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Proffered Paper – Immunotherapy of cancer Proffered Paper session

1174O - Pembrolizumab in microsatellite instability high cancers: Updated analysis of the phase II KEYNOTE-164 and KEYNOTE-158 studies (ID 569)

Presentation Number
1174O
Lecture Time
10:15 - 10:30
Speakers
  • Luis A. Diaz (New York, United States of America)
Location
Barcelona Auditorium (Hall 2), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:15 - 11:45

Abstract

Background

Pembrolizumab (pembro) is indicated for patients (pts) with microsatellite instability-high (MSI-H) solid tumors after 1 prior therapy, and MSI-H colorectal cancer (CRC) after prior fluoropyrimidine, oxaliplatin, and irinotecan, based in part on data showing durable clinical benefit with pembro in the phase II studies KEYNOTE (KN)164 ([NCT02460198] in 61 pts (cohort A) with MSI-H CRC) and KN158 ([NCT02628067] in19 pts with MSI-H non-CRC). Here, we report results of the antitumor activity of pembro in pts with MSI-H tumors from a pooled analysis of KN164 and KN158, with ≥18 mo of additional follow-up across 28 tumor types.

Methods

KN164 enrolled pts with MSI-H CRC (cohort A [≥2 prior], cohort B [≥1 prior therapy]), while KN158 included pts with MSI-H non-CRC (≥1 prior therapy). MSI-H status was determined locally by IHC or PCR or centrally by PCR. Eligible pts in both received pembro 200 mg Q3W. Tumor response was assessed every 9 wk. Primary endpoint was ORR by central review per RECIST v1.1. Data cutoff date was Sept 4, 2018 for KN164 and Dec 6, 2018 for KN158.

Results

At data cutoff, 357 pts (124 with MSI-H CRC, 233 with MSI-H non-CRC) were enrolled. Pts had median age of 59 years (range 20-87) and 350 (98%) had ≥1 prior therapy. Common MSI-H non-CRC tumor types included endometrial (n = 49), gastric (n = 24), cholangiocarcinoma (n = 22), pancreatic (n = 22), small intestinal (n = 19), ovarian (n = 15), brain (n = 13), sarcoma (n = 9), neuroendocrine (n = 7), cervical and prostate (n = 6) cancers. Median follow-up was 18.0 mo (range 0.1-35.6). Confirmed ORR was 34% (n = 121; 95% CI 29-39); 30 (8%) pts had CR. Median DOR was not reached (range 2.9 to 31.3+); 54% of pts had response duration ≥18 mo. Median OS was 27.8 months mo (95% CI 21.3 to not reached), with 2-year OS rate of 52%. Median PFS was 4.0 mo (95% CI 2.5-4.3) with 2-year PFS rate of 31%. Serious drug-related events occurred in 11 (9%) pts with MSI-H CRC and 18 (8%) pts with MSI-H non-CRC. The safety profile was consistent with that previously seen for pembro. A pooled safety analysis will be presented.

Conclusions

Pembro provides robust antitumor activity with durable responses and a manageable safety profile in pts with MSI-H cancers independent of tumor type.

Clinical trial identification

KN164 NCT02460198 KN158 NCT02628067.

Editorial acknowledgement

Luana Atherly-Henderson, Merck Sharp & Dohme, a subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck & Co., Inc.

Disclosure

L.A. Diaz: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck & Co., Inc.; Advisory / Consultancy: Caris; Advisory / Consultancy: Lyndra; Advisory / Consultancy: Genocea Biociences; Advisory / Consultancy: Illumina; Advisory / Consultancy: Cell Design Labs; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neophore; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: PGDx; Officer / Board of Directors: Jounce Therapeutics; Licensing / Royalties: Johns Hopkins; Licensing / Royalties: MSKCC; Spouse / Financial dependant: Amgen. D. Le: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck & Co., Inc.; Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Aduro Biotech. M. Maio: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: GSK; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: MedImmune. P.A. Ascierto: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution): Array; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Pierre Fabre, Incyte; Advisory / Consultancy: Genmab; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: MedImmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Syndax; Advisory / Consultancy: Sun Pharma; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Idera; Advisory / Consultancy: Ultimovacs; Advisory / Consultancy: Sandoz; Advisory / Consultancy: Immunocore; Advisory / Consultancy: 4SC. R. Geva: Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy, Educational grant to the research unit - Novartis: Novartis; Honoraria (institution), Travel / Accommodation / Expenses: BMS; Honoraria (institution): Lilly; Honoraria (institution): Medison; Honoraria (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution): Janssen; Honoraria (institution): Takeda; Honoraria (institution), Travel / Accommodation / Expenses: Merck & Co., Inc. D. Motola-Kuba: Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Asopharma; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD. T. André: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: HalioDx; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Servier. E. Van Cutsem: Advisory / Consultancy: Astellas; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Servier; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Ipsen. J. Delord: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis. D. Jäger: Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer. T.W. Kim: Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer. R. Guimbaud: Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: MSD; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Merck & Co., Inc.; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Novartis. T. Yoshino: Research grant / Funding (institution): Novartis K.K.; Research grant / Funding (institution): MSD K.K.; Research grant / Funding (institution): Sumitomo Dainippon Pharma ; Research grant / Funding (institution): Chungai Pharmaceutical; Research grant / Funding (institution): Sanofi K.K.; Research grant / Funding (institution): Daiichi Sankyo Company; Research grant / Funding (institution): PAREXEL International Inc; Research grant / Funding (institution): Ono Pharmaceutical Co. M. Chen: Full / Part-time employment: Merck & Co., Inc. K. Norwood: Full / Part-time employment: Merck & Co., Inc. P. Marinello: Full / Part-time employment: Merck & Co., Inc. A. Marabelle: Advisory / Consultancy: Merck Serono; Advisory / Consultancy: eTheRNA; Advisory / Consultancy: Lytix pharma; Advisory / Consultancy: Kyowa Kirin Pharma; Honoraria (institution), Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: BMS; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Genmab; Advisory / Consultancy: Amgen; Advisory / Consultancy: Biothera; Advisory / Consultancy: Nektar; Advisory / Consultancy: GSK; Advisory / Consultancy: Oncovir; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Flexus Bio; Advisory / Consultancy: Roche/Genentech; Honoraria (institution), Speaker Bureau / Expert testimony: Roche; Honoraria (institution): Pierre Fabre; Honoraria (institution): Onxeo; Honoraria (institution): EISAI; Honoraria (institution): Genticel; Honoraria (institution): Rigontec; Honoraria (institution): Daiichi Sankyo; Honoraria (institution): Imaxio; Honoraria (institution): Sanofi; Honoraria (institution): BioNTech. All other authors have declared no conflicts of interest.

