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Sandip Pravin Patel
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-57 - Post-Ensartinib Outcomes in Refractory Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC) (ID 2800)
09:45 - 18:00 | Presenting Author(s): Sandip Pravin Patel
- Abstract
Background
The effectiveness of the next-generation ALK inhibitor, ensartinib, in refractory ALK-rearranged, advanced NSCLC patients represents a promising therapeutic option. With the advent of novel ALK inhibitors utilized in sequence, the survival of patients with ALK-rearranged tumors has improved dramatically. This case series serves to compare tumor response rates and long-term survival outcomes among four patients treated with ensartinib over the course of four years at our institution.
Method
We conducted an open-label, first-in-human, IRB approved phase 2 clinical trial using single-agent ensartinib at a dose of 225 mg once daily. Patients were selected from UC San Diego Moores Cancer Center with ALK-rearranged NSCLC who had previously progressed on crizotinib. Other prior therapies included platinum/pemetrexed chemotherapy (n=3) and pembrolizumab (n=1). Objective response was determined every eight weeks according to RECIST 1.1. Patients were treated until disease progression or unacceptable toxicity. Circulating tumor DNA (ctDNA) sequencing was obtained in 3 patients at baseline and 2 patients at the time of progression.
Result
Four patients were enrolled (age range, 43-61 years) and all had brain metastases at baseline. All four patients achieved an objective partial response to ensartinib, including one patient with an acquired ALK F1174V crizotinib resistance mutation. Intracranial responses included one partial response, two stable disease, and resolution of a non-target lesion in another patient. The median progression free survival was 12.5 months (range, 8-15 months) and the median decrease in tumor size was 42% (range, 39-48%). Primary sites of disease progression included lung (n=1), brain (n=2), both lung and brain (n=1). No somatic alterations were identified in the two patients who received post-ensartinib ctDNA sequencing. At progression, all patients received brigatinib as subsequent therapy with clinical benefit; one received lorlatinib after brigatinib failure and response is ongoing. Median post-ensartinib survival was 27 months (range, 20-38 months). Two patients remain alive 27 and 95 months after first anti-cancer therapy. The most common adverse events with ensartinib were mild rash, diarrhea, and fatigue that did not require dose reduction.
Conclusion
Ensartinib is well tolerated and has clinical activity in advanced ALK-rearranged NSCLC patients with brain metastases, despite previously progressing on crizotinib, with durable post-ensartinib survival on subsequent next-generation ALK inhibitors such as brigatinib and lorlatinib. (Trial funded by Xcovery Holdings, Inc.; ClinicalTrials.gov number: NCT01625234)
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-05 - MAGELLAN: Phase 1B Study of Durvalumab with Novel Oncology Therapies, With/Without Chemotherapy, in Untreated Stage IV NSCLC (ID 194)
10:15 - 18:15 | Presenting Author(s): Sandip Pravin Patel
- Abstract
Background
Immunotherapy with anti-PD-1/PD-L1 antibodies, with or without chemotherapy, is the standard of care in the first-line (1L) treatment for metastatic NSCLC. Despite advances, patients treated with anti-PD-1 directed regimens in metastatic NSCLC have demonstrated median PFS of <1 year. Targeting novel mechanisms in the tumor may improve response rates and survival. For example, danvatirsen is an antisense oligonucleotide that downregulates STAT3, a master regulator of immune suppression, and oleclumab is an anti-CD73 monoclonal antibody that alleviates adenosine-mediated immunosuppression. MAGELLAN is a Phase 1B, open-label, multicenter, biomarker-enriched, multicohort study (NCT03819465), designed to assess the safety and efficacy of durvalumab in combination with novel oncology therapies (danvatirsen, oleclumab), with or without chemotherapy, as 1L treatment for patients with Stage IV NSCLC. Additional novel therapies will be added to this study as supportive preclinical/clinical datasets emerge.
Method
Adult patients with Stage IV NSCLC (histologically/cytologically documented), tumors lacking activating EGFR mutations and ALK rearrangements, WHO/ECOG PS 0–1, and no prior chemotherapy or systemic therapy for Stage IV NSCLC are eligible. Eligible patients will be assigned to the PD-L1 tumor cell (TC) ≥50% or PD-L1 TC<50% cohorts, as confirmed by the VENTANA PD-L1 (SP263) Assay. Immunohistochemical staining with the SP263 assay is concordant with that for the 22C3 assay, another PD-L1 diagnostic assay. Patients in the PD-L1 TC≥50% cohort will be assigned to durvalumab monotherapy (1500 mg q4w), durvalumab+danvatirsen, or durvalumab+oleclumab. Patients in the PD-L1 TC<50% cohort will be assigned to durvalumab+chemotherapy (1500 mg durvalumab q3w up to 4 cycles [+chemotherapy], then q4w [–chemotherapy]), durvalumab+chemotherapy+danvatirsen, or durvalumab+chemotherapy+oleclumab. All therapy will be administered intravenously until disease progression. Oleclumab (1500 mg starting dose) and danvatirsen (200 mg starting dose) in combination with durvalumab or durvalumab+chemotherapy will be administered using a rolling 6-patient design to evaluate for toxicity. The chemotherapy backbone for use with immunotherapy, per investigator’s choice, will be nab‑paclitaxel+carboplatin for squamous and non-squamous NSCLC, gemcitabine+cisplatin/carboplatin for squamous NSCLC, and pemetrexed+carboplatin/cisplatin for non-squamous NSCLC. Patients receiving pemetrexed+carboplatin/cisplatin who do not progress after 4 cycles of chemotherapy will receive pemetrexed maintenance therapy and immunotherapy, unless contraindicated. The primary endpoint is safety and tolerability. Secondary endpoints are objective response rate and PFS (both RECIST v1.1), duration of response, OS, and pharmacokinetics and immunogenicity of durvalumab, oleclumab, and danvatirsen. Identification of candidate biomarkers from blood and tissue samples that may correlate the likely clinical benefit with the treatments under investigation will also be explored. Enrollment is ongoing.
Result
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Conclusion
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