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D.B. Costa
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-031 - Mutations in TP53, PIK3CA, PTEN and Other Genes in EGFR Mutated Lung Cancers: Correlation with Clinical Outcomes (ID 5254)
14:30 - 15:45 | Author(s): D.B. Costa
- Abstract
Background:
The degree and duration of response to epidermal growth factor receptor (EGFR) inhibitors in EGFR mutated lung cancer are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors, which is currently largely unknown in view of the prevailing single gene assay diagnostic paradigm in clinical practice, could play a role in clinical outcomes and/or mechanisms of resistance.
Methods:
We retrospectively probed our institutional lung cancer patient database for tumors harboring EGFR kinase domain mutations that were also evaluated by more comprehensive molecular profiling, and assessed tumor response to EGFR tyrosine kinase inhibitors (TKIs).
Results:
Out of 171 EGFR mutated tumor-patient cases, 20 were sequenced using at least a limited comprehensive genomic profiling platform. 50% of these harbored concurrent TP53 mutation, 10% PIK3CA mutation, and 5% PTEN mutation, among others. The response rate to EGFR TKIs, the median progression-free survival (PFS) to TKIs, the percentage of EGFR-T790M TKI resistance and survival were higher in EGFR mutant/TP53 wild-type cases when compared to EGFR mutant/TP53 mutant tumors; with a significantly longer median PFS in EGFR-exon 19 deletion mutant/TP53 wild-type cancers treated with 1st generation EGFR TKIs.
Conclusion:
Concurrent mutations, specifically TP53, are common in EGFR mutated lung cancer and may alter clinical outcomes. Additional cohorts will be needed to determine if comprehensive molecular profiling adds clinically relevant information to single gene assay identification in oncogene-driven lung cancers.
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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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P2.06-007 - A Phase 1/2 Trial of the Oral EGFR/HER2 Inhibitor AP32788 in Non–Small Cell Lung Cancer (NSCLC) (ID 5047)
14:30 - 15:45 | Author(s): D.B. Costa
- Abstract
Background:
Approximately 4%–9% of EGFR-mutated NSCLC tumors have EGFR exon 20 insertion mutations, and no targeted treatment options are currently approved for patients with these mutations. In addition, approximately 2%–4% of patients with NSCLC have HER2 mutations, the majority of which are exon 20 insertion mutations. The irreversible EGFR/HER2 inhibitor AP32788 was designed to selectively inhibit EGFR or HER2 kinases with EGFR/HER2 exon 20 mutations. In preclinical studies, investigational agent AP32788 had potent inhibitory activity against all EGFR and HER2 mutants tested, including exon 20 insertion mutants, while sparing wild-type EGFR.
Methods:
This phase 1/2 trial is a first-in-human, open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of orally administered AP32788 (NCT02716116). The study will be conducted in 2 parts: a dose-escalation phase with a 3+3 design and an expansion phase of 4 histologically and molecularly defined cohorts after the recommended phase 2 dose (RP2D) is determined. Patients (≥18 years) must have locally advanced or metastatic NSCLC. In phase 1, the dose-escalation phase, patients refractory to standard available therapies will be enrolled. The primary endpoint of phase 1 is identification of the RP2D of AP32788. Secondary endpoints include safety, dose-limiting toxicities, maximum tolerated dose, and plasma pharmacokinetics. Expected phase 1 enrollment is 20–30 patients. In phase 2, the expansion phase, 4 cohorts will be enrolled, patients with: 1. EGFR exon 20 activating insertions, without active, measurable CNS metastases; 2. HER2 exon 20 activating insertions or point mutations, without active, measurable CNS metastases; 3. EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. other targets against which AP32788 has demonstrated preclinical activity (eg, EGFR exon 19 deletions or exon 21 substitutions [with/without the T790M mutation] and other uncommon activating mutations in EGFR). The primary endpoint of phase 2 is investigator-assessed objective response rate (ORR) per RECIST v1.1 for all expansion cohorts except Expansion Cohort 3, for which the primary endpoint is intracranial ORR. Phase 2 secondary endpoints include safety, pharmacokinetics, and additional efficacy assessments (ORR per independent review committee, best overall response, best target lesion response, duration of response, disease control rate, progression-free survival, and overall survival; for Expansion Cohort 3: duration of intracranial response and intracranial progression-free survival). Expected phase 2 enrollment is 80 patients (total). The first patient was enrolled in phase 1 in June 2016.
Results:
Section not applicable.
Conclusion:
Section not applicable.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-046 - Safety, Clinical Activity and Biomarker Results from a Phase Ib Study of Erlotinib plus Atezolizumab in Advanced NSCLC (ID 5215)
14:30 - 15:45 | Author(s): D.B. Costa
- Abstract
Background:
Targeted therapy with erlotinib is effective in reducing tumor burden in EGFR-mutant non-small cell lung cancer (NSCLC). However, resistance to therapy develops almost universally. Atezolizumab, an engineered mAb that inhibits binding of PD-L1 to its receptors, PD-1 and B7.1, has demonstrated promising monotherapy activity in NSCLC. Given that atezolizumab may enhance and perpetuate anti-tumor immunity, we hypothesized that combining atezolizumab with erlotinib may improve both clinical response and durability in EGFR-mutant NSCLC.
Methods:
This Phase Ib study consisted of a safety-evaluation stage in patients with NSCLC regardless of EGFR status followed by an expansion stage in TKI-naïve patients with tumors harboring activating EGFR mutations. Patients were enrolled regardless of PD-L1 status. After a 7-day run-in with 150mg erlotinib PO QD alone, patients received 150mg erlotinib PO QD and 1200mg atezolizumab IV q3w. To evaluate immune biology, biopsies were obtained in expansion-stage patients pre-treatment, after erlotinib run-in, at weeks 4-6, and at progression. The primary objective was to evaluate the safety and tolerability of the combination. Secondary objectives included evaluation of the clinical activity per RECIST v1.1. Data cutoff, 11 April 2016.
Results:
Twenty-eight patients (safety stage, n = 8; expansion stage, n = 20) who received ≥ 1 dose of erlotinib or atezolizumab were considered safety evaluable. Median age was 61y (range, 47-84); median survival follow-up was 11.2mo (range, 0.8-24.2). The incidence of either treatment-related G3-4 AEs was 39% and for serious AEs, 50%. The most common atezolizumab-related G3-4 AEs were pyrexia and increased ALT. No pneumonitis was reported. No treatment-related G5 AEs occurred. Five patients discontinued atezolizumab due to treatment-emergent AEs. No DLTs were observed. In the expansion-stage population, ORR was 75% (95% CI, 51-91). Disease control rate (CR + PR + SD ≥ 24 weeks) was 90% (95% CI, 68-99), median PFS was 11.3mo (95% CI, 8.4-NE) and median DOR was 9.7mo (range, 4.2-11.7). Increases in intratumoral CD8+ T cells post-erlotinib run-in were observed in 8/13 evaluable paired biopsies. Higher intratumoral CD8+ T-cell prevalence and immune gene expression signatures at baseline were associated with improved PFS.
Conclusion:
The combination of full dose erlotinib plus atezolizumab demonstrated a manageable safety profile. While response rates and median PFS for combination treatment appear similar to those observed with erlotinib monotherapy, the addition of atezolizumab to erlotinib may lead to more durable clinical responses in some patients. Additional follow-up is required to evaluate the full potential of this combination treatment. NCT02013219
