Background

Randomized phase III NATCH trial in early-stage non-small cell lung cancer (NSCLC) patients (p) reported no statistically differences in disease-free survival (DFS) or overall survival (OS) with the addition of preoperative or adjuvant chemotherapy to surgery. In pre-operative arm, those p who achieved a complete response obtained a benefit in 5-year DFS rate (59% vs. 38%). Recently, major pathological response (MPR) to preoperative chemotherapy (10% or less of residual viable tumor after preoperative therapy) has reported as surrogate marker of OS. The aim of this study is to validate MPR as prognostic factor in a cohort of patients included the NATCH trial.

Methods

MPR was analysed in a whole cohort of 57 early-stage NSCLC p treated in the preoperative arm into NATCH trial from 2 institutions. OS according to MPR was analysed (long-rank test) in the whole population and by histologic subtype.

Results

In this cohort, median age was 67 years (47-78), 48 p (84%) were males, 26 p (46%) squamous subtype. By stage according to 6^th TNM: 9 p (16%) stage IA, 35 p (61%) stage IB, 12 p (21%) stage IIB and 1 p (2%) stage IIIA. 95% p completed 3 cycles of preoperative treatment. Surgical procedures: 81% lobectomies, 14% pneumonectomies, 5% no surgery. 13 out of 57 p (22.8%) had MPR. In the whole population, there was an increase in 5-year OS among those patients with MPR compare to p without MPR (84.6% vs. 58.5%, p = 0.106). According to histological subtype, 5-year OS in squamous NSCLC p with MPR was significantly longer than in p without MPR (100% vs. 47.1%, p = 0.026), but not differences in OS in non-squamous were detected (66.7% vs. 66.7%, p = 0.586).

Conclusions

MPR is a prognostic value in squamous NSCLC p who receive preoperative chemotherapy. Validation in extended cohort merits further evaluation.

Legal entity responsible for the study

Enriqueta Felip

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The study of the tumour microenvironment is leading to a better understanding of the evasion of immune surveillance and the development of new therapies. This research focuses on the analysis of immunoregulatory genes as potential prognostic biomarkers in resectable non-small cell lung cancer (NSCLC).

Methods

The expression of 8 genes involved in immune-regulation (PD-L1, PD-L2, IDO-1, IDO-2, ICOS-LG, CD5, CD6 and CD200) was analysed by RTqPCR in 257 paired fresh frozen tumour and normal tissue samples of resected NSCLC. Relative expression was calculated by Pfaffl formulae using ACTB, CDKN1B and GUSB as endogenous controls. Non-parametric tests were used for correlations between clinico-pathological and analytical variables and survival was assessed by Kaplan-Meier curves (long rank-test), considering significant p < 0.05.

Results

Patient`s median age was 64 years, 82% were males, 88% were former or current smokers, 47% were adenocarcinomas (ADC). Patients with higher expression of CD5 and IDO2 had a significant increase in overall survival (OS, 53.3 vs NR months, p = 0.032; 51.9 vs NR months, p = 0.049, respectively). A signature combining the expression of CD5 and IDO2 was able to better prognosticate survival (40.4 vs NR months, p = 0.028). The multivariate analysis (including clinico-pathological and analytical variables) showed that this signature has independent prognostic information OS (HR = 0.553 [0.344-0.887], p = 0.016). Moreover, in the subgroup of ADC increased expression of CD5 and IDO2 was associated with longer OS as well as increased relapse-free survival (RFS, 19.1 vs NR months, p = 0.045; 18.8 and 67.0 months, p = 0.029, respectively). The multivariate analysis established this gene signature as an independent prognostic biomarker for OS (HR = 0.380 [0.166-0.872]; p = 0.026) and RFS (HR = 0.288 [0.139-0.597]; p = 0.002).

Conclusions

The analyses revealed the prognostic value of CD5 and IDO2, being their combination an independent prognostic marker in resectable NSCLC. Supported by grants from FEDER and PI12-02838 and PI15-00753 from ISCIII.

Legal entity responsible for the study

Fundación para la Investigación del Hospital General Universitario de Valencia

Funding

Supported by grants from FEDER and PI12-02838 and PI15-00753 from ISCIII.

Disclosure

All authors have declared no conflicts of interest.

Background

Treatment resistance and relapse have been associated to cancer stem cells (CSCs), a highly tumorigenic subpopulation of cells with self-renewal properties and the ability to grow forming tumorspheres in non-adherent conditions. The aim of this study was to isolate and characterize CSCs from lung cancer cell lines and tumor-tissue from resectable non-small cell lung cancer (NSCLC).

