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

Osimertinib, a 3rd-generation EGFR-TKI selective for both sensitising and EGFR T790M resistance mutations, has shown efficacy in pts with CNS metastases; encouraging activity has been reported in pts with LM at 160 mg once daily (QD) (BLOOM; NCT02228369). We report LM activity with osimertinib 80 mg QD in pts with LM from studies across the AURA program (NCT01802632; NCT02094261; NCT02442349; NCT02151981).

Methods

Pts with EGFR T790M positive advanced NSCLC and progression on EGFR-TKI received osimertinib 80 mg QD. Patients with LM and CNS metastases were eligible if asymptomatic and stable. Baseline brain scans were mandated in pts with known or treated CNS metastases at study entry; pts with evidence of LM by neuroradiological blinded independent review (BICR) were included for retrospective analysis. Follow-up brain scans were assessed for radiologic LM response by LM BICR per Response Assessment in Neuro-Oncology LM criteria. LM objective response rate (ORR), LM duration of response (DoR), LM progression-free survival (PFS) and overall survival (OS) were assessed retrospectively. Results are based on individual data cutoffs for each study. A longitudinal analysis overlaid changes from baseline non-CNS tumour size with LM responses at each visit for AURA LM and BLOOM LM pts.

Results

22 LM pts from the AURA studies were included for analysis. Median treatment exposure was 7.3 mo (range 2.3–16.5). Baseline characteristics were broadly consistent with the overall AURA study population: median age 58 yrs; female 59%; Asian 82%; WHO PS 1 82%. LM ORR was 55% (95% CI 32, 76); complete or partial LM response reported in 6 pts (27%) each. Median LM DoR was not reached (95% CI 2.8, not calculable [NC]). Median LM PFS was 11.1 mo (95% CI 4.6, NC). OS was 18.8 mo (95% CI 6.3, NC). Graphical assessment of longitudinal analysis showed similar non-CNS and LM responses in AURA LM and BLOOM LM pts.

Conclusions

Consistent with early efficacy outputs from BLOOM (160mg QD), osimertinib 80 mg QD showed a clinically meaningful benefit in pts with T790M-positive NSCLC and radiographically-detected LM. Additional studies are needed to further evaluate the CNS efficacy of osimertinib 80 mg QD in pts with EGFRm NSCLC and LM.

Clinical trial identification

AURA extension (NCT01802632), AURA2 (NCT02094261), AURA3 (NCT02151981), AURA17 (NCT02442349).

Editorial acknowledgement

Medical support was provided by Robert Harrison, PhD, of iMed Comms, Macclesfield, UK, an Ashfield Company, part of UDG Healthcare plc, and funded by AstraZeneca, Cambridge, UK, in accordance with Good Publications Practice (GPP3) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M-J. Ahn: Speakers’ bureau: AstraZeneca, MSD, ONO, Lilly, Roche; Consultant: Alpha Pharmaceutical. C-H. Chiu: Honorarium: AZ, BI, Novartis, Pfizer, Roche. J-Y. Han: Honoraria: Roche, AstraZeneca, BMS, MSD; Advisory role: AstraZeneca, BMS, MSD, Lilly, Novartis, Pfizer; Research fund: Roche, Pfizer, ONO. S.B. Goldberg: Research support: AstraZeneca; Advisory board member: AstraZeneca, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Genentech, Amgen, Spectrum. A. Greystoke: Consultancy fees, speaker fees: AstraZeneca. J. Crawford: Scientific advisor: Amgen, Enzychem, Merck, Pfizer; Consultant: Amgen, AstraZeneca, Coherus, Enzychem, Merck, Pfizer; Research support: AstraZeneca, Genentech, Helsinn; Chair/DSMB member: Beyond Spring, G1 Therapeutics, Janssen, Merrimack, Mylan, Roche. X. Huang, M. Johnson, K. Vishwanathan, A. Mendoza-Naranjo: Employee, shareholder: AstraZeneca. T.S.K. Mok: Leadership (for-profit): ChiMed, Sanomics Ltd.; Leadership (non-profit): IASLC, ASCO, Chinese Society of Clinical Oncology; Shareholder: Sanomics Ltd.; Honoraria: AZ, BI, Roche/Genentech, Pfizer, Lilly, Merck Serono, MSD, Novartis, SFJ, ACEA, Vertex, BMS, Oncogenex, Celgene, Ignyta, Cirina, Fishawack Facilitate, Takeda Oncology, Janssen, ChiMed; Consulting/advisory role: AZ, BI, Roche/Genentech, Pfizer, Lilly, Merck Serono, MSD, Novartis, SFJ Company, ACEA, Vertex, BMS, GeneDecode, Oncogenex, Celgene, Ignyta, Cirina, Fishawack Facilitate, Janssen, Takeda Oncolog, ChiMed; Research funding: AZ, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS, Eisai, Taiho, Merck Serono, XCovery. All other authors have declared no conflicts of interest.

