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Marjorie Zauderer
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MA12 - New Frontiers from Pathology to Genomics (ID 138)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
- Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)
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MA12.10 - Novel Germline Mutations in DNA-Damage Repair and DNA Replication Identified in Patients with Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 1419)
14:00 - 15:30 | Author(s): Marjorie Zauderer
- Abstract
- Presentation
Background
Recent efforts to characterize the germline genetic landscape of MPM have uncovered a surprising prevalence of pathogenic variants in DNA-damage sensing and repair genes. Increasingly, next-generation sequencing has helped bring new insight into critical mutations or pathways involved in the development of MPM. Additionally, observations from these studies could direct new screening, prevention, and therapeutic approaches for patients and families.
Method
With IRB approval, we performed deidentified analysis on 87 additional cancer-predisposing genes on our NGS platform among patients with MPM previously consented to a BAP1 germline testing protocol. Additionally, germline variants in an additional 380 genes associated with somatic alterations in cancer, but not associated with hereditary cancer predisposition, were screened for loss of function variant or pathogenic entries in ClinVar. All variants were reviewed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus guidelines. Founder mutations were excluded. Clinicopathologic information was also collected. Comparisons were done using Fisher’s exact test. P values <0.05 were considered significant.
Result
Of 88 patients with MPM analyzed, 11% (10/88) had pathogenic variants. Clinical characteristics such as age, sex, histology, and self-reported asbestos exposure, were similar between patients with and without pathogenic variants (Table 1). Pathogenic variants previously unreported in mesothelioma were identified: MSH3 1/88 (1%; 95% CI: 0-7%), BARD1 1/88 (1%; 95% CI: 0-7%), and RECQL4 2/88 (2%; 95% CI: 0-8%). We also identified pathogenic variants previously associated with mesothelioma: BAP1 in 3/88 (3%; 95% CI: 1-10%), BRCA2 1/88 (1%; 95% CI: 0-7%), and MRE11A 1/88 (1%; 95% CI: 0-7%). One patient had a potentially pathogenic alteration in SHQ1, which has not been associated with a heightened susceptibility to cancer. Patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer compared to those without germline mutations (40% vs 13%; p = 0.049).
Conclusion
While the overall incidence of germline mutations identified is similar to prior reports, we identified germline pathogenic alterations in three DNA damage repair and replication genes not previously reported in mesothelioma. Furthermore, we describe a novel germline alteration in SHQ1, which has not been reported with hereditary cancer predisposition. Whether these variants increase the risk of mesothelioma is still under investigation, but given the high rate of germline pathogenic variant in individuals with pleural mesothelioma, germline testing for hereditary cancer susceptibility should be considered in all patients with MPM.
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MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Ramon Palmero Sánchez, Raphael Bueno
- Coordinates: 9/10/2019, 14:30 - 16:00, Copenhagen (1980)
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MA23.05 - A Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 943)
14:30 - 16:00 | Author(s): Marjorie Zauderer
- Abstract
- Presentation
Background
Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGF, FGF, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy.
Method
Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and >4 pts had to have a PFS of ≥4 months to proceed to the second stage.
Result
Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS=1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea.
Conclusion
Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for >4 months thus potentially deriving some clinical benefit from treatment.
Supported by Boehringer Ingelheim.
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-07 - Phase 1 Study of CA-170: First-in-Class Small Molecule Targeting VISTA/PD-L1 in Patients with Malignant Pleural Mesothelioma (ID 2341)
10:15 - 18:15 | Presenting Author(s): Marjorie Zauderer
- Abstract
Background
In contrast to PD-L1, VISTA is expressed in up to 90% of malignant pleural mesothelioma (MPM) patients with strong expression on infiltrating lymphocytes and on mesothelioma cells. Recent work also found that expression of VISTA in epithelioid MPM is strikingly higher than in other solid tumors. PD-1 and PD-L1 immune checkpoint inhibitors (ICI) have shown modest activity in ≥2nd line MPM which has fueled interest in novel targets, such as VISTA. Many genes associated with VISTA signaling are proliferative and may help drive cancer, providing strong rationale for inhibitors blocking VISTA. VISTA and PD-1 are independent immune checkpoints negatively regulating T-cell function. VISTA is expressed on immune and tumor cells and implicated in resistance to ICI. Preclinical studies show that dual blockade of VISTA and PD-L1 can be synergistic. CA-170, a small molecule inhibitor of VISTA and PD-L1, has demonstrated anti-tumor activity in multiple in vivo models including syngeneic models that do not respond to anti-PD-1 treatment. Phase 1/2 trialsof CA-170 monotherapy showed that CA-170 has a favorable safety profile with preliminary signs of anti-tumor activity in PD-1 malignancies. Pharmacological activity, as measured by immune-modulating effects, was observed across a wide dose range. Development of CA-170 is on-going with evaluation of BID doses in VISTA expressing tumors, such as MPM.
Method
CA-170-101 is a Phase 1 dose finding study in advanced solid tumors and lymphomas. Selected dose levels can be expanded with additional patients in tumor types of interest. Two pharmacologically active doses, 200 and 1200 mg BID, were selected to further expand with MPM patients to better understand CA-170 activity in this high VISTA-expressing tumor type. As of April 2019, 12 patients with MPM have been enrolled; 8 have completed the 21-day safety evaluation period without DLT. Objectives: tolerability and RP2D (primary), anti-tumor activity (PFS and ORR, secondary) and exploratory biomarkers and PD effects. Key eligibility: histologically confirmed epithelioid, ≥1 prior therapy including pemetrexed-platinum doublet, no prior ICI, measurable disease, paired tumor biopsies if medically feasible, ECOG 0-1, life expectancy >3 months, and adequate organ function. Clinical trial: NCT02812875.
Result
Section not applicable
Conclusion
Section not applicable
