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Jonathan W. Goldman
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.07 - A Phase II Study of Pembrolizumab in EGFR Mutant, PD-L1+, Tyrosine Kinase Inhibitor (TKI) Naïve Patients with Advanced NSCLC (ID 9525)
11:40 - 11:45 | Author(s): Jonathan W. Goldman
- Abstract
- Presentation
Background:
Pembrolizumab, a humanized monoclonal antibody that inhibits the interaction between programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) has demonstrated significant antitumor activity and produced durable responses in non-small cell lung cancer (NSCLC). However, data to date suggests that responses are less frequent in patients whose tumors harbor mutations in the epidermal growth factor receptor (EGFR) gene. Our single center experience with the KEYNOTE-001 trial suggested that EGFR mutation positive NSCLC patients with a history of prior tyrosine kinase inhibitor (TKI) therapy had worse clinical outcomes than those who were TKI naïve. However, that analysis was limited by small sample size. As a result of this observation, we are currently enrolling an open-label, phase II trial, of front-line pembrolizumab in EGFR mutation positive NSCLC patients that are PD-L1+.
Method:
This is an open-label, phase II trial of pembrolizumab in patients with EGFR mutation positive NSCLC whose tumors are PD-L1 positive [>1% tumor membranous staining by immunohistochemistry (IHC), 22C3 pharmDx test in a CLIA certified laboratory]. Patients receive pembrolizumab 200mg by IV infusion every three weeks and are evaluated every 9 weeks +/- 1 week with radiographic imaging to assess response to treatment for a maximum of 35 trial treatments of pembrolizumab. After progression on pembrolizumab, patients are followed for evaluation of EGFR TKI efficacy. The primary end point of the study is objective response rate (ORR) to pembrolizumab, per RECIST 1.1. Secondary endpoints include safety and efficacy [progression-free survival (PFS), overall survival (OS)] of front-line pembrolizumab in this population, as well as efficacy [PFS, OS, ORR] of subsequent EGFR TKI after progression on pembrolizumab. Correlative analyses include whole exome sequencing and IHC of patient specimens. To date, 8 out of the 25 planned patients have been enrolled.
Result:
Section not applicable
Conclusion:
Section not applicable
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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.03-026 - Interim Results of a Phase I Study of Nivolumab plus Nab-Paclitaxel/Carboplatin in Patients with NSCLC (ID 8478)
09:30 - 09:30 | Presenting Author(s): Jonathan W. Goldman
- Abstract
Background:
Chemotherapy, including taxanes, may augment the effects of immune checkpoint inhibitors through tumor cell lysis and subsequent antigen release. This phase I trial is evaluating safety and efficacy of nivolumab plus nab-paclitaxel in NSCLC (+ carboplatin), pancreatic cancer (± gemcitabine), and metastatic breast cancer. Interim results for Arm C, in which patients with NSCLC were treated with nivolumab starting in cycle 1, are presented.
Method:
Potential dose-limiting toxicities (DLTs) were evaluated in Part 1 before Part 2 expansion. Chemotherapy-naive patients with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] days 1, 8, 15 plus carboplatin AUC 6 day 1 plus nivolumab 5 mg/kg day 15 of each 21-day cycle. In cycles ≥ 5, single-agent nivolumab was continued as maintenance therapy. Primary endpoints are number of patients with DLTs (Part 1) and percentage of patients with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1/2). DLT-evaluable patients were those who received ≥ 2 complete nivolumab cycles and remained on study for 14 days after the last nivolumab dose in cycle 2, received ≥ 1 nivolumab dose and discontinued due to DLT before completing 2 nivolumab cycles, or experienced an equivocal DLT after ≥ 1 nivolumab dose. Secondary endpoints included PFS, DCR, ORR, DOR (all by RECIST v1.1), OS, and safety.
Result:
All patients (N = 22) received nab-paclitaxel/carboplatin; results for those who received nab-paclitaxel/carboplatin plus nivolumab (n = 20) are presented. The median age was 65.5 years (55% ≥ 65 years), 70% had ECOG PS 1, 75% were female, and 80% were white. More patients had adenocarcinoma (50%) than squamous cell carcinoma (35%; adenosquamous carcinoma, atypical, and data pending, 5% each). No DLTs were reported among 6 DLT-evaluable patients (Part 1). The most common grade 3/4 TEAEs were neutropenia (45%) and anemia (40%). No grade 3/4 colitis or pneumonitis was reported. Best ORR was 50% (1 CR [5%] and 9 PRs [45%]; 10 patients [50%] had SD); ORR was 43% (3 PRs among 7 patients) and 54% (1 CR and 6 PRs among 13 patients) in those with squamous and nonsquamous histologies, respectively. Median PFS was 10.5 months (95% CI, 4.9-18.1 months); 10.5 and 10.2 months for those with squamous and nonsquamous histologies, respectively.
