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Paul K. Paik
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MTE 18 - Treatment for Squamous Cell Carcinoma (Sign Up Required) (ID 567)
- Event: WCLC 2017
- Type: Meet the Expert
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 07:00 - 08:00, Room 313 + 314
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MTE 18.01 - Treatment for Squamous Cell Carcinoma (ID 7800)
07:00 - 08:00 | Presenting Author(s): Paul K. Paik
- Abstract
- Presentation
Abstract:
Squamous cell lung cancers (SQCLC) account for between 15-25% of non-small cell lung cancer (NSCLC) cases. They are, biologically, quite distinct from lung adenocarcinomas, though this remains a fact that has had little positive effect to date in the management of this disease. Indeed, despite the FDA approval of a handful of new drugs for patients with SQCLCs since 2014, progress has been, for most, limited, reflecting the modest gains in survival achieved by these new agents. Navigating the treatment landscape has been, by turns, straight-forward and frustrating. This is most evident in the first-line setting where, apart from patients whose tumors exhibit high expression of PD-L1, a variety of platinum-based chemotherapy options are available, all with more or less equivalent efficacy as shown in Table 1:
Second-line therapy is dictated then largely through exclusion. Patients who received pembrolizumab as first-line treatment will cycle through platinum-based chemotherapy. Patients who received platinum-based chemotherapy will, by and large, cycle through any one of a number of FDA-approved PD-1/PD-L1 antibody therapies, all with equivalent efficacy (pembrolizumab, nivolumab, atezolizumab). Docetaxel +/- ramucirumab is thus relegated to the de facto third-line option. There are, arguably, few clinically meaningful therapeutic options beyond this; the data behind these options will be discussed in further detail. Most recently, attempts have been made to target putative oncogenic drivers in this disease, based on larger scale genomic analyses and pre-clinical experiments generated TCGA and others.(4-6) Three relatively large-frequency signaling pathways and targets have been tested in early phase trials, including FGFR1 amplification, PI3K pathway alterations, and G1/S checkpoint aberrations both by individual groups and SWOG (LUNG-MAP, S1400). In short, there has been modest to no efficacy in targeted therapy trials to date. These studies are summarized in Table 2:cisplatin + gemcitabine + necitumumab(1) cisplatin + gemcitabine(1) carboplatin + nab-paclitaxel(2) carboplatin + paclitaxel(2) cisplatin + docetaxel(3) ORR (%) 31 29 41 24 37 Median PFS (mo) 5.7 5.5 5.6 5.7 - Median OS (mo) 11.5 9.9 10.7 9.5 11.3
Most of these studies have lacked detailed molecular analyses of patient tumor samples, hampering our ability to determine why these targeted efforts have largely failed. One exception is the study of AZD4547 in FGFR1 amplified SQCLCs, where correlative tests demonstrated that focal amplification of FGFR1 in the 8p11 amplicon does not occur in the majority of cases, commensurate with relatively low mRNA and protein expression of the gene.(7) Overall, heterogeneity with regard to aberrations in overlapping signaling pathways and clonal diversity remains a concern. The rationale for and data from other studies will also be discussed, including early data from combination chemotherapy plus PD-1/L1 inhibition trials as well as potential future directions for research. References 1. Thatcher N, Hirsch F, Luft A, Szczesna A, Ciuleanu T, Szafranski W, et al. A randomized, multicenter, open-label, phase III study of gemcitabine-cisplatin (GC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus GC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC). J Clin Oncol. 2014:abstr 8008. 2. Socinski MA, Bondarenko I, Karaseva NA, Makhson AM, Vynnychenko I, Okamoto I, et al. Weekly nab-Paclitaxel in Combination With Carboplatin Versus Solvent-Based Paclitaxel Plus Carboplatin as First-Line Therapy in Patients With Advanced Non–Small-Cell Lung Cancer: Final Results of a Phase III Trial. Journal of Clinical Oncology. 2012;30:2055-62. 3. Kubota K, Watanabe K, Kunitoh H, Noda K, Ichinose Y, Katakami N, et al. Phase III Randomized Trial of Docetaxel Plus Cisplatin Versus Vindesine Plus Cisplatin in Patients With Stage IV Non-Small-Cell Lung Cancer: The Japanese Taxotere Lung Cancer Study Group. Journal of Clinical Oncology. 2004;22:254-61. 4. TCGA Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489(7417):519-25. 5. Paik PK, Shen R, Won H, Rekhtman N, Wang L, Sima CS, et al. Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases. Cancer Discovery. 2015;5:610-21. 6. Kim Y, Hammerman PS, Kim J, Yoon J-a, Lee Y, Sun J-M, et al. Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients. Journal of Clinical Oncology. 2014;32:121-8. 7. Paik PK, Shen R, Berger MF, Ferry D, Soria J-C, Mathewson A, et al. A Phase 1b Open Label Multicentre Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers. Clinical Cancer Research. 2017. 8. Nogova L, Sequist LV, Garcia JMP, Andre F, Delord J-P, Hidalgo M, et al. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. Journal of Clinical Oncology. 2017;35:157-65. 9. Lim SH, Sun J-M, Choi Y-L, Kim HR, Ahn S-M, Lee JY, et al. Efficacy and Safety of Dovitinib in Pretreated Advanced Squamous Non-small Cell Lung Cancer with FGFR1 Amplification: A Single-arm, Phase II Study. Cancer. 2016. 10. Vansteenkiste JF, Canon J-L, De Braud F, Grossi F, De Pas T, Gray JE, et al. Safety and Efficacy of Buparlisib (BKM120) in Patients With PI3K Pathway-Activated Non-Small Cell Lung Cancer (NSCLC): Results From the Phase II BASALT-1 Study. Journal of Thoracic Oncology. 2015;Publish Ahead of Print. 11. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al. Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discovery. 2016.Target Frequency Drug ORR FGFR1 amplification Up to 20% AZD4547(7) 8% BGJ-398(8) 15% Dovitinib(9) 11.5% PI3K pathway Up to 50% BKM120(10) 0% GDC-0032(ASCO 2017) 5% G1/S checkpoint Up to 50% Abemaciclib(11) 17%
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:00 - 12:30 | Author(s): Paul K. Paik
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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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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P1.03-028 - A Phase II Trial of Albumin-Bound Paclitaxel and Gemcitabine in Patients with Untreated Stage IV Squamous Cell Lung Cancers (ID 8556)
09:30 - 16:00 | Presenting Author(s): Paul K. Paik
- Abstract
Background:
Therapeutic options for squamous cell lung cancer (SQCLC) patients remain limited. Platinum-based chemotherapies, which have been the standard first-line treatments for nearly 20 years, are associated with ORR=30-40%, median PFS=4-5.7mo, and median OS=9-11.5mo. We previously reported the results of a phase 1/2 trial of albumin-bound paclitaxel (ABP) in 40 patients with untreated stage IV NSCLC, noting an ORR of 30%, median PFS of 5mo, and median OS of 11mo (Rizvi JCO 2008). These data suggest that platinum adds little when coupled to ABP. Conversely, compelling evidence of anti-tumor synergy between gemcitabine and ABP was recently demonstrated by Frese et al. who showed that ABP downregulates cytidine deaminase (which inactivates gemcitabine), leading to increased intratumoral [gemcitabine] (Cancer Disc 2012). Based on these data, we sought to assess the efficacy of ABP + gemcitabine in patients with SQCLC.
Method:
This is a phase II trial of ABP (100mg/m[2]) + gemcitabine (1000mg/m[2]) given on D1, D8, D15 of an every 4 week cycle (A1) in patients with untreated stage IV SQCLC. Patients received up to 6 cycles and were followed thereafter (A1). The primary endpoint is best objective response (RECIST 1.1). The study utilizes a Simon two-stage design with H0=25% (6/17 responses) and H1=45% (16/41 responses). After clearing the first stage, the study was amended to a 3 week cycle (D1, D8 treatment); to allow ABP + gemcitabine until progression; and to allow maintenance ABP to begin after C4 for tolerability (A2). PFS, TTP, and OS were calculated using the Kaplan-Meier method. Patients underwent NGS by MSK-IMPACT for genotype-phenotype correlation.
Result:
N=17 patients (14 evaluable) were treated on A1 and, to date, N=3 patients (2 evaluable) have been treated on A2. Median age=70, female=30%, median KPS=90%, smokers=90%, median pack years=32. Median cycles of therapy in A1=4. Grade ≥3 related AEs included: peripheral neuropathy (5%); diarrhea (5%); elevated ALT (5%); anemia (15%); and decreased neutrophils (25%). Three patients (15%) experienced a related SAE including G3 decreased WBC, G3 diarrhea, and G3 lung infection. There was 1 unrelated death as a result of complications from a G3 mechanical fall. ORR in A1=50% (7/14 PRs). ORR in A2=100% (2/2 PRs). ORR in A1+A2=56% (9/16 PRs). SD=6 (38%) and PD=1 (6%). Median PFS=5.8mo; TTP=6.9mo; OS=13.3mo.
Conclusion:
ABP + gemcitabine has promising efficacy and is relatively well-tolerated, particularly when compared to platinum regimens. Accrual to the study is ongoing and updated data, including NGS correlates, will be presented.