Methods

The study was performed on tumour cells from 8 resected NSCLC patients and 12 NSCLC cell lines grown in monolayer and as spheroids. The expression of 60 genes, including CSC-markers, pluripotency inducers, cell cycle regulators, invasion promoters and components of Notch, Wnt and Hedgehog pathways was analysed by RTqPCR. In addition, protein levels of CSC-markers (ALDH1A1, CD133, CD166, CD44 and EpCAM), pluripotency inducers (Nanog, Oct-4 and Sox2), Wnt components (Wnt3 and β-catenin) and Notch1 were assessed by western blot and immunofluorescence.

Results

Lung tumorspheres had significantly higher expression levels of CSC-related genes EPCAM1, CD44, ALDH1A1, CDKN1A, CCND1, and KLF4 compared to their paired-adherent cells. Similarly, epithelial to mesenquimal transition (EMT) inducer SNAI1 and integrins ITGA2, ITGA6 and ITGB1 were overexpressed in lungspheres. Notch pathway ligands, JAG1 and DLL4, receptors, NOTCH1, NOTCH2 and NOTCH3, and the effector factor HES1 showed increased expression in spheroids. In Wnt, higher expression levels of WNT3, CTNNB1 and GSK3B were found in tumorspheres. No significant differences were found for the rest of genes analyzed. Western blot and immunofluorescence analyses revealed that CD44, CD133, Sox2 and β-catenin were highly expressed in spheroids from cell lines and patients’ samples. The expression of the rest of proteins evaluated differed among specimens.

Conclusions

Our results suggest four molecules which could act as markers for CSCs in NSCLC. Genes related to Notch and Wnt signaling pathways were more expressed in spheroids compared to the cells grown in adherence, suggesting that both pathways could be interesting targets against lung CSCs. Supported by grants RD12/0036/0025 from RTICC-FEDER, and PI12-02838 and PI15-00753 from ISCIII.

Legal entity responsible for the study

Fundación de Investigación Hospital General Universitario de Valencia.

Funding

Supported by grants RD12/0036/0025 from RTICC-FEDER, and PI12-02838 and PI15-00753 from ISCIII.

Disclosure

All authors have declared no conflicts of interest.

Background

Stage IIIB NSCLC treatment is definitive chemo-radiotherapy (CRT). In our SAKK 16/01 trial, neoadjuvant chemotherapy (CT) followed by neoadjuvant accelerated radiotherapy (RT) and surgery showed a median survival of 28.7 months (mos) in selected stage IIIB patients (pts). These promising results are the rationale for the current trimodality concept, introducing concomitant cetuximab (CET) to neoadjuvant CRT.

Methods

Pts with pathologically proven resectable stage IIIB (T4N0-3M0 or T1-4N3M0, 6th TNM) NSCLC, PS 0-1, and adequate organ function were treated with 3 cycles of neoadjuvant CT (cisplatin 100 mg/m² and docetaxel 85 mg/m² d1, q3w) followed by accelerated concomitant boost RT (44 Gy in 22 fractions in 3 weeks), both with concomitant weekly CET (250mg/m²) and subsequent surgery. The primary endpoint was progression-free survival (PFS) at 1 year (yr).

Results

69 pts were treated in 11 Swiss centers. 2/3 were men, median age was 60 yrs. Histology was squamous in 41% and adenocarcinoma in 49%, with T4 disease in 61%, N3 in 46% and both in 7%. A median relative total dose intensity of 99% of CT and 91% of CET was delivered. Per protocol RT was delivered to 95% of pts. 57 (83%) pts underwent surgery, with complete resection (R0) in 74% and a postoperative 30d mortality of 4%. Response rate after CT-immunotherapy was 57% and 64% after CRT-immunotherapy (CRT-I). Major pathologic response was found in 36% of the resected pts. 1-yr PFS based on Kaplan-Meier estimation was 50% (95% CI: 37%-62%). Median PFS was 12 mos (95% CI: 9-16), median OS was 21 mos (95% CI: 14-25), with a 2 and 3-yr survival of 41% and 30%, respectively.

Conclusions

This is one of the largest prospective phase II trials to evaluate the role of induction CRT-I and surgery in resectable stage IIIB disease, and the first to associate concurrent CET to the neoadjuvant strategy. Trial treatment is feasible with excellent adherence to the protocol and promising clinical and pathological response rates, PFS and OS, supporting an aggressive approach including surgery in selected IIIB pts. As compared to our previous SAKK 16/01 experience, the addition of CET does not improve the outcome of this group of locally advanced NSCLC pts.

Clinical trial identification

SAKK 16/08, NCT01059188, original version dated: 24.08.2009, including amendments: 04.07.2013.