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Proffered Paper 2 – Non-metastatic NSCLC and other thoracic malignancies (mesothelioma and thymic carcinoma) Proffered Paper session

1844O - Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma: Preliminary results from a multicenter phase II (REMORA) trial (ID 803)

Presentation Number
1844O
Lecture Time
11:18 - 11:30
Speakers
  • Shoichi Itoh (Hyogo, Japan)
Location
Pamplona Auditorium (Hall 2), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:15 - 11:45

Abstract

Background

Thymic carcinoma is a rare malignant disease. Standard treatments have not been established for patients with advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy. Several trials reported the efficacy of multi-targeted inhibitors mainly targeting vascular endothelial growth factor receptor (VEGFR) for thymic carcinoma. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, fibroblast growth factor receptor (FGFR), RET, c-Kit etc.; it has shown anti-tumor activity with manageable toxicity profiles in several cancer types. We investigated the efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma (JMA-IIA00285).

Methods

An open-label, single-arm, multi-center phase II trial was conducted in patients with histologically confirmed thymic carcinoma. The eligibility criteria were disease progression after at least one prior platinum-based chemotherapy, ECOG-PS of 0 or 1, measurable lesions, and adequate organ functions. Patients received 24 mg of lenvatinib orally once daily until progression or unacceptable toxicities. The primary endpoint was objective response rate (ORR) by independent radiological review. As per the SWOG two-stage design, the sample size of 40 had 80% power with one-sided alpha error of 5%; threshold ORR, 10%; and expected ORR, 25%.

Results

Between May 2017, and Feb 2018, 42 patients were enrolled from 8 institutions in Japan. The median follow-up period was 15.5 months (IQR 13.1-17.5). The 42 assessable patients had ORR of 38.1% (90%CI, 25.6-52.0), indicating statistically significant improvement in ORR. Of them, 16 had partial response, and 24 achieved stable disease. The most treatment-related adverse events of any grade were hypertension, diarrhea, and hand-foot syndrome, proteinuria, hypothyroidism, and decreased platelet count.

Conclusions

The efficacy and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These encouraging results suggest that lenvatinib could become one of the standard treatment options in patients with advanced or metastatic thymic carcinoma.

Clinical trial identification

JMA-IIA00285.

Legal entity responsible for the study

The authors.

Funding

Center for Clinical trials, Japan Medical Association and Eisai.

Disclosure

M. Satouchi: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Chugai; Honoraria (self): Taiho; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Ignyta. J. Sato: Speaker Bureau / Expert testimony: AstraZeneca K.K.. Y. Okuma: Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai Pharmaceutical; Research grant / Funding (self): Takeda Pharmaceutical Company Ltd; Speaker Bureau / Expert testimony: AstraZeneca K.K.; Speaker Bureau / Expert testimony: Nippon Boehringer Ingelheim Co.; Speaker Bureau / Expert testimony: Bristol‐Myers Squibb Japan; Speaker Bureau / Expert testimony: MSD K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical.. S. Niho: Research grant / Funding (self): Merck Serono; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Eli Lilly; Honoraria (self): Chugai; Honoraria (self): Taiho; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Shionogi. H. Mizugaki: Speaker Bureau / Expert testimony, Research grant / Funding (self): Boehringer Ingelheim; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Chugai Pharmaceutical. H. Murakami: Honoraria (self): AstraZeneca; Honoraria (self): Chugai pharma; Honoraria (self): Lilly Japan; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb Japan; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim. T. Kozuki: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai Pharmaceutical ; Honoraria (self), Research grant / Funding (self): Eli-Lilly; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical ; Honoraria (self): Ono Pharmaceutica; Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self): Beohringer-Ingelheim; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self): Pfizer; Research grant / Funding (self): Merck Biopharma. K. Nakamura: Speaker Bureau / Expert testimony: Eisai. A. Kuchiba: Speaker Bureau / Expert testimony: Chugai. N. Yamamoto: Research grant / Funding (self): Astellas; Speaker Bureau / Expert testimony, Research grant / Funding (self): Chugai; Advisory / Consultancy, Research grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Kyowa-Hakko Kirin; Advisory / Consultancy, Research grant / Funding (self): Takeda; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono; Research grant / Funding (self): Janssen Pharma; Research grant / Funding (self): MSD; Research grant / Funding (self): Merck; Advisory / Consultancy: Otsuka; Advisory / Consultancy: Cimic. All other authors have declared no conflicts of interest.

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Proffered Paper – Supportive and palliative care Proffered Paper session

1754O - Prediction of serious complications in patients with cancer and pulmonary embolism: Validation of the EPIPHANY index in a prospective cohort of patients from the PERSEO study (ID 824)

Presentation Number
1754O
Lecture Time
10:39 - 10:51
Speakers
  • Manuel Sanchez Canovas (Murcia, Spain)
Location
Valencia Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
10:15 - 11:45

Abstract

Background

The EPIPHANY decision tree is the first algorithm developed to predict serious complications in patients with cancer and pulmonary embolism (PE) (PMID: 28267709).

Methods

The objective is to evaluate the discriminatory ability of EPIPHANY in a prospective multicenter cohort. Patients with PE diagnosed by objective methods were recruited from October 2017 to April 2019. The association between the increase in prognostic category and in complications at 15 days was assessed using the linear by linear association test.

