared to chemotherapy, placebo or no treatment. In EGFR-mutant patients, adjuvant TKIs decreased the risk of disease recurrence by 48% (5 trials, 560 participants, HR = 0.52, 95%CI 0.35–0.78), improved the 2-year DFS (6 trials, 599 participants, HR = 0.53, 95%CI 0.43–0.66) but had no effect on OS (4 trials, 662 participants, HR = 0.64, 95%CI 0.22–1.89).

Conclusions:
Adjuvant TKIs significantly decrease the risk of recurrence in EGFR-mutant NSCLC patients but do not improve OS. Yet, OS data are still immature and longer follow up is needed for a definitive assessment of this outcome measure. Further results from ongoing well-designed trials will define the role of adjuvant TKI in NSCLC and provide stronger conclusions.

Clinical trial identification:
N/A

Legal entity responsible for the study:
Jacques Raphael

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Abstract not provided