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M.G. Kris
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MA04 - HER2, P53, KRAS and Other Targets in Advanced NSCLC (ID 380)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA04.02 - Neratinib ± Temsirolimus in HER2-Mutant Lung Cancers: An International, Randomized Phase II Study (ID 4302)
16:06 - 16:12 | Author(s): M.G. Kris
- Abstract
- Presentation
Background:
Combined inhibition of HER2 and mTOR is synergistic in models of HER2 (or ERBB2)-mutant lung cancers. PUMA-NER-4201 is an adaptive, multinational, randomized phase II study comparing the pan-HER inhibitor neratinib (Puma Biotechnology) ± the mTOR inhibitor temsirolimus in patients with advanced HER2-mutant lung cancers. In stage 1 of the study, neratinib + temsirolimus met predefined criteria for expansion into stage 2 [Besse et al. ESMO 2014].
Methods:
Patients with stage IIIB/IV locally determined HER2-mutant cancers were randomized to receive oral neratinib 240 mg once daily ± intravenous temsirolimus 8 mg once weekly (escalated to 15 mg/week after a 3-week cycle if tolerated) with loperamide prophylaxis. Primary endpoint: overall response rate (RECIST v1.1). Secondary endpoints: duration of response, progression‑free survival, overall survival, toxicity assessments (NCI-CTCAE, v4.0). ClinicalTrials.gov: NCT01827267.
Results:
Of 62 randomized patients, 60 received ≥1 dose of neratinib: neratinib alone (n=17); neratinib + temsirolimus (n=43). Baseline characteristics: male/female 32%/68%; median age 66 years; never smokers 60%; adenocarcinoma 98%. HER2 (or ERBB2) mutation type: exon 20 insertions 93.5%; missense substitutions 3.2%; unspecified 3.2%. The most common HER2 allelic variant was A775_G776insYVMA. Exploratory biomarker analysis from available tumor and plasma samples will be presented at the meeting. Efficacy and safety results are shown in the table. With loperamide prophylaxis, the incidence of grade 3 diarrhea was 12% with neratinib and 14% with neratinib + temsirolimus, which lasted for a median duration of 1.5 (interquartile range, 1.0‒2.0) days and 4.0 (interquartile range, 2.0‒16.0) days, respectively. Figure 1
Conclusion:
Neratinib (240 mg/day) + temsirolimus (8 or 15 mg/week) produced responses lasting 2 to 18+ months in 19% of patients with HER2‑mutant lung cancers. Correlative data will be presented at the meeting. Diarrhea was manageable with loperamide prophylaxis.
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.07 - Improved Small Cell Lung Cancer (SCLC) Response Rates with Veliparib and Temozolomide: Results from a Phase II Trial (ID 5517)
15:02 - 15:08 | Author(s): M.G. Kris
- Abstract
- Presentation
Background:
PARP1 is overexpressed in small cell lung cancer (SCLC) and represents a novel therapeutic target for this disease. Preclinical data indicates that combining veliparib (an oral PARP-1/2 inhibitor) and temozolomide (TMZ) results in synergistic tumor growth delay or regression. In this study, we investigated whether adding veliparib to TMZ would improve outcomes in patients with relapsed sensitive and refractory SCLCs. Candidate predictive biomarkers, including SLFN11, were then explored.
Methods:
SCLC patients previously treated with 1 or 2 prior regimens were enrolled in the trial and randomized 1:1 to receive oral TMZ 150-200mg/m[2]/day (D1-5) with either veliparib or placebo 40mg twice daily, orally (D1-7) (NCT01638546). Primary endpoint was 4-month progression free survival (PFS). Data were analyzed in patients with platinum sensitive (progression >60 days after 1st line therapy) or refractory disease (progression ≤60 days after 1st line therapy, or in need of 3rd line treatment). Archived tissue was available for 53 patients for biomarker analysis.
Results:
104 patients were enrolled and 100 patients were treated. Baseline characteristics were balanced between treatment arms: 52% female; median age 62.5 (range, 31-84); 59% refractory disease; 33% needing 3rd-line therapy. Progression free survival at 4-months was similar between the two arms, 36% vs. 27% (p=0.39). However, in 93 evaluable pts, response rate was significantly higher in pts treated with veliparib/TMZ compared to TMZ alone (39% vs 14%, p =0.016). Median overall survival: 8.2 mos (95% CI: 6.4-12.2) in veliparib arm and 7 mos (95% CI: 5.3-9.5) in placebo arm, p = 0.50. Grade 3/4 thrombocytopenia and neutropenia more commonly occurred in the veliparib/TMZ arm: 50% vs 9% and 31% vs 7%, respectively. Levels of SLFN11, a marker of SCLC response to PARP inhibition in preclinical models, were assessed by immunohistochemistry. High SLFN11 in patient tumors (obtained at original diagnosis) was associated with a trend towards better overall survival in the veliparib/TMZ arm, but no difference in outcome in the TMZ alone arm. Additional correlative studies are ongoing, including assessment of MGMT promoter methylation, and will be available at the time of presentation.
