Background

Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLCs poorly responsive to systemic therapy. It is a heterogenous tumour with both epithelial and sarcomatoid components. MET variants are targetable aberrations and have recently been reported to be more frequent in PCs. The relationship between MET and PD-L1 expression is not well understood. We determined PD-L1 expression in PCs and its relationship with MET variants.

Methods

80 cases of pleomorphic carcinoma were identified from the biobank and diagnostic archives of Royal Brompton Hospital and Imperial College Healthcare NHS trust. DNA was isolated for determination of a. MET copy number by digital droplet PCR (ddPCR) and b. Genomic MET aberrations by NGS. IHC of PD-L1 (28-8) with % positive cells were scored by two pathologists independently and >49% tumour staining was defined as high.

Results

78 cases were evaluated for PD-L1 status with a median score of 44%. 23/63 (36%) cases had MET CN of > 2.2. METex14 splice variants were identified in 5/73 (7.2%) cases. 2/73 (2.7%) cases had deleterious MET mutations. By MET CN status: low/normal MET CN (<2.3) median PDL1 expression was higher (50%) than in high MET CN ( > =2.3: 37.5%; P = 0.18). This translates into a significantly fewer number of high PD-L1 expressors (>49%) in cases with high MET CN (>2.2; P = 0.06; Table). There was no significant difference in PDL1 expression between MET mutation vs. wild-type (P = 0.9)Table: 1O

MET copy number and PDL-1 expression

Conclusions

PCs have high levels of PD-L1 expression. There is an inverse relationship between MET CN and PD-L1 expression. This has implications when using checkpoint inhibitors for cases with MET copy number gain in NSCLC. Further evaluation is needed to better understand response to checkpoint inhibitors of PC cases with MET CN gain.

Legal entity responsible for the study

The Royal Marsden Foundation NHS Trust.

Funding

National Institute for Health Research (NIHR) and British Lung Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

PACIFIC (NCT02125461) was a randomised, placebo-controlled, phase 3 trial evaluating the immune checkpoint inhibitor durvalumab in patients (pts) with unresectable, Stage III non-small cell lung cancer (NSCLC) who did not have disease progression after concurrent chemoradiotherapy (cCRT). Both primary endpoints of progression-free survival and overall survival were met and significantly improved with durvalumab, with similar safety, versus placebo (Antonia et al, NEJM 2017; 2018). We report exploratory analyses of the prevalence of tumour PD-L1 expression by baseline pt, disease and sample characteristics and by response to prior treatment for pts in PACIFIC.

Methods

If available (provision of formalin-fixed paraffin-embedded tumour resection or biopsy samples was optional), archived pre-cCRT tumour tissue was tested retrospectively for PD-L1 tumour cell (TC) expression using the VENTANA PD-L1 (SP263) immunohistochemistry assay and scored at validated pre-specified (≥25%) and post-hoc (≥1%) cutoffs. Overall PD-L1 prevalence (regardless of treatment arm) was summarised by pt subgroups defined by various characteristics, and assessed using a Pearson’s chi-squared test for between-group differences.

Results

Of 713 randomized pts, 451 (63.2%) were evaluable for PD-L1 status. Among PD-L1-evaluable pts, 67.2% (303/451) had TC ≥ 1% and 35.3% (159/451) had TC ≥ 25% (similar to previous reports in metastatic NSCLC). PD-L1 prevalence by various characteristics at the TC ≥ 1% cut-off are reported in the table.

Conclusions

There were no important differences noted in PD-L1 prevalence between relevant subgroups at the TC ≥ 1% or TC ≥ 25% cut-offs (latter data to be presented). PD-L1 status was unaffected by sample type or age or biopsy location, suggesting expression is stable from pre-cCRT diagnostic biopsies, and supports the use of either primary tumour or lymph node biopsies for PD-L1 testing.

Clinical trial identification

NCT02125461.

Editorial acknowledgement

Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Andrew Gannon of Cirrus Communications, an Ashfield company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

D. Planchard: Personal fees: AstraZeneca, Boehringer Ingelheim, BMS, MSD, Pfizer, Novartis, Roche, Celgene, outside the submitted work. M.C. Garassino: Personal fees: AstraZemeca, Roche, BMS, MSD outside the conduct of this study. L. Paz-Ares: Advisory board fees: BMS, Lilly, MSD, AstraZeneca, Roche, Pfizer, Novartis, Incyte, Merk, Boehringer Ingelheim. C. Faivre-Finn: Research funding:AstraZeneca, MSD. A. Spira: Advisory fees, institutional research support: AstraZeneca. Y. Gu, J. Whiteley, M. Scott, J. Walker: Employment, stock: AstraZeneca. C. Wadsworth, P.A. Dennis: Employment, stock: AstraZeneca, outside the conduct of the study. A-M. Boothman: Employment, stock options: AstraZeneca, outside the conduct of the study. M. Ratcliffe: Consultant fees: AstraZeneca, outside the conduct of the study. All other authors have declared no conflicts of interest.