Results

The sample contains 463 patients with PE (39.7% suspected and 60.3% unsuspected). 68.3% (n = 316) showed clinical or haemodynamic instability, while 31.7% (n = 147) were normotensive PE with apparent clinical stability. The breakdown of initial risk criteria is: sudden or progressive dyspnea (58.7%), tachycardia >110 lpm (17.3%), hypotension <100 mmHg (9.9%), hypoxemia <90% (11%), elevated haemorrhagic risk (18.6%), tachypnea >30 rpm (3.2%), thrombopenia < 50000 (2.2%) and major bleeding (0.9%). Based on the entire decision tree, 21.8% were classified as low (n = 101), 22% as intermediate (n = 102), and 56.15% as high risk (n = 260). The serious complications rate at 15 days increased significantly throughout these prognostic categories: 3%, 5.9% and 26.5%, for low, intermediate and high-risk patients, respectively (p = 0.001). Serious complications occurred in 16.8% (n = 78) after a median of 5 days, being the most frequent: respiratory failure (56.4%), major bleeding (21.8%) and hypotension (20.5%). 28 patients died within the first 15 days post-PE, of which 2 belonged to the medium- and 26 to the high-risk group. The 3 main etiologies of exitus were: mixed origin (57.1%), complications of PE (32.1%) and progression of cancer (28.1%).

Conclusions

EPIPHANY is the only model available for the classification of patients with cancer and PE, based on their short-term risk of complications, with potential implications for decision making.

Legal entity responsible for the study

Asociación de Investigación de la Enfermedad Tromboembólica Venosa de la Región de Murcia.

Funding

Leo Academy.

Disclosure

M. Sanchez Canovas: Research grant / Funding (institution): Leo Pharma. All other authors have declared no conflicts of interest.

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Proffered Paper session - Basic Science Proffered Paper session

1O - Suppression of KRAS-G12D and BRAF-V600E oncogene transcription with PNA-conjugates (ID 861)

Presentation Number
1O
Lecture Time
16:30 - 16:42
Speakers
  • Jeffrey H. Rothman (New York, NY, United States of America)
Location
Valencia Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

We have developed a strategy to block transcription of oncogenes such as BRAF V600E and KRAS G12D directly using modified complementary peptide nucleic acid (PNA) oligomers that target oncogenesis specifically causing inhibition of tumour growth. This proof of principle strategy against BRAF V600E and KRAS G12D in vitro and in vivo should provide a new means to develop PNA-delivery peptide conjugates as targeted drug therapeutics across a broad range of oncogenes that drive cancer cell growth.

Methods

Obstruction of KRAS G12D and BRAF V600E expression was evaluated through suppression of cell proliferation and specific mRNA transcription. Tumour reduction was assessed through Xenograft mouse models.

Results

Exposure of KRAS G12D-dependent cell line to modified PNA-peptide conjugate complementary to KRAS G12D mutation sequence also results in concentration-dependent and time-dependent inhibition of cell growth and specific and complete suppression in mRNA transcription. Cell lines expressing KRAS WT and KRAS G12C, both differing by a single nucleobase, show no suppression. Exposure of the melanoma cell lines to a modified PNA-peptide conjugate complementary to BRAF V600E mutation sequence results in a concentration-dependent and time-dependent inhibition of cell growth that is specific for the BRAF V600E mutant melanoma cell lines with inhibition of mRNA and protein expression. Xenograft mouse trials show tumour growth delay and necrosis compared to PNA controls. This 50mg/kg dose was well tolerated without associated weight loss. By H&E staining, tumor tissue from trials shows ablation and extensive scaring upon exposure to BRAF V600E-complementary PNA-peptide conjugate whereas saline and scramble PNA sequence controls do not. Similarly quantitative measurement shows a 2.5-fold decrease in Ki67 and a 3-fold increase in TUNEL expression.

Conclusions

Our results indicate that these PNA-peptide derivatives could represent a novel and promising new therapy for patients with genes specific for and causative of tumorigenesis. This strategy could be applied to a multitude of cancers either with specific translocations or mutations differing from wild-type cells even by only a single base pair.

Legal entity responsible for the study

The authors.

Funding

Celgene, Fortress Biotech.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

393O - Is immuno-oncology therapy effective in hypermutator glioblastoma with somatic or germline mutations? (ID 1170)

Presentation Number
393O
Lecture Time
16:51 - 17:03
Speakers
  • Carlos Kamiya-Matsuoka (Houston, United States of America)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

Immuno-oncology (IO) is an effective strategy for the management of non-glioma tumors and it may be enhanced in hypermutators. Hypermutator glioblastoma (HmGB) is seen as initial tumor diagnosis or at recurrence after temozolomide (TMZ) treatment. We describe clinical and molecular features of HmGB treated with IO.

Methods

Retrospective review at MD Anderson between Feb, 2012 through Feb, 2017 identified 312 gliomas with tissue analyzed by next-generation sequencing (T200-1, Oncomine, FoundationOne). HmGB was defined as histologically proven GB with tumor mutational burden (TMB-30) of 30 or more mutations (mut) per Mb, or displaying mut in mismatch repair (MMR) or DNA polymerase (Pol) genes.

Results

30 (9.6%) patients had HmGB. From those, 9 (30%) received IO. 5 (55%) were men. Median age at HMGB diagnosis was 38 years (31-66). 7 (78%) had mut in MMR and 2 (22%) in Pol gene. 5 cases had IDH1 mut. 5 MGMT were umethylated. HmGB was found as initial diagnosis in 5 (56%) cases, the rest after TMZ. Of those patients with initial HmGB, 3 had MMR mut and 2 Pol mut. 8 had somatic mut and only 1 had germline MMR mut (Lynch Syndrome, MSH2, c.652C>T [p.Gln218*]). For post-treatment/recurrent HmGB, the most common alteration was MMR mut (N = 4). 8 HmGB patients received either CPI off protocol or cellular therapy (T-cells or NK cells) at recurrence of HmGB after TMZ, only 1 patient received CPI at initial HmGB diagnosis, concurrently with standard of care. In HmGB with somatic mut, OS from initial brain tumor and HmGB diagnosis was 39 and 22 months. PFS and 6m-PFS after starting IO was 72 days and 0% respectively. The PFS after TMZ, in those treated with CPI, reactive T-cells and natural killer cells was 51, 41 and 175 days, respectively, whereas the PFS in the one with newly diagnosed HmGB was 96 days. The median cumulative dose of pembrolizumab was 720 mg per patient. The patient with germline HmGB is on pembrolizumab and is the only one with stable disease for more than 12 months.