Conclusion:
The combination of veliparib/TMZ increased response rates significantly, compared to TMZ alone. Hematologic toxicities of the combination may have impacted PFS (which was not significantly different between the arms) by limiting dosing. Biomarkers such as SLFN11, ATM, or MGMT promoter methylation could potentially help guide patient selection in the SCLC population.
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OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:L.M. Montuenga, J. Heymach
- Coordinates: 12/06/2016, 11:00 - 12:30, Stolz 2
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OA11.05 - A Phase 2 Study of Cabozantinib for Patients with Advanced RET-Rearranged Lung Cancers (ID 5731)
11:35 - 11:45 | Author(s): M.G. Kris
- Abstract
- Presentation
Background:
RET rearrangements are actionable drivers found in 1-2% of non-small cell lung cancers. We previously reported the efficacy and safety of the multikinase RET inhibitor cabozantinib in 16 patients with RET-rearranged lung cancers in the first stage of our Simon two-stage phase 2 clinical trial (overall response rate 38%; Drilon, ASCO 2015). This study has since completed accrual of both stages, now with 26 patients treated with cabozantinib.
Methods:
This was an open-label, single center, phase 2 trial (NCT01639508). Eligibility criteria: stage IV pathologically-confirmed lung cancers, presence of a RET rearrangement, KPS >70%, and measurable disease. RET rearrangements were detected by FISH or next-generation sequencing. Cabozantinib was administered in tablet form at 60 mg daily until progression of disease or unacceptable toxicity. The primary objective was to determine the overall response rate (ORR, RECIST v1.1). Secondary objectives included determining progression-free survival (PFS), overall survival (OS), and toxicity. 5 responses in 25 response-evaluable patients were required to meet the primary endpoint (Simon two-stage minimax design: H~0~ 10% vs H~A~ 30% ORR). All patients who received at least one dose of cabozantinib were evaluable for toxicity.
Results:
26 patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The median number of prior chemotherapy lines was 1 (0-5). One patient who discontinued therapy in cycle 1 and did not undergo a response assessment was not response-evaluable as per protocol. The study met its primary endpoint with confirmed partial responses observed in 7 (ORR 28% [95% CI 12-49%]) of 25 response-evaluable patients. The median PFS was 5.5 months (95% CI 3.8-8.4). The median OS was 9.9 months (95% CI 8.1-not reached). Response by RET fusion partner: Unknown (FISH+) 2/6 (33%), KIF5B 3/15 (20%), CLIP1 1/1, TRIM33 1/1, CCDC6 0/1, ERC1 0/1. In 26 patients evaluable for toxicity, the most common all-grade treatment-related adverse events were increased alanine aminotransferase in 25 (96%) patients, increased aspartate aminotransferase in 19 (73%) patients, hypothyroidism in 18 (69%) patients, diarrhea in 16 (62%) patients, and palmar plantar erythrodysesthesia in 15 (58%) patients. Nineteen (73%) patients required dose reduction.
Conclusion:
This study met its primary endpoint. Cabozantinib is an active agent in patients with RET-rearranged lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed therapy.
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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: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-005 - Phase 1 Study of Ramucirumab or Necitumumab in Combination with Osimertinib (AZD9291) in Advanced T790M-Positive EGFR-Mutant NSCLC (ID 4278)
14:30 - 14:30 | Author(s): M.G. Kris
- Abstract
Background:
Despite the likelihood of an initial response to 1st or 2nd generation EGFR-TKI, EGFR mutant patients develop disease progression. The most frequent mechanism of acquired resistance is the EGFR T790M gatekeeper mutation. Novel treatment options are needed in this treatment resistant patient population. Osimertinib, a third-generation EGFR TKI targeting mutant EGFR including T790M, is an oral, irreversible, selective inhibitor. Ramucirumab and necitumumab are human IgG1 monoclonal antibodies to VEGFR-2 and EGFR, respectively. This phase 1, open-label, multicenter study with expansion cohorts (JVDL; NCT02789345) is designed to evaluate the safety and preliminary efficacy of ramucirumab or necitumumab in combination with osimertinib in patients with advanced EGFR T790M-positive NSCLC who have progressed after EGFR TKI therapy.