Conclusion:
These results suggest that nab-paclitaxel/carboplatin plus nivolumab is tolerable for patients with NSCLC. Preliminary efficacy findings indicate promising antitumor activity across histologies. (NCT02309177)
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-004 - Safety and Efficacy of Nab-Paclitaxel plus Carboplatin in Elderly Patients with NSCLC (ABOUND.70+) (ID 7561)
09:00 - 09:00 | Author(s): Jonathan W. Goldman
- Abstract
Background:
A subanalysis of a phase III registrational trial demonstrated a 9.5-month survival benefit with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin for patients ≥70 years with advanced NSCLC. ABOUND.70+ evaluated 2 schedules of nab-paclitaxel/carboplatin to determine whether a 1-week break could improve tolerability.
Method:
Patients ≥70 years with locally advanced/metastatic NSCLC were randomized to receive first-line nab-paclitaxel 100mg/m[2] on days 1, 8, 15 and carboplatin AUC 6 on day 1 of a 21-d cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: the percentage of patients with grade ≥2 peripheral neuropathy or grade ≥3 myelosuppression; key secondary endpoints: progression-free survival (PFS), overall survival (OS), and overall response rate (ORR), for which statistical analyses did not control for type I error (P values unadjusted).
Result:
At interim evaluation, the primary endpoint was similar across treatment arms leading to early closure of enrollment. Baseline characteristics were well balanced between arms (Arm A, n = 71; Arm B, n = 72). Primary endpoint results are presented in the table. Overall, confirmed ORR was 23.9% vs 40.3% (P = 0.038), median PFS was 3.6 vs 7.0 months (HR 0.48 [95% CI, 0.30-0.76]; P = 0.002), and median OS was 15.2 vs 16.2 months (HR 0.72 [95% CI, 0.44-1.19]; P = 0.197). Among patients who received second-line therapy across treatment arms (n = 61), median OS from start of first-line treatment was 22.7 months (95% CI, 11.79-not estimable [NE]) and 16.4 months (95% CI, 12.12-NE) in patients receiving chemotherapy and immunotherapy, respectively.
Conclusion:
nab-Paclitaxel/carboplatin was well tolerated and efficacious in elderly patients with advanced NSCLC. Incidence of grade ≥2 peripheral neuropathy or grade ≥3 myelosuppression (primary endpoint) was similar in both treatment arms. A signal of improvement was observed in PFS and ORR in Arm B. NCT02151149Primary Endpoint Event, n (%) Arm A n = 68 Arm B n = 70 Patients with either grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression 52 (76.5) 54 (77.1) Grade ≥ 2 peripheral neuropathy 25 (36.8) 25 (35.7) Grade ≥ 3 myelosuppression 48 (70.6) 45 (64.3) Neutropenia 39 (57.4) 39 (55.7) Anemia 14 (20.6) 17 (24.3) Thrombocytopenia 17 (25.0) 12 (17.1)
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P2.01-013 - Nab-Paclitaxel/Carboplatin in Elderly Patients with NSCLC (ABOUND.70+): Analysis of Safety and Quality of Life (QoL) by Cycle (ID 8185)
09:00 - 09:00 | Author(s): Jonathan W. Goldman
- Abstract
Background:
ABOUND.70+ evaluated 2 schedules of first-line nab-paclitaxel/carboplatin in patients ≥70 years with advanced NSCLC to determine whether a 1-week break can improve tolerability. Safety and QoL by cycle are reported.
Method:
Patients ≥70 years with locally advanced/metastatic NSCLC were randomized to first-line nab-paclitaxel 100mg/m[2] on d1, 8, 15 and carboplatin AUC 6 on d1 of a 21-d cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: percentage of patients with grade ≥2 peripheral neuropathy (PN) or grade ≥3 myelosuppression (laboratory values). QoL (exploratory endpoint) was assessed using Lung Cancer Symptom Scale (LCSS) on d1 of each cycle. Safety analyses included patients receiving ≥1 dose of study medication. AEs/QoL were analyzed at each of the first 6 cycles.