Legal entity responsible for the study

Swiss Group for Clinical Cancer Research (SAKK)

Funding

Merck Serono

Disclosure

All authors have declared no conflicts of interest.

Background

Platinum-based combination chemotherapy is a standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has been demonstrated to have a good efficacy with less toxicity for advanced NSCLC treatment. S-1 might be also useful in the adjuvant setting for surgical NSCLC.

Methods

We performed a phase II randomized open label multi-institutional study in surgical patients with pathological stage IB (T > 5 cm), II or III NSCLC (7^th TNM classification), who underwent complete resection from 2009 to 2013. One hundred and thirty-nine patients were randomly assigned to two arms: S-1 80mg/m2 oral, day1 to 14, q3w, 1year (arm A, n = 70) or S-1 80mg/m2 oral day1 to 21, q5w + cisplatin 60mg/m2 day8, q5w, 4 courses, followed by S-1 80mg/m2 oral day1 to 14, q3w, total 1year (arm B, n = 69). The primary endpoint was the disease free survival (DFS) rate at 2 years and was evaluated using Bayesian method. Either treatment arm would deserve further study if the Bayesian posterior probability that the 2-year DFS rate would exceed a value of 40% were more than 0.85. The secondary endpoints were overall survival (OS), safety, and feasibility.

Results

The clinical characteristics of the patients were well balanced in terms of age, sex and pathological stage between the two arms. The DFS rate at 2 years was 51.4% (95% confidence interval [CI], 0.399–0.628) in arm A and 59.4% (95% CI, 0.476 – 0.702) in arm B. Both treatment arms met the primary endpoint: the probability of a DFS rate ≥ 40% at 2 years was over 0.97 in Arm and 1 in arm B. Neither DFS nor OS were significantly different (log-rank test; p = 0.1695 and p = 0.8684, respectively). No treatment-related deaths were observed in either treatment. The main G3/4 adverse events were appetite loss (arm A vs. arm B, 4.3% vs. 11.6%) and anemia (0% vs. 5.8%), which were not statistically different between the two arms. Treatment completion rate did not differ between the two arms (arm A vs. arm B: 45.7% [95% CI, 41.9–66.3%] vs. 43.5% [95% CI, 44.0–68.4%]).

Conclusions

Oral S-1 based adjuvant chemotherapy was feasible and promising for patients with completely resected NSCLC.

Clinical trial identification

UMIN000001765, 2009/03/12

Legal entity responsible for the study

academic group

Funding

Kyushu University Lung Surgery Study Group

Disclosure

All authors have declared no conflicts of interest.

Background

We investigated whether concurrent chemoradiotherapy (CCRT) would increase survival in patients with completely resected unsuspected N2-positive non-small cell lung cancer (NSCLC), compared with adjuvant chemotherapy alone.

Methods

Eligible patients were randomly assigned (1:1 ratio) to either the CCRT arm or the chemotherapy arm. In the CCRT arm, patients received concurrent thoracic radiotherapy (50 Gy in 25 fractions) with five cycles of weekly paclitaxel (50 mg/m²) and cisplatin (25 mg/m²), followed by two additional cycles of paclitaxel (175 mg/m²) plus cisplatin (80 mg/m²) at three-week intervals. In the chemotherapy arm, patients received four cycles of adjuvant paclitaxel (175 mg/m²) and carboplatin (AUC 5.5) every three weeks. The primary endpoint was disease-free survival.

Results

We enrolled and analyzed 101 patients. The median disease-free survival of the CCRT arm was 24.7 months, which was not significantly different from that of the chemotherapy arm (21.9 months; hazard ratio [HR] 0.94, 95% CI: 0.58–1.52, P = 0.40). There was no difference in overall survival (CCRT: 74.3 months, chemotherapy: 83.5 months, HR: 1.33, 95% CI: 0.71–2.49). Subgroup analysis showed chemotherapy alone increased overall survival in never-smokers and multi-station N2-positive patients. The pattern of disease recurrence was similar between the two arms.

Conclusions

There was no survival benefit from adjuvant CCRT compared with platinum-based chemotherapy alone for completely resected unsuspected N2-positive NSCLC. However, the role of sequential radiotherapy administered after adjuvant chemotherapy is being evaluated, and further study is needed to evaluate the optimal radiotherapy approach for completely resected N2-positive NSCLC.

Clinical trial identification

(NCT01066234)

Legal entity responsible for the study

Keunchil Park

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Patients with non-small cell lung cancer (NSCLC) and interstitial lung disease (ILD) are often excluded from clinical trials because they are considered to be at high risk for acute exacerbation (AE) of ILD triggered by radiotherapy. Therefore, data on the clinical course in these patients are limited. We examined the relationship between chemoradiotherapy (CRT) and occurrence of AE of ILD as well as the clinical course in these patients at our institution.