Methods:
This study includes patients with advanced or metastatic EGFR T790M-positive EGFR activating mutant (exon 19 deletions or L858R) NSCLC, with measurable disease and ECOG performance status 0-1 who have experienced disease progression on one prior EGFR TKI regardless of prior chemotherapy. Patients previously treated with an EGFR antibody or 3rd generation EGFR TKI for NSCLC are not eligible. In the phase 1a dose de-escalation portion (3+3 design), all patients (n=6 to 24) will be administered daily oral osimertinib (80 mg) with either an initial dose of 10 mg/kg IV ramucirumab on day 1 of every 2-week cycle or 800 mg IV necitumumab on days 1 and 8 of every 3-week cycle. One level of dose de-escalation is planned for each arm. A dose reduction (level -1) to 8 mg/kg IV ramucirumab or 600 mg IV necitumumab is planned if 2 or more patients have DLTs in either arm. After the DLT evaluation, the study will open a dose-expansion portion (phase 1b) and 25 patients in each Arm will receive study treatment until disease progression or a criterion for discontinuation is met. The primary objective is to assess safety and tolerability of ramucirumab or necitumumab in combination with osimertinib. Secondary endpoints include preliminary efficacy and pharmacokinetics. An exploratory biomarker objective includes the assessment of correlations between EGFR-mutations in tissue and serial blood samples with clinical outcomes. Primary analyses will be conducted approximately 6 months after the last patient receives initial dose.
Results:
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Conclusion:
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P2.06-019 - A Phase II Study of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients (pts) with Resectable Non-Small Cell Lung Cancer (NSCLC) (ID 4642)
14:30 - 14:30 | Author(s): M.G. Kris
- Abstract
Background:
There is no curative treatment for patients with NSCLC who develop metastatic disease after resection. Trials of neoadjuvant and adjuvant chemotherapy have demonstrated an absolute survival benefit of 5% for patients with stages IB, II, and IIIA disease. Clearly, developing new treatment strategies to improve survival following resection is critical to improving outcomes for this patient population. Immunotherapy with checkpoint inhibitors such as antibodies to PD-1 and PD-L1 has demonstrated superior survival compared to chemotherapy in randomized clinical trials. PD-L1 expression is being investigated as a predictive biomarker for these therapies, but its ability to predict response has varied in published trials. Atezolizumab is a humanized IgG1 monoclonal PD-L1 antibody that was recently evaluated in the POPLAR trial (NCT01903993), a phase II randomized trial of patients with NSCLC who progressed on platinum based chemotherapy. Atezolizumab therapy improved overall survival compared with docetaxel (12.6 months vs. 9.7 months, HR 0.73 [95% CI 0.53 – 0.99]) with a manageable safety profile. Improvement in survival correlated with PD-L1 immunohistochemistry expression of tumor and tumor-infiltrating immune cells.
Methods:
Trial design: This phase II, open-label, single-arm study is designed to evaluate the efficacy and safety of atezolizumab as a neoadjuvant therapy in patients with Stage IB, II, or IIIA NSCLC prior to curative-intent resection. Approximately 180 patients with NSCLC will be enrolled in this study at 15 academic medical centers in the United States. There are two parts to this study: the first/primary part will evaluate the ability of neoadjuvant atezolizumab to produce objective pathologic responses in patients with early stage NSCLC. Atezolizumab 1200 mg IV will be given every 3 weeks for two doses. Surgical resection of tumors following treatment will allow determination of pathologic response rates and potential predictive biomarkers. Part 2 is exploratory and will evaluate atezolizumab adjuvant therapy for up to 12 months in patients who demonstrate clinical benefit (evidence of pathologic response or absence of radiographic progression) in Part 1. After surgical resection, patients may receive SOC adjuvant chemotherapy (with or without radiation) before starting atezolizumab adjuvant therapy in Part 2. The primary objectives are safety and major pathologic response based on surgical resection. Secondary objectives include overall response rate based on PD-L1 status, mutational load, antigen burden, and RNA-sequencing. This trial presents a unique opportunity to evaluate exploratory biomarkers, including pre- and post-treatment biopsy assessment of evolution of immune related markers associated with response.
Results:
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Conclusion:
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