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Jonathan Goldman
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)
14:00 - 15:30 | Author(s): Jonathan Goldman
- Abstract
- Presentation
Background
Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.
Method
620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.
Result
Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.
Conclusion
In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.
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MA14 - The Adequate MTarget Is Still the Issue (ID 140)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:Diego Signorelli, Juergen Wolf
- Coordinates: 9/09/2019, 15:45 - 17:15, Hilton Head (1978)
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MA14.03 - EGFR M+ Subgroup of Phase 1b Study of Telisotuzumab Vedotin (Teliso-V) Plus Erlotinib in c-Met+ Non-Small Cell Lung Cancer (Now Available) (ID 1622)
15:45 - 17:15 | Author(s): Jonathan Goldman
- Abstract
- Presentation
Background
Telisotuzumab vedotin (ABBV-399; teliso-v) is an anti-c-Met antibody conjugated with monomethyl auristatin E, a tubulin polymerization inhibitor. Preliminary activity was reported for the teliso-v + erlotinib combination in c-Met overexpressing (c-MET+) non-small cell lung cancer (NSCLC) patients, with an activating EGFR mutation and for whom prior EGFR TKI failed. We present mature data from the EGFR M+ subgroup of the teliso-v + erlotinib cohort of a phase 1b study (NCT02099058).
Method
Teliso-v was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg intravenously once every 3 weeks, and erlotinib at 150 mg orally once a day/prior tolerated dose in adult patients with advanced NSCLC. For efficacy analysis, c-Met+ was defined as central lab IHC H-score ≥150 or local lab MET amplification (MET/CEN7 ≥2); EGFR M+ was defined as del19 or L858R by local lab. Pharmacokinetics were assessed. All patients who received teliso-v + erlotinib were evaluated for safety.
Result
As of Dec 2018, 42 NSCLC patients received teliso-v + erlotinib; 37 were c-MET+ (36 evaluable: 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 patients (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (of these: 48% had T790M, 10% had MET amplification, 3% had polysomy, 97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Grade 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Grade ≥3 (≥10%) AE: pulmonary embolism (14%). Pharmacokinetics of teliso-v for the combination were similar to single-agent teliso-v. The table presents efficacy data.
Patients with EGFR mutation
(n=29)Objective response rate*, % (95% CI)
Complete response, n34.5 (17.9, 54.3)
1Median duration of response, months
(95% CI)NR
(2.8, NE)Median PFS, months (95% CI) NR
(2.8, NE)Median follow-up, months 4 6-month PFS rate, % (95% CI) 51 (30, 69)
Median treatment duration, month (range)
Teliso-v
Erlotinib
3.5 (0.71–10.4)
5.3 (0.71–25.4)Objective response rate by subgroup of interest, n (%)
Received prior 3rd generation EGFR TKI
C-met amplified, copy number gain, or polysomy
EGFR TKI-containing regimen as last-line therapies
6/16 (37.5)
5/7 (71.4)
8/20 (40.0)*RECIST version 1.1.
EGFR, epidermal growth factor receptor; NE, not estimable; NR, not reached; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor;
Conclusion
These data suggest acceptable safety and promising activity of teliso-v + erlotinib in patients with c-Met+ NSCLC with an activating EGFR mutation and for whom EGFR TKI has failed.
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P1.12 - Small Cell Lung Cancer/NET (ID 179)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.12-22 - A Phase 1b/2 Study of Niraparib Plus Temozolomide Versus Standard Care as Maintenance Therapy in Extensive-Stage Small Cell Lung Cancer Patients (ID 504)
09:45 - 18:00 | Author(s): Jonathan Goldman
- Abstract
Background
Maintenance therapy is a promising therapeutic approach for extensive-stage small cell lung cancer (ES-SCLC), especially in light of IMpower 133 (Horn NEJM 2018). SCLC models of poly (ADP-ribose) polymerase (PARP) protein 1 and 2 inhibition suggested synergy with temozolomide (TMZ) (Wainberg AACR 2016). Combining PARP inhibition with TMZ after first-line therapy for ES-SCLC may improve disease control.