Background

Tumor Treating Fields (TTFields), a non-invasive, loco-regional, antimitotic treatment approved for glioblastoma (GBM), are delivered via transducer arrays to tumor region. Localized dermatitis underneath the arrays were main adverse events (AEs) reported in phase 3 GBM trials. The safety of TTFields was analyzed in two phase I-II studies in non-small-cell lung cancer (NSCLC) [EF-15, NCT00749346] and malignant pleural mesothelioma (MPM) [STELLAR, NCT02397928].

Methods

TTFields studies in this pooled analysis were EF-15 (n=41, advanced NSCLC; plus pemetrexed) and STELLAR (n=80, MPM; plus platinum and pemetrexed). TTFields were applied 12 - 18 hours/day at a frequency of 150 kHz. All patients received standard of care systemic chemotherapy for their disease in addition to TTFields. Severity and frequency of AEs, and association with TTFields treatment were evaluated (CTCAE criteria version 4.0).

Results

Patients were aged 27-78 years: STELLAR: 67 (27-78) and EF-15: 63 (44-78), ECOG 0-1; 7 patients in EF-15 had ECOG 2. The incidence of grade 1-2 gastrointestinal (GI) toxicities was 35%. The most common low grade GI toxicities were: nausea (17%), vomiting (6%), constipation (10%) and diarrhea (6%). Grade 1-2 general disorders (16% fatigue and 11% asthenia) were common. Dyspnea Grade 1-2 (12%) and Grade 3-4 (5%) were considered related to standard chemotherapy or underlying disease. Grade 1-2 cardiovascular AEs were 7%; one case of severe arrhythmia (atrial flutter) was unrelated to TTFields. The only common TTFields-related adverse event was dermatitis below the transducer arrays. 59% patients had dermatological AEs: 53% Grade 1-2 dermatitis, 4% grade 3 dermatitis and 11% Grade 1-2 pruritus.

Conclusions

Treatment of solid tumors with TTFields 150 kHz to the thorax did not result in serious AEs or treatment-related pulmonary, cardiac, hematological or gastrointestinal toxicities. Expected dermatological toxicity beneath the device transducer arrays was seen in 59% patients, and resolved after a short treatment break or termination of treatment. These safety results and encouraging survival outcomes support the potential use of TTFields therapy in NSCLC and mesothelioma.

Clinical trial identification

NCT00749346 and NCT02397928.

Legal entity responsible for the study

Novocure.

Funding

Novocure.

Disclosure

G.L. Ceresoli: Travel support: Novocure. All other authors have declared no conflicts of interest.

Background

To evaluate the capability of pulmonary MR imaging with zero echo time (ZTE) in pulmonary nodules assessments, using low-dose computed tomography (LDCT) as the reference standard.

Methods

Institutional review board approval and informed consent were obtained. Eight-nine consecutive patients (51 males: mean age, 69 years and 38 females: mean age, 71 years) with various pulmonary nodules were examined with chest LDCT and pulmonary MR imaging with ZTE. The interval between two examinations was within two weeks for each patient. Lung images were visually scored by two experienced radiologists who assessed the probability of nodule presence in comparison with LDCT. To compare nodule detection capability of the two methods, consensus for performances was evaluated by means of kappa statistics and χ² test, and receiver operating characteristic analyses were used to compare diagnostic performance of both methods.

Results

There was no significant difference (F = 0.75, P = 0.56) in figure of merit between methods (LDCT, 0.84 Vs. MR imaging with ZTE, 0.86). Intermethod agreements between ZTE MR imaging and LDCT were significant (0.70 ≤ κ ≤ 0.98; P < 0.001). Areas under the curve for pulmonary nodules on LDCT were significantly larger than those on MR imaging with ZTE (P = 0.02).

Conclusions

Pulmonary thin-section MR imaging with ZTE was useful in nodule detection, and it is considered at least as effective as low-dose thin-section CT.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Lung cancer is the leading cause of cancer death worldwide. Two large randomized controlled trials (NLST,NELSON) founded a significant decrease in lung cancer mortality with an annual low dose CT screening among selected current or former smockers.While being now recommended in many countries, the French National Authority for Health claimed that conditions were not sufficient for implementation of such a screening program in France. The aims of our study were to assess the feasibility and effectiveness of a lung cancer screening pilot program with LD CT scan in a French department. We report here the results of the first screening round.

