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S.K. Padda
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-012 - A Phase II Study of Etirinotecan Pegol (NKTR-102) in Patients with Refractory Brain Metastases and Advanced Lung Cancer (ID 4345)
14:30 - 14:30 | Author(s): S.K. Padda
- Abstract
Background:
Up to 40% of lung cancer patients develop brain metastases. As brain metastases often progress following radiotherapy, chemotherapeutics with central nervous system (CNS) activity are needed. Etirinotecan pegol (NKTR-102) is a PEG-conjugate prodrug of irinotecan, resulting in a half-life of 37 days and accumulation in tumors with permeable vasculature. This phase II trial evaluated the CNS activity of etirinotecan pegol in patients with lung cancer and refractory brain metastases.
Methods:
Patients with lung cancer and brain metastases were eligible who had received prior systemic therapy and prior brain-directed neurosurgery, radiation/radiosurgery, or refused whole brain radiotherapy (WBRT). Measurable brain metastases were defined as one >= 10 mm; or one 5-9 mm with others >= 3 mm, totaling >= 10 mm. Etirinotecan pegol was administered at 145 mg/m2 IV every 3 weeks. Response (modified RECIST 1.1) was assessed with brain MRI and systemic CT every 6 weeks. The primary endpoint was a 25% or greater 12-week CNS disease control rate (CNS-DCR; defined as unconfirmed response or stable disease with systemic non-progression) in a non-small cell lung cancer (NSCLC) cohort. Another exploratory cohort enrolled small cell lung cancer (SCLC) patients.
Results:
In the NSCLC cohort, twelve patients were enrolled, all with adenocarcinoma. Genomic alterations included six (50%) with EGFR mutation, and one each with HER2, KRAS, ROS1, and NRAS. Patients received a median of 2.5 prior systemic treatments. Two (17%) patients had prior neurosurgery, ten patients (83%) had irradiation - 3 WBRT, 9 radiosurgery. Common related toxicities were nausea and diarrhea (each in 50%), vomiting (22%) and blurred vision (22%). One patient died after developing diarrhea and dehydration. CNS responses lasting 24, 8, and 6 weeks were observed in 25% (3/12) - all EGFR mutation positive. The 6-week CNS-DCR was 50% (6/12), but 12-week CNS-DCR was 17% (2/12). Median progression-free survival was 11.4 weeks (95% CI 5.3-11.7) and median overall survival from study entry was 29.6 weeks (95% CI 22.3-38.2). In the SCLC cohort, two patients were enrolled. One patient with prior PCI had CNS response at 5 weeks but died of neutropenic infection; one who refused prior WBRT had CNS progression at 6 weeks.
Conclusion:
Radiographic responses of brain metastases were observed in patients following administration of etirinotecan pegol, but the study did not meet the primary endpoint because the 12-week CNS-DCR was 17%. Further study of etirinotecan pegol is ongoing in patients with breast cancer and brain metastases.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-004 - A Phase 1b Study of Erlotinib and Momelotinib for EGFR TKI Naïve EGFR Mutated Metastatic Non-Small Cell Lung Cancer (ID 4778)
14:30 - 14:30 | Author(s): S.K. Padda
- Abstract
Background:
Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Methods:
Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose.
Results:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses).
Conclusion:
MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.
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SC14 - Immunotherapy of NSCLC (ID 338)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:N. Rizvi, C. Zielinski
- Coordinates: 12/06/2016, 11:00 - 12:30, Hall C2
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SC14.04 - The CD47 Macrophage Checkpoint as a New Immunotherapy Target (ID 6656)
11:55 - 12:10 | Author(s): S.K. Padda
- Abstract
- Presentation
Abstract:
Background: Hu5F9-G4 is a humanized monoclonal antibody that targets CD47, blocking its anti-phagocytic “don’t eat me” signal through macrophage receptor SIRPα, leading to tumor phagocytosis. CD47 is overexpressed on human cancers and also on red blood cells (RBCs). In primate toxicology studies, Hu5F9-G4 caused a transient anemia that was improved with a single lower Priming Dose allowing higher Maintenance Doses. Materials and Methods: Relapsed/refractory solid tumors and lymphomas were included. This dose escalation study included: Part A, to determine the Priming Dose and Part B, to determine the Maintenance Dose. The maximum tolerated dose (MTD) in part A was used for the single Priming Dose in part B (Hu5F9-G4 dosed weekly). The primary objective is to determine safety and secondary objectives are to determine PK and PD. Preliminary data reported from data cutoff of July 22, 2016.Results: 25 patients have enrolled. Part A included 0.1 (N=1), 0.3 (N=2), 1 (N=6), and 3 (N=2) mg/kg. There were 2 dose-limiting toxicities (DLTs) in Part A at the 3 mg/kg dose: grade (G) 3 abdominal pain and G3 hemagglutination (H) (protocol-specific scale of G1 H on peripheral blood smear (PBS) and G2 headache). 1 mg/kg was selected as the Priming Dose, with no >G2 anemia. Pharmacodynamic studies show almost 100% RBC receptor occupancy at the Priming Dose. Treatment-related adverse event (TRAE) in Part A included: anemia (3 G1, 3 G2), hyperbilirubinemia (3 G1, 2 G2; unconjugated), headache (6 G1, 1 G2), H on PBS (8 G1), and nausea (3 G1). Part B included 3 (N = 4), 10 (N = 3), and 20 mg/kg (N=6, ongoing). There have been no DLTs in 3 patients on 10 mg/kg, and one DLT (headache with hemagglutination) in 6 patients at the 20 mg/kg maintenance dose (ongoing). Most toxicities were was associated with the initial single Priming Dose and were completely reversible. TRAE in Part B at 3 mg/kg included: anemia (2 G1, 2 G2), hyperbilirubinemia (1 G1, 1 G3), headache (3 G1), H on PBS (1 G1), retinal toxicity (G2 protocol-specific scale, asymptomatic). TRAE at 10 mg/kg included: anemia (3 G1), headache (2 G1), and nausea (1 G1). Two patients with adenoid cystic carcinoma in Part A had stable disease for 16 and 8 months. In Part B, 2 of 3 patients have had prolonged stable disease at 10 mg/kg for 8+ months (follicular thyroid cancer) and 7+ months (myoepithelioma of the head and neck). Evaluation of subjects in the 20 mg/kg cohort is ongoing. Conclusions: Hu5F9-G4 is well tolerated at 10 mg/kg weekly, with 1 mg/kg Priming Dose. Part B with a Maintenance Dose of 20 mg/kg is ongoing. Acknowledgements: Stanford Clinical and Translational Research Unit; California Institute for Regenerative Medicine; Forty Seven, Inc.Trial Registration: NCT02216409References: 1. Willingham SB, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J t al. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345. References 1. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-7. 2. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J, Chao M, Weissman IL, Majeti R. Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS One. 2015 Sep 21;10(9):e0137345.Figure: CD47 is a myeloid-specific immune checkpoint. Figure 1Figure 2
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