Method
This is a phase 1b/2, randomized, open-label study of TMZ plus niraparib, a PARP inhibitor, versus best supportive care (BSC) as maintenance therapy in adult patients with ES-SCLC after completion of platinum-based first-line chemotherapy. The primary outcome for phase 1b is the RP2D of TMZ in combination with niraparib, and for phase 2, progression-free survival (PFS). Secondary endpoints include safety and overall survival. Exploratory endpoints include patient-reported outcomes on health-related quality of life and adverse events which will be collected electronically through a patient portal. Phase 1b participants are required to have an advanced and incurable solid malignancy. An accelerated lead-in of 12 participants will be treated in cohorts of 6 with an initial dose level of niraparib 200 mg po daily in 28-day cycles in addition to low-dose TMZ 40 mg po daily on days 1-5 of each cycle. For phase 2, participants are required to have ES- SCLC with a complete response or partial response per RECIST 1.1 following 4 to 6 cycles of platinum-based chemotherapy and ability to proceed to randomization within 7 weeks after day 1 of the last cycle of prior chemotherapy. Prophylactic WBRT is allowed prior to study. 52 participants will be stratified by a history of brain metastases and randomized 1:1 to RP2D niraparib plus TMZ versus BSC. There will be no cross-over between arms.
Result
Section not applicable.
Conclusion
Section not applicable.
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P2.12 - Small Cell Lung Cancer/NET (ID 180)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.12-09 - Phase 2 Study of Talazoparib Plus Low-Dose Temozolomide in Patients with Relapsed/Refractory Extensive-Stage Small Cell Lung Cancer (ID 954)
10:15 - 18:15 | Presenting Author(s): Jonathan Goldman
- Abstract
Background
Talazoparib exhibits cytotoxic effects by inhibiting poly (ADP-ribose) polymerase (PARP) proteins 1 and 2 in addition to “trapping” PARP on DNA. Temozolomide (TMZ) has been shown to increase antitumor response when combined with a PARP inhibitor in small cell lung cancer (SCLC) models (Wainberg AACR 2016). Combining PARP inhibition with TMZ as second-line therapy for ES-SCLC may improve disease-related outcomes.
Method
This is a phase 2, open-label, single-arm study of the safety and efficacy of talazoparib plus TMZ in patients with extensive-stage SCLC. The primary endpoint is objective response rate (ORR) based on RECIST 1.1 criteria. Secondary endpoints include progression-free survival, overall survival, duration of response, and time to response. Exploratory endpoints include biomarker studies such as DNA damage response gene analysis and patient reported outcomes (PRO).
Participants are required to have relapsed (progressed within 6 months) or refractory (progressed
during or within 4 weeks of completing 1stline platinum-based regimen) ES-SCLC. Those with a best response of progressive disease to first-line therapy per RECIST 1.1 or more than one line of cytotoxic therapy are excluded. Prior immunotherapy is allowed. Participants receive talazoparib 0.75 mg po daily on 28-day cycles with TMZ 37.5 mg/m2 po on days 1-5. 15 participants will be enrolled in the first part of a Simon two-stage design; if 3 or more responses are seen, an additional 13 participants will be enrolled. The null hypothesis will be rejected if 8 or more objective responses are observed compared to a historical control of 15% ORR in second-line topotecan (Horita Sci Rep 2015).