Methods

A retrospective analysis was performed on 37 patients with stage III NSCLC and ILD treated with first-line CRT in a clinical setting between January 2009 and December 2014 at our institution.

Results

Patient characteristics are shown in Table 1. Patients treated with CRT had milder ILD than those treated with chemotherapy alone. Eighteen patients treated with CRT received corticosteroids for the treatment of AE of ILD. Univariate analysis revealed that the risk factors for AE of ILD were ILD classification, smoking history, and V20. In multivariate logistic regression analysis, the independent risk factor for AE of ILD was ILD classification. AE of ILD occurred in nine (82%) patients with usual interstitial pneumonia (UIP) pattern and in nine (35%) with non-UIP pattern. Median overall survival (mOS) was 34.6 months. Univariate analysis and multivariate logistic regression analysis revealed that the prognostic factor for patients with stage III NSCLC and ILD treated with CRT was ILD classification. mOS was 10.9 and 43.0 months in UIP and non-UIP patterns, respectively.rnTable:

1289PD

Conclusions

In conclusion, this retrospective analysis suggests that ILD classification (UIP or non-UIP) is associated with the occurrence of AE of ILD and prognosis in patients treated with first-line CRT.

Clinical trial identification

The study protocol was approved by the Institutional Review board of Shizuoka Cancer Center (28-J167-28-1-3).

Legal entity responsible for the study

Haruki Kobayashi

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Given the burden of comorbidities, lack of curative agents, and high mortality in pts with SCLC, novel treatment options with limited toxicity are needed. BMS-986012 is a first-in-class, fully human mAb with enhanced antibody-dependent cell-mediated cytotoxicity that binds to fucosyl-GM1, a ganglioside highly expressed on SCLC. BMS-986012 monotherapy is well tolerated and has shown evidence of antitumor activity in some pts with rel/ref SCLC in a phase 1/2 study (NCT02247349; Chu et al. Ann Oncol. 2016;27(6 suppl) [abstract 1427PD]). Here we present initial results of BMS-986012 + nivolumab (anti–programmed death-1 mAb) in pts with rel/ref SCLC (NCT02247349).

Methods

Pts with SCLC who relapsed after or were refractory to first-line therapy received BMS-986012 400 or 1000 mg + nivolumab 360 mg IV Q3W. Dose escalation was based on a modified toxicity probability interval design. Primary objectives were safety and tolerability and determination of dose-limiting toxicities (DLT) and maximum tolerated dose. Secondary objectives included pharmacokinetics, antitumor activity, and immunogenicity.

Results

To date, 16 pts received BMS-986012 (400 mg, n = 8; 1000 mg, n = 8) + nivolumab. Demographic and safety data are based on 14 pts treated as of the April 3, 2017 cutoff. Median age was 64 y (range, 49-79 y), ECOG status was 0 (29%) or 1 (71%), and all pts were current (29%) or former (71%) smokers. All pts had prior platinum-based first-line therapy. The most common treatment-related AEs (TRAEs) were generalized pruritus (71%), vulvovaginal pruritus (21%), and dry skin (21%). Only 2 pts, both treated with 1000/360 mg, had G3/4 TRAEs (G3 pruritus with G4 lipase increase; G3 hepatic failure [DLT; led to discontinuation]). As of May 1, 2017, 4 of the 16 pts evaluable for efficacy achieved partial responses (2 unconfirmed). Updated efficacy data as well as data from ongoing biomarker analyses will be presented.

Conclusions

BMS-986012 in combination with nivolumab is well tolerated in pts with rel/ref SCLC, with no evidence of additive toxicity. Promising initial antitumor activity was observed with BMS-986012 + nivolumab in pts with rel/ref SCLC.

Clinical trial identification

NCT02247349

Legal entity responsible for the study

Bristol-Myers Squibb

Funding

Bristol-Myers Squibb

Disclosure

N.B. Leighl: Research funding (institution) - Novartis. Travel/honoraria (unrelated CME) - AstraZenenca, Pfizer, Bristol-Myers Squibb, Merck, Sharpe & Dohme. R.A. Juergens: BMS: advisory board member, honoraria, and grant support; clinical trials funding to my institution (outside of submitted work). P. Basciano, S. Tannenbaum-Dvir, D. Williams, G. Kolaitis: BMS employee; Owner of BMS stock. D. Lathers, K. Urbanska: BMS employee; Ownership of BMS stock. G. Kollia: BMS employee owning company stock. C. Darby: Employee of Mindlance, Inc. and working at Bristol-Myers Squibb under contract. N. Ready: Personal fees from Bristol Myers Squibb, Merck, Celgene, AstraZeneca, and Abbvie outside of submitted work. All other authors have declared no conflicts of interest.