Background

EVIDENS is an observational, prospective, multicenter cohort study following lung cancer patients initially treated with nivolumab between Oct 2016 and Nov 2017 in 146 French centers. Interim efficacy and safety results were consistent with those from nivolumab clinical trials. This analysis describes temporal changes in HRQoL.

Methods

HRQoL was measured using the EQ-5D-3L, a 3-level version consisting of the 5 dimensions descriptive system (EQ-5D) and the visual analogue scale (VAS; 0–100 [worst–best health]). Outcomes for each dimension were described as the proportion of patients with no change, improvement or deterioration, and the utility index and VAS mean changes from baseline (minimally important difference [MID] = 0.08 and ±7 point change, respectively).

Results

Overall 1,394 NSCLC patients were followed-up for a median of 11.5 months. Baseline characteristics: median age 66.0 years, 69.2% men, 89.6% current/former smokers, 83.2% PS 0-1, 31.1% squamous (SQ) histology. Baseline completion rates for EQ-5D-3L/VAS were 80.2%/77.0%. At 9 and 12 months (276 and 78 patients at risk, respectively), they were 51.4%/48.9% and 69.2%/66.7%, respectively. The table summarizes HRQoL outcomes. Of note, mean change of VAS from baseline was statistically significant at 9 and 12 months regardless of histology and MID was achieved at 12 months for SQ (+7.6 [2.1 ; 13.1]).

Conclusions

Twelve months after initiating nivolumab, all the 5 dimensions measured by EQ-5D-3L were stable in at least half of NSCLC patients and a clinically meaningful improvement of VAS was observed in the SQ patients.

Clinical trial identification

NCT03382496.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

M. Pérol: Boards: Roche, Genentech, Eli Lilly, Pfizer, Boehringer Ingelheim, Clovis Onco, MSD, BMS, Novartis, Pierre Fabre, Takeda, AZ; Symposia: Eli Lilly, Roche, Pfizer, Amgen, Boehringer Ingelheim, BMS, Takeda, AstraZeneca. A. Dixmier: Advisory board: BMS, Roche, Novartis; Support for congress participation: BMS, Roche, AstraZeneca, Boehringer Ingelheim, MSD, Amgen, Lilly. F. Barlesi: Fees: AstraZeneca, BMS, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda. D. Debieuvre: Consulting: Roche; Honoraria as speaker: AstraZeneca, Chugai, Lilly, Roche, Novartis, Pfizer, MSD, BMS; Grant for research: Roche, AstraZeneca, BMS, Boehringer Ingelheim, Chiesi, Chugai, Janssen, Pfizer, MSD, Novartis, GSK, Sandoz; Advisory boards : Roche, Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis; Support for congress participation: Roche, Boehringer Ingelheim, Novartis, Pierre Fabre, Pfizer, Mundipharma, BMS. C. Raspaud: Fees: Novartis, Boehringer Ingelheim, GSK, Chiesi, BMS, MSD, AstraZeneca, SOSO2, AgirAdom, Lilly. J.B. Auliac: Advisory boards: AstraZeneca, Boehringer Ingelheim, BMS, Roche; Speakers bureau: AstraZeneca, Amgen, BMS, Roche, Lilly, Pfizer, MSD. N. Benoit : Fees: BMS, AstraZeneca. P. Bombaron: Fees: BMS, Novartis, Boehringer Ingelheim, Roche, Amgen. D. Moro-Sibilot: Fees: BMS, MSD, Roche, AstraZeneca, Pfizer, Lilly. B. Asselain: Speakers bureau: BMS. F-E. Cotté, P. Lamoureux, N. Karam, N. Ozan, C. Calvet, B. Bryan, V. Allan: Employee: BMS. C. Audigier Valette: Principal investigator : AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche, MSD, Pfizer; Consulting: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, MSD, Pfizer, Roche AbbVie; Speaker: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Novartis, Pfizer, Roche, MSD, AbbVie.