Result
As of 8 March 2019, 3 participants were evaluable for treatment response. Median age was 51 (range 46-80). One participant had a confirmed partial response (PR) with 50% reduction in target lesions, one had stable disease with 16% reduction in target lesions, and one had progressive disease (PD). Biomarker and PRO analysis correlated with the radiographic response. In the participant with PR, Guardant circulating tumor DNA testing showed PIK3CA amplification and TP53 mutations at baseline that were not detectable at week 5 of treatment, whereas the other subjects has persistent ctDNA. Patient-reported outcomes similarly noted improvement in the participant with PR within 2 weeks while the one with PD showed no improvement throughout treatment course. Adverse events were hematologic, including one grade 4 thrombocytopenia that resolved within 2 weeks.
Conclusion
Combination talazoparib and TMZ used as second-line therapy in ES-SCLC is tolerable and has shown promising preliminary results. The trial will continue to enroll. Updated response and biomarker data will be presented.
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PL02 - Presidential Symposium including Top 7 Rated Abstracts (ID 89)
- Event: WCLC 2019
- Type: Plenary Session
- Track:
- Presentations: 1
- Now Available
- Moderators:Giorgio Vittorio Scagliotti, Ramon Rami-Porta
- Coordinates: 9/09/2019, 08:00 - 10:15, Barcelona (2005)
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PL02.11 - Overall Survival with Durvalumab Plus Etoposide-Platinum in First-Line Extensive-Stage SCLC: Results from the CASPIAN Study (Now Available) (ID 2265)
08:00 - 10:15 | Author(s): Jonathan Goldman
- Abstract
- Presentation
Background
Extensive-stage (ES)-SCLC is a recalcitrant disease associated with a median OS of ~10 months following etoposide-platinum (EP); new treatments that prolong survival are needed. CASPIAN (NCT03043872) is an open-label, phase 3 study of durvalumab (anti-PD-L1), ± tremelimumab (anti-CTLA-4), combined with EP as first-line treatment for patients with ES-SCLC. Here we report results for durvalumab + EP (D+EP) versus EP from a planned interim analysis.
Method
Patients with previously untreated ES-SCLC (ECOG PS 0/1) were randomised (1:1:1) to durvalumab 1500 mg + EP q3w; durvalumab 1500 mg + tremelimumab 75 mg + EP q3w; or EP q3w. Patients in immunotherapy arms received up to 4 cycles of EP followed by maintenance durvalumab until progression. Patients in the EP arm received up to 6 cycles of EP and prophylactic cranial irradiation (PCI), at the investigator’s discretion. Investigator’s choice of cisplatin or carboplatin was allowed across all arms and was a stratification factor at randomisation. The primary endpoint was OS. Data cutoff: 11 March 2019.
Result
268 patients were randomised to D+EP and 269 to EP. Baseline characteristics were well balanced between arms. In the EP arm, 56.8% of patients received 6 cycles of EP. At the interim analysis, D+EP significantly improved OS compared to EP with a HR of 0.73 (95% CI, 0.591-0.909; p=0.0047); mOS 13.0 versus 10.3 months, respectively. 33.9% of patients were alive at 18 months with D+EP versus 24.7% with EP. Secondary endpoints of PFS and ORR were also improved with D+EP compared to EP: PFS HR 0.78 (95% CI, 0.645-0.936); mPFS 5.1 versus 5.4 months; 12-month PFS rate 17.5% versus 4.7%; investigator-assessed ORR (RECIST v1.1; unconfirmed) 79.5% versus 70.3% (odds ratio, 1.64 [95% CI, 1.106-2.443]). The incidences of grade 3/4 AEs (61.5% versus 62.4%) and AEs leading to discontinuation (9.4% each) were similar between arms; the incidence of haematological toxicities was numerically higher in the EP arm. The durvalumab + tremelimumab + EP arm continues blinded to final analysis.
Conclusion
The addition of durvalumab to EP as first-line treatment for ES-SCLC significantly improved OS (27% reduction in risk of death) versus a robust control arm that permitted up to 6 cycles of EP and PCI. Of note, this chemo-immunotherapy regimen offers flexibility in platinum choice (carboplatin or cisplatin), reflecting current clinical practice for this challenging disease. No new safety signals were identified.
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