Result:
At interim evaluation, primary endpoint was similar across arms, resulting in early closure of enrollment. Of 143 randomized patients, 68 and 70 in Arms A and B received ≥1 dose of study drug. Table lists primary endpoint and key safety results by cycle. Grade ≥2 PN occurred earlier in Arm A. Incidence of grade ≥3 myelosuppression was highest in the first 2 cycles, progressively declining after cycle 3 (both arms). Dose reductions occurred in earlier cycles for Arm A; at the start of cycle 4, 36% vs 47% of patients received the maximum dose (100mg/m[2]) of nab-paclitaxel in Arms A and B. Generally, QoL was maintained throughout treatment. LCSS item of cough improved with each cycle; mean change from baseline at the end of cycle 6 was 25.4 and 13.8mm (visual analog scale).
Conclusion:
Although the overall rate of grade ≥2 PN and grade ≥3 myelosuppression was similar between arms, analysis by cycle showed that grade ≥2 PN and dose reductions occurred earlier in Arm A. QoL was maintained in both arms. NCT02151149
.Arm A n = 68 Arm B n = 70 Safety Primary endpoint, % 76 77 P value 0.9258 Peripheral neuropathy, % Grade ≥ 2[a] Grade ≥ 3[a] Grade ≥ 2[a] Grade ≥ 3[a] All cycles 37 13 36 17 Cycle 1 6 0 0 0 Cycle 2 6 4 1 0 Cycle 3 7 4 9 1 Cycle 4 4 0 7 1 Cycle 5 6 3 4 1 Cycle 6 4 1 4 9 Myelosuppression, % Grade ≥ 3 Grade ≥ 3 All cycles 71 64 Cycle 1 35 37 Cycle 2 22 10 Cycle 3 3 10 Cycle 4 6 1 Cycle 5 1 3 Cycle 6 3 3 [a ]Calculated by first occurrence of adverse event of respective grade.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-038 - Thyroid Dysfunction Arising During KEYNOTE-001 Associated with Improved Efficacy of Pembrolizumab in NSCLC Patients at UCLA (ID 9531)
09:30 - 09:30 | Author(s): Jonathan W. Goldman
- Abstract
Background:
PD-1/PD-L1 blockade has rapidly been adopted for treatment of NSCLC. However, much remains to be learned about the implications of the side-effect profile of PD-1/PD-L1 blockade. We previously showed that the 38 patients who experienced a treatment related AE (trAE) on the KEYNOTE-001 trial at UCLA had superior clinical outcomes compared to the 59 that did not. Treatment related hypothyroidism was the most predictive trAE for response to therapy [objective response rate (ORR): 83.3% (5/6 patients with response)]. The highly predictive nature of treatment related hypothyroidism led us to further evaluate the implications of thyroid dysfunction in our patient cohort by analyzing the association between therapeutic efficacy and thyroid specific laboratory values obtained on trial.
Method:
We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 12/2016). Patients had Thyroid Stimulating Hormone (TSH), free Thyroxine 4 (fT4), and Triiodothyronine (T3) assessed at baseline (prior to therapy), cycle 2, and every other cycle thereafter. In some instances, labs were obtained at safety follow-up and unscheduled visits. Tumor response was evaluated using investigator assessed immune related response criteria (irRC), with imaging q9wks.
Result:
97.9% (95/97) of the patients treated at UCLA on KEYNOTE-001 had a baseline set of thyroid indices, while 74.7% (68/97) had >3 sets of values. Patients with an abnormal TSH during study participation had a higher ORR, 35.5% (11/31), than those that did not, 14.1% (9/64) (p=0.0296), with an acquired TSH abnormality (first observed after C1D1) more predictive of response than a baseline abnormality [acquired TSH abnormality: ORR 42.9% (9/21) vs baseline abnormality: ORR 20% (2/10)]. An abnormal fT4 or abnormal T3 on trial were also both independently associated with improved response to therapy [fT4 abnormality+: ORR: 50% (5/10) vs fT4 abnormality-: 17.7% (15/85) (p=0.0317) and T3 abnormality+: ORR 47.4% (9/19) vs T3 abnormality-: ORR 14.5% (11/76) (p=0.0037)]. As with TSH, acquired fT4 and T3 abnormalities were associated with higher ORR than baseline abnormalities.
Conclusion:
Thyroid dysfunction, assessed by abnormalities in TSH, fT4, or T3, was associated with improved efficacy of pembrolizumab on the KEYNOTE-001 trial at UCLA and an acquired thyroid abnormality, defined as first occurrence after C1D1, was more predictive of improved efficacy than a baseline abnormality. Future work is ongoing to evaluate this association in a larger patient population and molecular mechanisms that may be underlying this observation.