Background

Racial differences in characteristics and prognosis of Asiatic and White patients receiving immunotherapy have not been well described.

Methods

We studied 390 patients from the POPLAR and OAK studies who received atezolizumab with evaluable biomarker parameters retrieved from a subsequent blood-based study. The differences of Asians versus Whites in baseline characteristics, outcomes and genetic mutations of atezolizumab therapy were assessed.

Results

Asiatic and White patients differed in characteristics including smoking history, baseline sum of the longest diameters (BLSLD), EGFR mutation frequency, programmed death-ligand 1 (PD-L1) expression and blood-based tumor mutational burden (bTMB) level. Overall survival (OS) was longer in Asians compared with Whites before (median OS: 18.7 vs. 11.1 mo; P = 0.005) and after (median OS: 20.9 vs. 12.6 mo; P = 0.005) propensity score matching (PSM). Race was an independent prognostic factor for OS (Asian vs White: HR 0.647, 95% CI 0.447-0.936, P = 0.021) in addition to performance status (PS), histology, BLSLD, and number of metastatic sites. The objective response rate (ORR) for Asians and Whites was 8.2% and 17.1%, respectively and disease control rate (DCR) was 51.2% and 47.7%, respectively. The blood-based mutational landscape differentiated between Asians and Whites. In the overall population, mutations of STK11, EGFR, KEAP1, POLE, GRM3, ATM and STAG2 were associated with treatment response while mutations of TP53, KEAP1, APC, RB1, CREBBP, EPHA5 and STAG2 were associated with OS. Comparing the frequency of efficacy- or prognosis- related mutations, Asians had more EGFR mutations and less TP53 and STK11 mutations than Whites.

Conclusions

Asians and Whites differed in the clinicopathological features and mutational landscape which may explain the superior efficacy of atezolizumab in Asiatic patients with NSCLC. This study conveys implications for further studies on racial disparity in the treatment of immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Support (No. 20161434).

Disclosure

All authors have declared no conflicts of interest.

Background

Blood-based tumor mutational burden (bTMB), which is measured by targeted next-generation sequencing (NGS) using cell-free DNA (cfDNA), shows a positive correlation with tissue-based TMB and is a predictive biomarker for non-small cell lung cancer (NSCLC) patients receiving atezolizumab. However, the role of bTMB in other treatment settings, such as chemotherapy, is unknown. We hypothesized that advanced NSCLC patients with low bTMB would derive more benefit from chemotherapy.

Methods

The clinical and genetic data from docetaxel arm of OAK trial (n = 318, training cohort) and POPLAR trial (n = 106, validation cohort) were used. The FoundationOne CDx NGS assay was used to quantify bTMB. Efficacy was determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Durable clinical benefit (DCB) was defined as overall survival (OS) that last more than 12 months. Gene alterations and bTMB were compared among patients with DCB and no durable benefit (NDB). The cut-off value of bTMB for predicting OS was determined by time-dependent receiver operating characteristic (ROC) curve.

Results

Significantly lower bTMB was observed in DCB than NDB (median, 5 vs 9 SNVs/Mb; P < 0.001) and in patients with partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median, 5 vs 7 vs 10 SNVs/Mb; P = 0.007). The optimised cut-off value of bTMB for predicting OS was 7 SNVs/Mb by time-dependent ROC curve. In training cohort, the median OS of patients with low bTMB was 11.5 months and 6.4 months for those with high bTMB (HR 0.638; 95% CI 0.497-0.820; P < 0.001). The median PFS in the low bTMB group (4.3 months) was significantly longer than that in the high bTMB group (2.9 months; HR 0.588; 95% CI 0.466-0.742; P < 0.001). These results were confirmed in validation cohort. Variants in EGFR and KEAP1 associated with DCB and NDB, respectively.

Conclusions

Our data showed that low bTMB (≤ 7 SNVs/Mb) was a clinically biomarker for docetaxel treatment in NSCLC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Nintedanib (Vargatef®) is an oral triple angiokinase inhibitor of VEGF-, PDGF- and FGF-receptors approved in the EU and other countries for treatment of locally advanced or metastatic NSCLC of adenocarcinoma histology in combination with docetaxel after 1st line chemotherapy. Data are sparse regarding efficacy and safety of nintedanib in NSCLC pts who had been treated with ICIs.

Methods

This interim analysis included 22 pts with locally advanced or metastatic lung adenocarcinoma who received nintedanib and docetaxel in 3^rd line following ICIs in 2^nd line within the ongoing NIS VARGADO (cohort B).