Background

Lurbinectedin (PM01183, L) is a novel anticancer drug that inhibits activated transcription, induces DNA double-strand breaks generating apoptosis, and modulates tumor microenvironment. Relapsed SCLC still remains an unmet medical need.

Methods

Antitumor activity and safety of Lurbinectedin in SCLC was reviewed in three clinical trials (n = 83 patients): two phase I in combination with doxorubicin (L+DOX; n = 48, two cohorts) or paclitaxel (L+TAX, n = 7), and a phase II single-agent basket trial (n = 28).

Results

Median age was similar in these three studies. CNS was involved in 33% (L+DOX cohort A), 4% (L+DOX cohort B), 29% (L+TAX) and 0% of patients (L alone). Patients with sensitive disease were 52%, 64%, 71% and 71%, respectively. Activity was seen in the three studies (see Table). The most reported toxicity was hematological (G3-4 neutropenia/thrombocytopenia/febrile neutropenia: L+DOX Cohort A 96%/34%/34%; L+DOX Cohort B 89%/11%/14%; L+TAX 86%/0%/14%, and L alone 32%/4%/4%). Non-hematological toxicity was mainly G1-2 and included fatigue, nausea/vomiting, and transaminase increase.

Conclusions

Lurbinectedin shows activity as a single agent and in combination with other agents (DOX and TAX) in relapsed SCLC. Results were remarkable in terms of PFS, DCR and duration of response, especially in platinum-sensitive SCLC. Toxicity mainly consisted of transient myelosuppression, which was manageable with dose reductions and G-CSF use. A randomized Phase III with L+DOX is ongoing (ATLANTIS Study).Table:

1529PD

Clinical trial identification

NCT01970540

Legal entity responsible for the study

PharmaMar SA

Funding

PharmaMar SA

Disclosure

M. Forster: Consulting or advisor or travel and accomodation in Lilly, Pfizer, BI, Novartis Merck, Astrazeneca. E. Calvo: Speakers\' Bureau in Novartis and travel or accomodation expenses in Lilly, PsiOxus, Novartis. M.P. Lopez Criado: Relation with Lilly, Bristol, roche, and travel, accomodations with Bristol. J.A. Lopez-Vilarino de Ramos, X.E. Luepke-Estefan: Employee in PharmaMar. C. Kahatt, P. Lardelli, A. Soto-Matos: Employee and Stock in PharmaMar. All other authors have declared no conflicts of interest.

Background

Notch signaling is implicated in cancer stem cell biology and is an appealing target in the treatment of SCLC. TRXT, a fully human anti-Notch2/3 antibody, has shown preclinical efficacy in SCLC. A randomized phase 1b/2 study was conducted.

Methods

This was a randomized, placebo-controlled, multi-center study. Pts were randomized 1:1 to platinum (cisplatin 75 mg/m² or carboplatin AUC of 5 mg/ml*min on day 1, investigator’s choice) + etoposide (EP) 100 mg/m² on days 1-3 + TRXT 15 mg/kg on day 1 or EP + placebo (pbo) every 21 days. Chemotherapy was used for 6 cycles, and TRXT/pbo was continued until disease progression. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), safety, and PFS/OS in 5 biomarker groups.

Results

145 pts were enrolled (137 treated). Demographics and baseline pt characteristics were balanced between arms. PFS was similar between the treatment arms (median 5.5 mo in EP+pbo vs 5.5 mo in EP+TRXT, HR = 0.97, p = 0.94). OS was also similar between the treatment arms (median 10.3 mo in EP+pbo vs 9.3 mo in EP+TRXT, HR = 1.01, p = 0.95). ORR was 70.8% in EP+pbo vs 68.6% in EP+TRXT (p = 0.83). There were no statistically significant differences in OS or PFS according to Notch3, Hes1, Hey2, Hey1, or Hes6 gene expression levels. Adverse events (AE) were more common in EP+TRXT; most commonly increased drug-related AEs included diarrhea (33.8/76.8%), thrombocytopenia (17.6/58.0%), decreased appetite (23.5/37.7%), hypokalemia (7.4/33.3%), and vomiting (13.2/31.9%). Most commonly increased grade 3 or higher AEs in the EP+TRXT arm included thrombocytopenia (10.3/40.6%), anemia (20.6/27.5%), pneumonia (4.4/15.9%), diarrhea (0/18.9%), and hypokalemia (4.4/13%). AEs with fatal outcome were more common in EP+TRXT (4.4/8.7%).