Conclusions

IO seems to be ineffective in HmGB with somatic mut regardless the onset of diagnosis (newly/recurrent) or type of Hm phenotype. However, germline HmGB may have durable responses to IO. Further investigation is needed to determine the potential antitumor immune response in this population.

Legal entity responsible for the study

The authors.

Funding

This work was supported in part by the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, and the MD Anderson Cancer Center Support grant (P30 CA016672) MD Anderson Cancer Center.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper session - Basic Science Proffered Paper session

3O - Systemic gut microbial metabolites limit the anti-tumour effect of CTLA-4 blockade in hosts with cancer (ID 1203)

Presentation Number
3O
Lecture Time
17:24 - 17:36
Speakers
  • Clelia Coutzac (Paris, France)
Location
Valencia Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Gut microbiota composition might influence the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remained unclear. Molecular mechanism whereby the gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. The main metabolites of the gut microbiota are short-chain fatty acids (SCFAs), which are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluated in mice and in patients treated with anti-CTLA-4 if SCFAs levels could be related to the clinical outcome.

Methods

Thirty-nine patients with metastatic melanoma were treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S metagenomic analysis and quantitative PCR (Q-PCR) analyses for Faecalibacterium prausnitzii (F. prausnitzii) at baseline. Stool and serum concentrations of acetate, propionate and butyrate were also evaluated in two independent cohorts in accordance with clinical outcomes. Peripheral blood lymphocytes immunophenotypes were studied in parallel. The anti-CTLA-4 anti-tumor effect was also evaluated in mice models in with or without butyrate supplementation.

Results

Systemic butyrate was linked to Faecalibacterium prausnitzii enrichment in the stool of patients. High blood SCFAs levels (mainly propionate or butyrate) were associated with resistance to CTLA-4 blockade and were associated with a rise of Treg cells. During the course of anti-CTLA-4 treatment, butyrate limited the up-regulation of CD80/CD86 expression on dendritic cells, the induction of tumor-specific T cells and the accumulation of memory T cells in mice with cancer. In patients, restricted accumulation of memory T cells and IL-2 impregnation after ipilimumab treatment was observed.

Conclusions

Altogether, these results suggested that gut microbial metabolites might favor an immune tolerance profile that limits anti-CTLA-4 activity.

Legal entity responsible for the study

Institut Gustave Roussy.

Funding

This study was funded by Gustave Roussy Cancer Campus, Fondation Gustave Roussy, the Institut national de la santé et de la recherche médicale (INSERM), the Centre national de la recherche scientifique (CNRS), SIRIC SOCRATE (INCa DGOS INSERM 6043), SIRIC SOCRATE 2.0 (INCa-DGOS-INSERM_12551), MMO program: ANR-10IBHU-0001); Direction General de l’Offre de Soins (DGOS; TRANSLA 12-174); Institut National du Cancer (INCa; 2012-062 N_ Canceropole: 2012-1-RT-14-IGR-01). Dr. Clélia Coutzac was supported by fellowships from Fondation pour la Recherche Medicale (FRM) from 2015 to 2016.

Disclosure

C. Coutzac: Honoraria (self): AMGEN; Honoraria (self): Servier. L. Lacroix: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy: BMS; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: Illumina; Advisory/Consultancy: Qiagen; Advisory/Consultancy: Novartis Thermofisher; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Dyn; Speaker Bureau/Expert testimony: Vela diagnostics; Speaker Bureau/Expert testimony: Luye Pharma. F. Carbonnel: Advisory/Consultancy: enterome; Advisory/Consultancy: Amgen; Advisory/Consultancy: Astra; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Janssen; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Mayoly Spindler; Advisory/Consultancy: Takeda; Advisory/Consultancy: Pileje; Advisory/Consultancy: Roche. P.A. Ascierto: Advisory/Consultancy: Bristol Myers-Squibb; Advisory/Consultancy, Research grant/Funding (self): Roche-Genentech; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy, Research grant/Funding (self): Array; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy: Incyte; Advisory/Consultancy: NewLink Genetics; Advisory/Consultancy: Genmab; Advisory/Consultancy: Medimmune; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Syndax; Advisory/Consultancy: SunPharma; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Idera. C. Robert: Advisory/Consultancy: Roche; Advisory/Consultancy: GSK; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS. N. Chaput: Research grant/Funding (self): Cytune Pharma; Research grant/Funding (self): GSK; Speaker Bureau/Expert testimony, Research grant/Funding (self): Sanofi; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca. All other authors have declared no conflicts of interest.

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Proffered Paper 2 – Non-metastatic NSCLC and other thoracic malignancies (mesothelioma and thymic carcinoma) Proffered Paper session

1843O - SAKK 17/16 - Lurbinectedin as second or third line palliative chemotherapy in malignant pleural mesothelioma (MPM): A multi-center, single-arm phase II trial (ID 1316)

Presentation Number
1843O
Lecture Time
11:06 - 11:18
Speakers
  • Yannis Metaxas (Chur, Switzerland)
Location
Pamplona Auditorium (Hall 2), Fira Gran Via, Barcelona, Spain
Date
30.09.2019
Time
10:15 - 11:45

Abstract

Background

Available systemic 2nd or 3rd line options for MPM show a median progression-free survival (mPFS) of less than 2 months (mo) and median overall-survival (mOS) of 6-9 mo. Lurbinectedin (PharmaMar) is a novel compound with a dual role of binding to the DNA minor groove and inhibiting cytokine transcription of tumor-associated macrophages. Single MPM pts treated with lurbinectedin in early clinical trials showed encouraging outcome. The aim of current trial was to provide further data on safety and efficacy of lurbinectedin in progressive MPM.

Methods

MPM pts (all histologies) not amenable for local treatment and progressing after first-line platinum-pemetrexed chemotherapy +/- immunotherapy (IO) received 2nd or respectively 3rd line lurbinectedin. Lurbinectedin 3.2 mg/m2 every 3 weeks was given i.v. until progression or unacceptable toxicity. Primary endpoint was PFS at 12 weeks (PFS12wks) and would be met if achieved by at least 21 pts (p0 ≤ 35%; mPFS 2 mo). Secondary endpoints were mPFS, mOS and adverse events (AEs).