Methods

DEP KP80 was a single-arm, prospective study started in May 2016 and ended in December 2018 in a French department (Somme). The inclusion criteria were those of the NLST study. An annual LD CT scan was scheduled and 2 rounds were planned. Our algorithms considered nodules<5mm as negative, nodules> 10mm as positive and recommended a 3-month CT with measurement of the doubling time for nodules between 5 and 10 mm . Smoking cessation was encouraged as part of the protocol. This study was managed by the departmental cancer screening agency (ADEMA80). All General Practitioners (GP), pulmonologists (PN) and radiologists from the department were solicited by mail to participate in this study. Subjects were selected by GP or PN who checked the inclusion criteria and precribed the CT scan.

Results

218 GP, 17 PN and 28 radiologists accepted to participate. Over a 2.5 years period, 1307 subjects were recruited. the participation rate was of 73% (949 scans were performed). Screening was negative in 733 cases (77%), positive in 54 (5.7%) and indeterminate in 162 (17%). The prevalence of a detected lung cancer was 2.5% : 24 cancers with 16 adenocarcinomas,3 squamous cell carcinomas, 1 carcinoid tumour, 2 small cell carcinomas 1 undetermined and 1 unknown. There were 2 carcinoma in situ (8%),13 Stage IA (54%), 3 Stage IIB (12%), 2 Stage IIIA (8%) and 4 Stage III B,C (17%). A surgery was performed in 20 of these patients (83%) and one patient underwent surgery for benign lesion.

Conclusions

This study demonstrates, at a regional level, the feasibility and effectiveness of an organized and structured lung cancer screening by LD CT scan in France.

Legal entity responsible for the study

O. Leleu.

Funding

La ligue contre le cancer Agence Régionale de Santé Picardie and AstraZeneca.

Disclosure

All other authors have declared no conflicts of interest.

Background

Checkpoint inhibitors targeting programmed death receptor (PD)-1 or PD-ligand 1 (PD-L1) became the cornerstone in the treatment of advanced NSCLC. Several phase III trials showed a better overall survival by treating with combination chemotherapy and checkpoint inhibition, suggesting that addition of chemotherapy increased the response to checkpoint inhibitors. Recently, peripheral blood biomarkers such as Ki67+PD-1+CD8 cells were found to be predictive for clinical outcome with PD-1 treatment. Knowing more about immune modulatory capacities of chemotherapy can help us to design better treatment strategies. We investigated the immune-modulatory effects of paclitaxel/carboplatin/bevacizumab (PCB), focusing on known immune populations associated with response to checkpoint inhibitors in peripheral blood.

Methods

In the NVALT 12 study, 223 patients with advanced NSCLC were enrolled to receive PCB, with or without nitroglycerin patch. At baseline and after the first and second treatment cycle, peripheral blood was drawn. By flow cytometry, the proportions of T cells and several subsets and co-inhibitory receptors of these, B cells and monocytes were determined.

Results

6 weeks after starting treatment with PCB, the proportions of T cells were significantly increased compared to baseline values. Within the T cells subsets, proliferation of CD4 T cells remained stable whereas proliferation of CD8 T cells (Ki67+) were significantly increased. The proliferating Ki67+ CD8 T cells expresses more PD-1 compared to non-proliferating CD8 T cells. However, patients with >2 fold increased proliferation of T cells did not show a better outcome.

Conclusions

Paclitaxel/ carboplatin/ bevacizumab induces proliferation of CD8 T cells which expresses more co-inhibitory checkpoint molecules. Progression free and overall survival was unchanged by this increase on its own, showing the rationale to combine PCB with checkpoint inhibition in lung cancer, as used in Impower 150.

Clinical trial identification

NCT01171170.

Legal entity responsible for the study

The authors.

Funding

NVALT.

Disclosure

D. Dumoulin: Speakers fee: BMS, Roche, Pfizer, Novartis. A-M.C. Dingemans: Advisory boards, lectures: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda (honoraria to institution). J.G. Aerts: Advisory boards: BMS, Boehringer Ingelheim, MSD, AstraZeneca, Eli Lilly, Takeda, Amphera; Stock owner: Amphera B.V. All other authors have declared no conflicts of interest.