Conclusions

Tarextumab in combination with platinum-based therapy did not improve PFS, OS, ORR in previously untreated SCLC. Biomarker analysis failed to establish a predictive marker for TRXT efficacy. Pts treated with TRXT experienced more toxicity. Clinical development of TRXT has been discontinued.

Clinical trial identification

NCT01859741

Legal entity responsible for the study

OncoMed Pharmaceuticals

Funding

OncoMed Pharmaceuticals

Disclosure

S.V. Liu: Consultant: Ariad, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Genentech, Lilly, Pfizer. A. Kapoun, L. Faoro: Employee and stock holder at OncoMed Pharmaceuticals. All other authors have declared no conflicts of interest.

Background

About 5-10% of EGFR-mutant lung ACs transform to SCLC at the time of acquired resistance. The clinical course of patients (pts) with this finding is poorly characterized.

Methods

We retrospectively reviewed the records of all 16 pts with EGFR-mutant SCLC that have been seen at our center under an IRB-approved protocol and summarized demographics, disease features, and clinical outcomes.

Results

Among 16 pts, 10 were women. 15 had AC histology at diagnosis; one had de novo SCLC with EGFR del19. 11 were never-smokers. All but the de novo case received an EGFR tyrosine kinase inhibitor (TKI) prior to transformation (7 had > 1 prior TKI; 6 received a 3^rd-gen TKI) and 14/15 were on a TKI when the SCLC was noted. Median time from diagnosis to SCLC was 29.6 mo (95% CI 10.8-38.1). 15/16 of the SCLC tumors were genotyped; all kept their founder EGFR mutation and none had T790M, including 5 pts with prior T790M-positivity. Not all samples were assessed for genotype by the same assay, though recurrent mutations observed in at least 25% of cases were TP53, PIK3CA and RB1 (full genetic data will be shown at meeting). The most common therapy given directly after SCLC diagnosis was platinum-etoposide (n = 9); all SCLC treatment lines considered, platinum-etoposide had a clinical response rate of 72% (8/11) and progression-free survival of 4.6 mo (95% CI 2.0-5.5). Seven pts also had a taxane at some point after the diagnosis of SCLC, and 4/7 (57%) responded. Median overall survival (mOS) from initial cancer diagnosis was 38.2 mo (95% CI 24.5-43.9) and mOS from time of SCLC diagnosis was 12.4 mo (95% CI 4.0-16.6).

Conclusions

EGFR-mutant AC that transforms to SCLC uniformly maintains its founder EGFR mutation and is mutually exclusive with T790M (though both can be observed sequentially). In our cohort, the median time from initial lung cancer diagnosis to transformation was 2.5 years. The mOS of 12.4 mo following diagnosis of SCLC is similar to that seen among pts with non-EGFR-mutant SCLC. Likewise, responses to platinum-etoposide were frequent, but transient. 4 pts also responded to a taxane. Interestingly, mOS from diagnosis was similar to expected mOS for pts that never transform to SCLC at 38.2 mo. Further investigation is needed to better elucidate optimal strategies for this group.

Legal entity responsible for the study

Lecia V Sequist

Funding

None

Disclosure

Z. Piotrowska: Advisory board/consulting honoraria from AstraZeneca, Boehringer-Ingelheim and Ariad Pharmaceuticals. A.F. Farago: Consulting for Pharmamar, Abbvie, Takeda, Merrimack, Intervention Insights. Honorarium from Foundation Medicine. A.N. Hata: Amgen - consulting and research support Novartis - research support L. Sequist: Consulting for AZ, Ariad, BMS and Genentech – and research support from Clovis, AZ, BI, Novartis, Merrimack, Pfizer, Genentech, Merck, Johnson & Johnson. All other authors have declared no conflicts of interest.

Background

Detection of mesothelioma from blood is challenging. Current proposed biomarkers mainly rely on single protein cancer products detected in serum or plasma. Here, we investigate if a mass spectrometry based multiplexed proteomic biomarker signature can improve accuracy of mesothelioma detection in serum.

Methods

We used targeted proteomics technology to investigate more than 400 serum samples from cohorts of mesothelioma and asbestos exposed donors from USA, Australia and Europe. Serum samples were processed for enrichment of N-linked glycoproteins on 96-well plates before peptide separation on ultra performance liquid chromatography (UPLC) followed by targeted analysis on a triple quadrupole type of mass spectrometer. The software Skyline was used for data visualization. Workflow for quantitative large scale data analysis was based on the software package MSstats.