Results

6 Swiss and 3 Italian centers recruited 42 pts (33 epithelioid, 4 biphasic, 5 sarcomatoid). 10/42 (23.8%) pts also received prior IO. At cut-off date (31st January 2019) PFS12wks was met by 22/42 pts (52.4%; 95%CI [38.7%; 63.5%]; p = 0.015) for mPFS of 4.1mo (95% CI [2.6; 5.5]) and mOS of 11.9mo (95% CI [9.2; 14.7]). 1 pt had complete, 1 pt partial response and 20 pts stable disease as best response. No significant difference in PFS12wks, mPFS and mOS was observed in epithelioid vs non-epithelioid MPM and prior-IO vs non-prior IO pts. All pts experienced AEs. Grade 3-4 toxicity was seen in 33 pts with most common being leuco-/lymphopenia (60.6%) and fatigue (24.2%). Febrile neutropenia was 9.1%. No pt discontinued treatment due to toxicity.

Conclusions

The primary efficacy endpoint was reached with acceptable toxicity. Lurbinectedin showed promising activity compared to historical data. Neither histology nor prior IO seems to affect efficacy of lurbinectedin, but respective pts numbers are small for definitive conclusions. Further evaluation of lurbinectedin in a large randomized trial is warranted.

Clinical trial identification

NCT03213301.

Legal entity responsible for the study

Swiss Group for Clinical Cancer Research.

Funding

PharmaMar; State Secretariat for Education, Research and Innovation (SERI).

Disclosure

Y. Metaxas: Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: PharmaMar; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyer Squibb; Honoraria (institution), Advisory / Consultancy: MSD; Research grant / Funding (institution): Krebsliga Graubünden; Research grant / Funding (institution): Suva Switzerland. M. Frueh: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Takeda. F. Grosso: Travel / Accommodation / Expenses: Novocure; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Boehringer Ingelheim; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Bristol-Meyer Squibb; Travel / Accommodation / Expenses: Amianto-Italia-Canada-Asbestos Committee; Honoraria (self): Merck; Honoraria (self): Italian Centro per la Prevenzione e Controllo delle Malattie; Research grant / Funding (self): Associazione Famigliari e Vittime Amianto. P.A. Zucali: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Pfizer; Honoraria (self): Ipsen; Honoraria (self): Tesaro. G.L. Ceresoli: Honoraria (self), Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self): Astellas; Honoraria (self): Pfizer; Travel / Accommodation / Expenses: Novocure. M.T. Mark: Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution), Advisory / Consultancy: Boehringer; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: Takeda. M.R.A. Perrino: Honoraria (self): Astellas; Honoraria (self): Bristol Meyer Squibb; Honoraria (self): Novartis. S. Schmidt: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Takeda. R. von Moos: Honoraria (institution), Advisory / Consultancy: Amgen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Elly Lilly; Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: Sanofi Aventis; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Bristol-Meyers ; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Vifor. All other authors have declared no conflicts of interest.

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Proffered Paper – Developmental therapeutics Proffered Paper session

440O - Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours (ID 1621)

Presentation Number
440O
Lecture Time
16:54 - 17:06
Speakers
  • Aung Naing (Houston, TX, United States of America)
Location
Malaga Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
29.09.2019
Time
16:30 - 18:00

Abstract

Background

Arginase (Arg), an enzyme secreted by myeloid-derived suppressor cells and neutrophils in the tumor milieu, suppresses T-cell activity via arginine depletion. This phase 1 study is evaluating 1158, an oral small molecule Arg inhibitor, as monotherapy (MT) and in combination (CT) w/ the PD-1 inhibitor PEM in checkpoint inhibitor (CPI) refractory and naïve adv/met solid tumors.

Methods

Dose escalation of 1158 MT and CT w/ PEM (200 mg Q3W) was followed by tumor expansion cohorts to evaluate safety/activity at the recommended phase 2 dose (RP2D) using a Simon 2 Stage design. Primary objective is safety/tolerability. Data cutoff: April 23, 2019.

Results

73 pts were enrolled in MT/CT dose escalation, 68 across 3 MT expansion cohorts (colorectal carcinoma [CRC], non-small cell lung cancer, basket) and 94 to date across 8 CT expansion cohorts (4 CPI refractory, 4 CPI naïve). Median age was 63 yrs (32-92), w/ median 3 prior therapies (1-11). No maximum tolerated dose of 1158 was reached up to 150 mg BID; RP2D was 100 mg BID. Plasma arginase inhibition was seen at all doses as were dose-related elevations in plasma arginine. Clinically significant urea cycle inhibition (on-target toxicity), defined as concomitant rise in urine orotic acid and plasma ammonia, was not seen. Immune-related adverse events (irAEs) in MT were G3 colitis and G2 malaise (1 each). Overall frequency/severity of irAEs for CT was similar to PEM MT. AEs were generally manageable and reversible. CRC expansion cohorts are most mature; MT CRC and CT MSS CRC cohorts met response criteria to advance to Simon Stage 2. Partial responses were seen in efficacy evaluable MSS CRC pts in MT and CT with overall response (ORR)/disease control rate (ORR + stable disease) of 3%/28% (n = 32) and 6%/37% (n = 35), respectively. Other expansion cohorts are ongoing in Stage 1.

Conclusions

Early data indicate that 1158 MT and CT w/ PEM was well tolerated and showed responses as MT and CT in pretreated MSS CRC pts. Updated safety and efficacy data will be presented.

Clinical trial identification

NCT02903914 Posted to clinicaltrials.gov: September 16, 2016.

Editorial acknowledgement

Medical writing support was provided by Ingrid Koo, PhD, and funded by Calithera Biosciences and Incyte Corporation.

Legal entity responsible for the study

Calithera Biosciences, Inc., and Incyte Corp.

Funding

Calithera Biosciences, Inc., and Incyte Corp.