Results

Median age was 58 years (range: 45 – 76), 15/22 pts (68.2%) were men, and 16/22 pts (72.7%) were ECOG PS0/1. 4/22 pts (18.2%) had brain metastases, and 19/22 pts (86.4%) were current or former smokers. 1^st line chemotherapy treatments included pemetrexed (15/22 pts, 68.2%), carboplatin (12/22 pts, 54.6%), cisplatin (12/22 pts, 54.6%), bevacizumab (6/22 pts, 27.3%), vinorelbine (4/22 pts, 18.2%), paclitaxel (2/22 pts, 9.1%), and docetaxel (1/22 pts, 4.4%). 2^nd line treatments consisted of nivolumab (17/22 pts, 77.3%) or pembrolizumab (5/22 pts, 22.7%). Under nintedanib and docetaxel, 7/12 pts (58.3%) developed a partial response and 3/12 pts (25.0%) showed stable disease; DCR was 83.3% (10/12 pts). Median PFS was 5.5 months (95%CI 1.9 – 8.7). Treatment emergent adverse events (TEAEs) grade ≥3, serious TEAEs, and TEAEs leading to discontinuation were observed in 13/22 pts (59.1%), 11/22 pts (50.0%), and 7/22 pts (31.8%), respectively.

Conclusions

Nintedanib, in combination with docetaxel, showed clinically relevant efficacy and an adequate safety profile in stage IIIB/IV lung adenocarcinoma pts following treatment with chemotherapy and ICIs. Further studies are justified to fully explore the potential of nintedanib and docetaxel in this novel setting. Therefore, anti-angiogenesis plus docetaxel may emerge as a subsequent therapeutic principle in patients progressing under ICI therapy.

Clinical trial identification

NCT02392455.

Legal entity responsible for the study

Boehringer Ingelheim Pharma GmbH & Co. KG.

Funding

Boehringer Ingelheim Pharma GmbH & Co. KG.

Disclosure

C. Grohe: Research funding/honoraria: AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, MSD, Pfizer, Hoffmann-La Roche, Lilly including membership on advisory boards. W. Gleiber: Honoraria for membership on advisory boards: Boehringer Ingelheim. J. Atz, R. Kaiser: Employee: Boehringer Ingelheim Pharma GmbH & Co. KG All other authors have declared no conflicts of interest.

Background

Brain metastasis (BM) is the intractable disease in patients (Pts) with advanced non-small-cell lung cancer (NSCLC). Previous studies reported that EGFR-TKI plus bevacizumab (Ebe) could result in a significant prolongation of progression-free survival (PFS) than EGFR-TKI (E) alone. This study aimed to investigate whether Ebe could provide survival benefit than E alone in EGFR-mutant NSCLC Pts with BM.

Methods

Pts with EGFR-mutant NSCLC and radiologically confirmed BM (number > 3) were included. Pts with liver or leptomeningeal metastases were excluded. Intracranial PFS (iPFS) was defined as the time from the date of initiation of 1^st treatment to the date of intracranial progression or death and was censored at the date of last tumor assessment (when carried out). Systemic PFS (sPFS) was defined as the time from the date of initiation of 1^st treatment to the date of systemic progression (except intracranial progression) or death and was censored at the date of last tumor assessment (when carried out).

Results

164 Pts were identified. 121 received E and 43 received Ebe as 1^st treatment. Response rate was marginally higher in Ebe group than that in monotherapy group (69.7% vs. 52.9%, P = 0.055). Ebe was associated with a significantly longer iPFS (13.5 vs. 7.3 m, P < 0.001) and sPFS (14.4 vs. 8.8 m, P < 0.001) than E monotherapy. Importantly, median OS was markedly longer in Ebe group than in E group (30.1 vs. 22.4 m, P < 0.001). Different types of EGFR-TKIs showed comparable efficacy when combined with bevacizumab. However, erlotinib was associated with a significantly longer iPFS but similar sPFS and OS when compared with gefitinb and icotinib monotherapy. Multivariate analysis revealed that addition of bevacizumab was independently associated with prolonged iPFS (HR = 0.45, P < 0.001), sPFS (HR = 0.47, P < 0.001) and OS (HR = 0.50, P < 0.001).

Conclusions

The current study indicated that Ebe demonstrated the prolonged survival benefit than E alone in EGFR-mutant NSCLC Pts with multiple BM. These findings suggest that this strategy should be further explored in large-scale, strictly designed clinical trials as a standard treatment option in this clinical scenario.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.