Results

We applied logistic regression models for a multiplexed signature of six peptides from six different proteins, including the biomarker mesothelin. In the receiver operating curve, signature had an area under the curve (AUC) of 0.76 in discriminating mesothelioma from asbestos exposed donors in a training set of 212 donors. AUC in a separated validation set of 193 donors was 0.72. In the validation set, AUC was 0.74 in separating mesothelioma early stages I/II from asbestos exposed. In comparison, single mesothelin peptide assessed by mass spectrometry discriminated mesothelioma from asbestos exposed with AUC of 0.71 in training and AUC of 0.64 in validation set, and mesothelioma early stages I/II were separated from asbestos exposed with AUC of 0.66 in the validation set.

Conclusions

Diagnostic strategies based on multiplexed targeted proteomics biomarkers bear potential of an increased accuracy for detection of mesothelioma in serum.

Legal entity responsible for the study

James Thoracic Center, The Ohio State University Medical Center

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. In a Phase II/III, double-blind, randomised LUME-Meso trial, primary Phase II analysis showed improved progression-free survival (PFS) with N and a trend for prolonged interim OS. FVC, a common pulmonary function test reflecting pt performance and quality-of-life, was also evaluated.

Methods

Pts with unresectable MPM (ECOG PS 0–1), stratified by histology, were randomised 1:1 to ≤ 6 cycles PEM (500 mg/m²)/CIS (75 mg/m², Day 1) + N or P (200 mg bid, Days 2–21), followed by N/P monotherapy until progression/unacceptable toxicity. The primary endpoint was PFS; OS was the secondary endpoint. FVC was a further endpoint, evaluated as percentage change from baseline for cycle (C)1–8 using a mixed-effect model with repeated measures.

Results

87 pts were randomised (N = 44; P = 43). At the primary OS analysis (71% of events), OS benefit favoured N (hazard ratio [HR]=0.77; 95% confidence interval [CI]: 0.46–1.29; p = 0.319) and primary PFS results were confirmed (HR = 0.54; [95% CI]: 0.33–0.87; p = 0.010). Benefit of N was greatest in epithelioid MPM for PFS (HR = 0.49; 95% CI: 0.30–0.82; p = 0.006; median [m] 9.7 vs 5.7 months [mo]) and OS (HR = 0.70; 95% CI: 0.40–1.21; p = 0.197; mOS 20.6 vs 15.2 mo). Adjusted mean (standard error [SE]) FVC change at C8 favoured N over P (all pts: +10.0 [SE: 3.5]% vs + 2.8 [SE: 3.7]%; mean treatment difference [TD]: 7.2 [SE: 4.5]%; pts with epithelioid histology: +14.1 [SE: 2.9]% vs + 4.2 [SE: 3.3]%; mean TD: 9.9 [SE 4.5]%). A trend towards improved FVC with N over P was observed from C2 in all pts and epithelioid histology. Neutropenia was the most frequent Grade ≥3 adverse event (AE; N, 43%; P, 12%); febrile neutropenia rate was low (4.5 vs 0%). AEs leading to discontinuation were lower with N than P (7 vs 17%).

Conclusions

Addition of N to PEM/CIS resulted in a substantial improvement in PFS, a trend for prolonged OS and improvement in the pulmonary function measure FVC. Treatment effect was most pronounced in pts with epithelioid histology; Phase III is recruiting in this population (NCT01907100).