Disclosure

A. Naing: Research grant / Funding (institution): NCI; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Healios Onc. Nutrition; Research grant / Funding (institution): Atterocor; Research grant / Funding (institution): Amplimmune; Research grant / Funding (institution), Travel / Accommodation / Expenses: ARMO Biosciences; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Incyte; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): CytomX Therapeutics; Research grant / Funding (institution): Neon Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): TopAlliance Bioscences; Research grant / Funding (institution): Kymab, PsiOxus; Spouse / Financial dependant: Immune Deficiency Foundation. T. Bauer: Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Leap Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy, Research grant / Funding (institution): Moderna; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Phosplatin Therapeutics; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Koltan Pharmaceuticals; Research grant / Funding (institution): Principa Biopharma; Research grant / Funding (institution): Peleton; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Alleron Therapeutics; Research grant / Funding (institution): Bristol-Meyer Squibb; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance Bioscience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, ARMO Biosciences. K.P. Papadopoulos: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): ArQule; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Calithera Biosciences; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Peloton Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): 3D Medicines; Research grant / Funding (institution): Formation Biologics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Syros Pharmaceuticals; Research grant / Funding (institution): Mersana, OncoMed, MabSpace Biosciences, Jounce Therapeutics. O. Rahma: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck; Advisory / Consultancy: Celgene; Advisory / Consultancy: Five Prime; Advisory / Consultancy: GFK; Advisory / Consultancy: Defined Health INC; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Puretech; Advisory / Consultancy: Leerink; Advisory / Consultancy: PRMA Consulting; Licensing / Royalties, Patent pending: Methods of using Pembrolizumab and trebananib: Patent; Speaker Bureau / Expert testimony: BMS. F. Tsai: Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals; Advisory / Consultancy: Tempus Lab; Licensing / Royalties: Caremission LLC. E. Garralda: Advisory / Consultancy, Research grant / Funding (institution): F. Hoffmann-La Roche; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: Neomed Therapeutics1 Inc; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services; Speaker Bureau / Expert testimony: Bristol-Meyers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck Sharp & Dohme; Research grant / Funding (institution), Travel / Accommodation / Expenses: Glycotope; Travel / Accommodation / Expenses: Menarini; Research grant / Funding (self), Scitron Project - VHI&Oacute;S Technology Platform to study tumor clonal evolution and Resistance to Immune and Targeted Therapies.: Novartis; Research grant / Funding (institution): Principia Biopharma Inc; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Genentech, Inc; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Symphogen A/S; Research grant / Funding (institution): Incyte Biosciences International, Pharma Mar S.A.U., Kura Oncology Inc, Macrogenics Inc, Pierre Fabre Medicameng, Cellestia Biotech, Menarini Ricerche Spa, Blueprint Medicines Corporation, Beigene USA Inc, Sierra Oncology Inc, Genmab B.V.; Non-remunerated activity/ies, ImCORE Translational Committee Member since 2017: Roche/Genentech; Non-remunerated activity/ies: ESMO, SEOM, AACR, ASCO, Cancer Core Europe; Leadership role: ESMO Women For Oncology - W40. J. Naidoo: Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Roche/Genentech; Research grant / Funding (institution): Merck. M.K. Gibson: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Non-remunerated activity/ies, Author: NCCN. I. Rybkin: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ARMO Biosciences; Research grant / Funding (institution): Beyond Spring Pharmaceutical; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Mirati Therapeutical Inc.; Research grant / Funding (institution): Nilogen, Inc.; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Polaris Group; Research grant / Funding (institution): Syndax Inc.; Research grant / Funding (institution): Xcovery Inc.; Research grant / Funding (institution): BerGenBio AS; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Amgen. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Advisory / Consultancy: Array BioPharm; Advisory / Consultancy, Research grant / Funding (institution): Genentech BioOncology; Advisory / Consultancy, Research grant / Funding (institution): Alkermes, Inc.; Advisory / Consultancy: Jounce Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): X4 Pharma; Advisory / Consultancy, Research grant / Funding (institution): Peloton Therapeutics; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Eli Lilly and Company; Research grant / Funding (institution): Prometheus Laboratories. M. de Miguel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Incyte/INC Research; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Menarini; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmamar; Research grant / Funding (institution): Roche. Y. Jenkins: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences; Spouse / Financial dependant: Second Genome. H. Kallender: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. S. Gogov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Incyte Corporation. E. Kuriakose: Shareholder / Stockholder / Stock options, Full / Part-time employment: Calithera Biosciences, Inc. M. Pishvaian: Speaker Bureau / Expert testimony: Sirtex; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Celgene; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Rafael; Advisory / Consultancy, Research grant / Funding (institution): ARMO; Advisory / Consultancy: Eisai; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Merrimack; Shareholder / Stockholder / Stock options: Perthera; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic, Novartis, Pfizer, BMS, Abbvie, Halozyme, Karyopharm, Bayer, Regeneron, Curegenix, Calithera, Pharmacyclics. All other authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

390O - Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study (ID 1638)

Presentation Number
390O
Lecture Time
16:00 - 16:12
Speakers
  • Fabrice Barlesi (Marseille, CEDEX 20, France)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

LM are seen in approximately 5% of ALK+ NSCLC patients (pts), and are associated with poor prognosis with standard treatment. Ceritinib is highly active in ALK+ NSCLC pts with previously reported intracranial/central nervous system activity. We report the efficacy and safety of ceritinib in ALK+ NSCLC pts with LM enrolled in the ASCEND-7 study (NCT02336451).

Methods

Pts with documented ALK + (FISH) NSCLC, CSF invasiveness with radiologically or cytologically confirmed LM, and ≥1 extracranial measurable lesion using RECIST v1.1 were eligible. The study objectives included evaluation of antitumor activity based on overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Data cut-off was Feb 6, 2019.

Results

Of the 18 LM pts enrolled, 14 pts (77.8%) also had brain metastases and 8 pts (44.4%) had measurable brain metastases at baseline. Majority of the pts (n = 16, 88.9%) had received prior crizotinib and 7 pts (38.9%) had received prior brain radiotherapy. Median duration of exposure to ceritinib was 18.1 weeks (range: 1.7–125.9). Whole body ORR by investigator assessment was 16.7% (95% CI: 3.6, 41.4) with median duration of response of 5.5 months (95% CI: 3.7, 9.9) and a clinically significant median PFS of 5.2 months (95% CI: 1.6, 7.2). Median duration of follow-up for PFS was 3.84 months (range: 0.5–13). Additional efficacy endpoints are included in the below Table. Adverse events (AEs, all grades, regardless of study drug relationship) were reported in all 18 pts. Grade 3/4 AEs occurring in ≥ 10% of pts were increased alanine aminotransferase (22.2%), hyperglycemia (16.7%), increased gammaglutamyltransferase (11.1%), pneumonia (11.1%), and increased lipase (11.1%). Table: Efficacy results

Endpoint per investigator assessmentArm 5 (ALK+ NSCLC pts with LM) N = 18
Whole body Response (RECIST v1.1)
ORR, % (95% CI)16.7 (3.6, 41.4)
DCR, % (95% CI)66.7 (41.0, 86.7)
Median DOR, (months) [95% CI]5.5 (3.7, 9.9)
Median PFS, (months) [95% CI]5.2 (1.6, 7.2)
Intracranial response* (modified RECIST v1.1)M = 8
ORR, % (95% CI)12.5 (0.3, 52.7)
DCR, % (95% CI)62.5 (24.5, 91.5)
Extracranial response (RECIST v1.1)
ORR, % (95% CI)22.2 (6.4, 47.6)
DCR, % (95% CI)72.2 (46.5, 90.3)
Median OS, months (95% CI)7.2 (1.6, 16.9)

In patients with measurable brain metastases M, number of patients with measurable brain metastases at baseline DCR, disease control rate; DOR, duration of response; NE, not estimable; ORR, overall response rate; OS, overall survival; PFS, progression free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

Conclusions

Ceritinib demonstrated a clinically meaningful efficacy and a safety profile similar to earlier reported results in this largest reported set of ALK+ NSCLC pts with LM.

Clinical trial identification

NCT02336451.

Editorial acknowledgement

Aarti Kamaraj, Novartis Healthcare Pvt Ltd (Hyderabad, India).

Legal entity responsible for the study

Novartis Pharmaceuticals.

Funding

Novartis Pharmaceuticals.

Disclosure

F. Barlesi: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology; Honoraria (self): F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): Abbvie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies, Principal investigator: AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR); Research grant / Funding (institution): Takeda. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/Medimmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. E.M. Bertino: Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. M.J. van den Bent: Honoraria (self): Celgene, Agios, Boehringer, BMS, Abbvie; Research grant / Funding (institution): Abbvie. H. Wakelee: Honoraria (self): Novartis, AZ; Advisory / Consultancy, Compensated: AstraZeneca, Xcovery, Janssen; Advisory / Consultancy, Not compensated: Merck, Takeda, Genentech/Roche; Research grant / Funding (institution): ACEA Biosciences, Arrys Therapeutics, AstraZeneca/Medimmune, Bayer (under Suki and not me), BMS, Celgene, Clovis Oncology, Exelixis,, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, Xcovery; Travel / Accommodation / Expenses: AstraZeneca; Officer / Board of Directors: International Association for the Study of Lung Cancer (IASLC). P.Y. Wen: Advisory / Consultancy: Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines, Tocagen; Speaker Bureau / Expert testimony: Merck, Prime Oncology; Research grant / Funding (institution): Agios, AstraZeneca, Beigene, Eli Lily, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. P. Garrido Lopez: Advisory / Consultancy: Roche, MSD, BMS, Boerhinger Ingelheim, Pfizer, Abbvie, Guardant Health, Novartis, Lilly, AstraZeneca, Jansen, Sysmex, Blueprint Medicines, Takeda; Speaker Bureau / Expert testimony: Roche, MSD, BMS, Pfizer, Novartis, Boerhinger Ingelheim, Rovi; Research grant / Funding (institution), Financial support for clinical trials: Roche, MSD, BMS, Takeda, Lilly, Pfizer, Novartis, Pharmamar, Celgene, Sanofi, GSK, Theradex Oncology, BluePrint Medicines; Research grant / Funding (institution), Financial support for contracted research: Guardant Health, Sysmex. M. Majem: Advisory / Consultancy: Roche, MSD, AstraZeneca, Boehringer, Tesaro, Takeda, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, BMS, MSD, AstraZeneca, Boehringer, Hellsin, Pierre Fabre, Amgen; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: BMS, MSD, AstraZeneca, Lilly. M. McKeage: Advisory / Consultancy: Novartis, Pfizer; Research grant / Funding (institution): Novartis, Pfizer, Roche. C. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer-Ingelheim. F.K. Hurtado: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corp.; Full / Part-time employment: Novartis Pharmaceuticals Corp. P. Cazorla Arratia: Shareholder / Stockholder / Stock options: Novartis Pharmaceuticals Corporation; Full / Part-time employment: Novartis Pharmaceuticals Corporation. Y. Song: Shareholder / Stockholder / Stock options, Restricted Stock Unit: Novartis Pharmaceutical Corporation; Full / Part-time employment: Novartis Pharmaceutical Corporation. F. Branle: Shareholder / Stockholder / Stock options: Novartis AG; Full / Part-time employment: Novartis AG. M. Shi: Shareholder / Stockholder / Stock options: Novartis; Full / Part-time employment: Novartis Pharmaceuticals Corporation. L.Q. Chow: Advisory / Consultancy: Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc., Alkermes, Amgen, Sanofi-Genzyme, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Merck, Genentech, AstraZeneca/Medimmune, Pfizer, Seattle Genetics, Novartis, Dynavax Inc. and Alkermes,Incyte, VentiRx and Lily/Imclone. All other authors have declared no conflicts of interest.

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Proffered Paper – CNS tumours Proffered Paper session

394O - Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients (ID 1688)

Presentation Number
394O
Lecture Time
17:03 - 17:15
Speakers
  • Giuseppe Lombardi (Padova, Italy)
  • Mario Caccese (Padova, Italy)
Location
Bilbao Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
27.09.2019
Time
16:00 - 17:30

Abstract

Background

REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in patients (pts) with relapsed GBM with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point.

Methods

HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided).

Results

Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM).

No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The rate of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.02).

Conclusions

In the REGOMA trial, HRQoL did not change during regorafenib treatment. Pts treated with regorafenib and lomustine reported no significant difference in HRQoL.