Clinical trial identification

NCT01907100

Legal entity responsible for the study

Boehringer Ingelheim Pharma GmbH & Co. KG

Funding

Boehringer Ingelheim Pharma GmbH & Co. KG

Disclosure

S. Novello: Honoraria from Roche, Boehringer Ingelheim, Bristol-Meyers Squibb, Eli Lilly, AstraZeneca, Pfizer and Novartis; payment as a consultant from Roche, A.K. Nowak: Payment as consultant from Aduro Biotech, Morphotek, Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer-Ingelhelm, Epizyme, Roche; travel expenses by Amgen and AstraZeneca; received research funding from Boehringer-Ingelhelm and AstraZeneca. F. Grosso: Travel expenses paid by Boehringer-Ingelhelm and PharmaMar. N. Steele: Honoraria from Pfizer, Novartis; payment as consultant from MSD, Boehringer-Ingelhelm and BMS; travel expenses paid by Pfizer, MSD, Boehringer-Ingelhelm and research funding from Merck Serono, AstraZeneca, Boehringer-Ingelhelm, BMS, Novartis and Roche. S. Popat: Honoraria from Pfizer, Boehringer-Ingelheim (BI), AstraZeneca, Roche, Eli-Lilly, Novartis; payment as consultant from Boehringer-Ingelheim, Roche, Eli-Lilly, Novartis, Pfizer; received funding from BI, Epizyme, BMS, Clovis Oncology, Roche and Eli-Lily. L. Greillier: Honoraria from Roche, Boehringer Ingelheim, BMS, Eli Lilly, AstraZeneca, Pfizer and Novartis; payment as a consultant from Roche, Boehringer Ingelheim and BMS; author’s institution has received research funding from Roche. T. John: Honoraria from Roche, Lilly, BMS, AstraZeneca/MedImmune, Pfizer; payment as consultant from AstraZeneca, AstraZeneca/MedImmune, Pfizer, Roche/Genentech and travel expenses paid by Boehringer-Ingelhelm, Roche and AstraZeneca. N.B. Leighl: Travel expenses paid for by AstraZeneca, MSD, BMS and Pfizer and has received research funding from Novartis. M. Reck: Honoraria, consultation payment and speakers bureau attendance from Boehringer-Ingelhelm, Roche, Eli-Lily, Proacta, AstraZeneca, BMS, MSD, Merck, Novartis, Pfizer and Celgene. N. Pavlakis: Honoraria and payment as consultant from Specialised Therapeutics, Pfizer, Boehringer-Ingelhelm, Merck Serono, Bayer, AstraZeneca, Novartis, Roche, AMtene. Author has also been paid to consult with Sanofi. J.B. Sorensen: Payment as consultant from Roche, Merck, Boehringer-Ingelhelm and Eli-Lilly. D. Planchard: Payment as consultant from Lilly, Boehringer-Ingelhelm, BMS, Pfizer, Clovis Oncology, MSD, Sanofi, AstraZeneca, Novartis and Roche and has received research funding from Novartis. G.L. Ceresoli: Research funding from Bayer. B. Hughes: Payment as consultant from MSD, BMS and Roche and has received travel expenses from MSD. J. Mazieres: Research funding received from BMS and Roche. M.A. Socinski: Honoraria and payment for consultation from Genetech and their institution has received funding from Pfizer. U. von Wangenheim, J. Barrueco, N. Morsli: Employed by Boehringer Ingelhelm. G. Scagliotti: Honoraria from Eli-Lily, AstraZeneca, Roche, Pfizer, MSD; payment as consultant from Eli-Lily; travel expenses by Bayer and has been paid by Eli-Lily and MSD to participate in a Speaker’s Bureau.

Background

Tumor immune microenvironment (TME) plays a role in Malignant Pleural Mesothelioma (MPM) pathogenesis and patients outcome. PD1/PDL1 checkpoint inhibitors are currently under investigation as innovative promising treatment of MPM, even though no definitive predictive markers have been defined so far. PDL1 expression and TME are dynamic in tumor samples. The object of this preliminary analysis is a subset of MPM paired samples analyzed before and after induction chemotherapy (ct) in order to assess TME and PDL1 heterogeneity and dynamism over time.

Methods

Inflammatory cells in the intratumoral (IT) e peritumoral (PT) stroma were characterized by immunohistochemistry (IHC) using monoclonal anti-CD20 (B lymphocytes), CD3, CD4 and CD8 (T lymphocytes) and CD68 (macrophages) antibodies, and quantified as percentage in neoplastic area. PDL1 expression in tumor cells (TC) and immune cells (IC) was evaluated by IHC using Ventana SP263 antibody (Roche) and quantified as percentage of expressing cells. Difference between naïve and treated samples was assessed through Mann-Whithey test.

Results

15 paired MPM specimens (14 epithelioid and 1 biphasic) obtained for diagnostic purpose before platinum-pemetrexed ct and at the time of resection were analyzed. After ct MPM samples showed PT and IT increase of CD68+ macrophages and CD3+ T lymphocytes, even though only peritumoral CD3+ lymphocytes significantly increased (p=0.008). CD4+ and CD8+ lymphocytes were lacking in naive samples, while CD8+ significantly increased after ct (median value PT pre vs. post-ct: 5% vs. 30%, p=0.02; median valule IT pre vs. post-ct: 5% vs. 15%, p= 0.007). CD8+/CD68+ ratio increased after ct, even though without statistical significance. No IT B lymphocytes were observed, a small increase at PT level was shown after ct. Ct induced PDL1 expression in tumor cells and even more in lymphomonocitic infiltrate (median value pre vs. post-ct 0% vs. 50%, p=0.003).

Conclusions

Ct significantly increases cytotoxic T lymphocytes at PT and IT level in MPM samples and PDL1 expression in IC. These data confirm the strong rationale for the combination of checkpoint inhibitors and ct as promising treatment of MPM.

Clinical trial identification

not applicable

Legal entity responsible for the study

Istituto Oncologico Veneto IRCCS

Funding

None

Disclosure

All authors have declared no conflicts of interest.