Legal entity responsible for the study

Giuseppe Lombardi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper – Translational research Proffered Paper session

1873O - PARP inhibition increases immune infiltration in homologous recombination repair (HRR)-deficient tumors (ID 1691)

Presentation Number
1873O
Lecture Time
08:45 - 09:00
Speakers
  • Benedetta Pellegrino (Parma, Italy)
Location
Pamplona Auditorium (Hall 2), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
08:30 - 10:00

Abstract

Background

HRR-deficient tumors are sensitive to PARP inhibitors (PARPi) and exhibit high levels of cytosolic DNA that can result in the activation of the STING pathway as well as upregulation of PD-L1. We aimed to address such controversy by studying whether PARPi-induces PD-L1 upregulation and limits PARPi efficacy, and if this is counteracted by anti-PD-L1 treatment.

Methods

25 Patient-Derived breast cancer (BrC) (19 BRCA1/2-mutated and 2 PALB2-mutated) and 3 ovarian cancer (OvC) Xenoimplant (PDXs) models grown in NMRI-Foxn1nu/nu exclusively lacking T cells were generated, exome sequenced and tested for the PARPi olaparib antitumor response, which were categorized according to the modified RECIST criteria as Complete or Partial Response (CR/PR), Stable or Progressive Disease (SD/PD). We also used the Brca1f22 − 24 transgenic mouse model (Tg). We quantified cells expressing CD45 (leukocytes), CD56 (NK cells), CD11b (myeloid cells) and CD3 (T cells) by IHC in PDXs and Tg. We analyzed PD-L1 expression by IHC in PDXs and by flow cytometry in Tg.

Results

BrC and OvC PDXs show distinct PARPi olaparib sensitivity (n = 5 CR, n = 3 PR, n = 3 SD and n = 17 PD) that fully correlates with the HRR-status, as measured by RAD51 foci. In PARPi-sensitive tumors (CR+PR), olaparib treatment significantly increases infiltration of stromal non-NK/non-myeloid-CD45+ immune cells. In contrast, in non-responders there is a recruitment of peritumoral non-NK/non-myeloid-CD45+ immune cells. PD-L1 is expressed in 40% PARPi non-responding models and it is not upregulated upon PARPi treatment (threshold 1%). Olaparib treatment in BRCA1-mutated Tg mice significantly increases infiltration of intratumoral CD3+ immune cells and stromal myeloid cells. PD-L1 in Tg tumor cells is maintained upon PARPi albeit it is expressed in intratumoral CD3+ cells.

Conclusions

In experimental models, olaparib elicits an antitumor immune response in PARPi-sensitive tumors. The expression of PD-L1 in tumors with poor responses to PARPi and in intratumoral lymphocytes suggests the combined use with anti-PD-L1 therapy. We are currently testing the combination of olaparib with anti-PDL1, and efficacy results will be presented at the meeting.

Legal entity responsible for the study

Vall d’Hebron Institute of Oncology.

Funding

AstraZeneca.

Disclosure

A. Musolino: Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (self): Macrogenics; Travel / Accommodation / Expenses: Eisai. J. Balmana: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Clovis; Advisory / Consultancy: BMS; Advisory / Consultancy: Tesaro; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar. M.J. O’Connor: Full / Part-time employment: AstraZeneca. V. Serra Elizalde: Research grant / Funding (self): AstraZeneca. All other authors have declared no conflicts of interest.

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Proffered Paper – Developmental therapeutics Proffered Paper session

441O - A platform trial with a registry study for rare cancers: MASTER KEY project (ID 1777)

Presentation Number
441O
Lecture Time
17:21 - 17:33
Speakers
  • Shoko N. Narita (Tokyo, Japan)
Location
Malaga Auditorium (Hall 5), Fira Gran Via, Barcelona, Spain
Date
29.09.2019
Time
16:30 - 18:00

Abstract

Background

Rare cancers have had a challenge in establishing standard therapies for patients compared to major cancers, due to the lack of basis for clinical studies and investigations. We started a biomarker driven basket/umbrella trial using a “master protocol”, called the MASTER KEY Project, which aims to find more efficient ways to evaluate treatments for rare cancers.

Methods

The project opened in April 2017 and consists of a prospective registry study part and a multiple clinical trials part. Patients with advanced rare cancers (annual incidence <6 / 100,000 population)/cancers of unknown primary/rare tissue subtypes of common cancers, undergoing a molecular diagnostic testing are enrolled. The primary objective of the registry study is to collect consecutive data on biomarker, patient background, and prognosis to build a database highly reliable for use as historical control data in future clinical trials. Sub-studies are placed under a “master protocol”, and each sub-study will enroll patients with the appropriate biomarker, regardless of tumor type.

Results

As of Feb. 2019, 515 patients were enrolled in the project, and 493 were available for their backgrounds. Most frequent cancer types were: soft tissue sarcomas (33.7%), neuroendocrine tumors (7.3%), tumors of CNS (5.9%), salivary gland tumors (4.5%), etc. 346 patients had next generation sequencing testing results. The most common alterations were TP53 (32.4%), KRAS (10.4%), PIK3CA (9.5%), MDM2 (5.2%), CDK42 (4.9%), CDKN2A (4.9%), and RB1 (4.9%). 278 patients already had 6 months follow-up, and 116 patients received 181 systemic chemotherapy regimens after enrollment. Of those regimens, 25 were biomarker-based therapies, and median progression free survival was 8.1 months compared to 4.8 months with other cytotoxic chemotherapy regimens (Hazard ratio 0.61; 95% confidential interval 0.32-1.07).

Conclusions

MASTER KEY Project is one of the largest platform trials focused only on rare cancers. The project provided the chance for rare cancer patients to receive biomarker-based treatment, and it showed better prognosis. This is a continuous project aimed to accelerate treatment development for rare cancers, with clinical trials directed towards new drug approvals.

Clinical trial identification

UMIN000027552.

Legal entity responsible for the study

The authors.

Funding

Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Kyorin Pharmaceutical, Novartis Parma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Taiho Pharmaceutical and Takeda Pharmaceutical.

Disclosure

All authors have declared no conflicts of interest.

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