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K. Kelly
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MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:P. Van Houtte, M. Zemanová
- Coordinates: 12/05/2016, 16:00 - 17:30, Strauss 2
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MA06.10 - A Pooled Analysis Comparing the Outcomes of Elderly to Younger Patients on NCTN Trials of Concurrent CCRT for Stage 3 NSCLC (ID 4219)
16:00 - 17:30 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT
Methods:
Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models
Results:
IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).
a: Log-rank test for survival times, chi-square test for AE’s, and Fisher’s exact test for deaths. The P-values from these tests are unadjusted. b: Data available on 2,091 patientsAge ≥ 70yrs Age < 70 yrs P-value[a] Median OS (months) 17.0 20.7 < 0.01 Median PFS (months) 8.7 9.1 0.68 All toxicities grade ≥3 86% 84% 0.04 Hematologic AE’s grade ≥3 65% 61% 0.04 Non-hematologic AE’s ≥3 68% 62% <0.01 Grade 5 AE’s 9.0% 4.4% <0.01 TRT related deaths[b] 3.2% 2.0% 0.12
Conclusion:
Elderly pts in CCRT trials had worse OS, similar PFS, & a higher rate of severe AE's.
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.09 - First-In-Human Phase 1 Study of ABBV-399, an Antibody-Drug Conjugate (ADC) Targeting C-Met, in Patients with Non-Small Cell Lung Cancer (NSCLC) (ID 5008)
14:20 - 15:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
The c-Met receptor is overexpressed in ~50% of patients with NSCLC. ABBV-399 is a first-in-class ADC composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data support ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells.
Methods:
In a 3+3 dose-escalation design, ABBV-399 was administered at doses ranging from 0.15 to 3.3 mg/kg once every 21 days to patients with advanced metastatic solid tumors (NCT02099058). ABBV-399 was then studied in a dose-expansion cohort in 16 patients with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC that had progressed on ≥2 prior lines of therapy. ABBV-399 was also studied in combination with erlotinib in 10 patients with NSCLC, 8 of whom were c-Met+. Overexpression of c-Met was assessed by an IHC assay utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).
Results:
As of June 27, 2016, 48 patients with solid tumors received ≥1 dose of ABBV-399. The dose-limiting toxicity (DLT) for ABBV-399 was febrile neutropenia, which occurred in 2 patients (1 each at 3 and 3.3 mg/kg). There were no treatment-related deaths. Monotherapy treatment-related adverse events (AEs) occurring in ≥10% of patients (including all dose levels and all grades) were fatigue (25.0%), nausea (22.9%), neuropathy (14.6%), decreased appetite (12.5%), vomiting (12.5%), and hypoalbuminemia (10.4%). Based primarily on safety and tolerability, a 2.7-mg/kg dose was chosen for dose expansion in patients with c-Met+ advanced NSCLC. Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC patients had a confirmed partial response (PR) with duration of response (DOR) 3+, 3, and 4.5 months. At week 12, 6 of 16 patients treated (37.5%) had disease control. Ten patients received ABBV-399 in combination with erlotinib. No DLTs were observed and AEs related to ABBV-399 occurring in ≥2 patients were acneiform rash (40.0%), fatigue (30.0%), and dry skin (20.0%). Three of 8 (37.5%) evaluable ABBV-399 + erlotinib-treated c-Met+ patients had a confirmed PR with DOR 2+, 4+, and 5+ months. Two of the 3 patients with PR had EGFR-mutated tumor, and previous TKI- and platinum-based chemotherapy had failed.
Conclusion:
ABBV-399 is well tolerated at a dose of 2.7 mg/kg every 21 days and has demonstrated antitumor activity in patients with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Updated data of antitumor activity and safety of ABBV-399 as monotherapy and in combination with erlotinib in c-Met+ NSCLC patients will be presented.
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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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MA11.06 - SWOG 0124: Platinum-Sensitivity Status and Post-Progression Survival in Patients with Extensive-Stage Small Cell Lung Cancer (ID 3974)
14:20 - 15:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
Patients with extensive stage small cell lung cancer (ES-SCLC) who progress after frontline platinum-based chemotherapy are often considered “platinum-sensitive” (progression ≥ 90 days from last platinum dose) or “platinum-refractory” (progression < 90 days), as each group reportedly has differential overall survival (OS) outcomes. In a pooled analysis of recent SWOG trials of second and/or third-line targeted therapy, we showed that platinum-sensitivity status may no longer be as strongly associated with OS (Lara et al, JTO 2015). We assessed post-progression survival (PPS) following frontline platinum-based therapy in the context of platinum sensitivity status in ES-SCLC patients treated on SWOG 0124, a phase III trial of Irinotecan/Cisplatin vs Etoposide/Cisplatin.
Methods:
Data from 657 patients enrolled in S0124 were pooled. PPS was calculated as OS from the reported progression date. Crude PPS was evaluated according to platinum-sensitivity status. Hazard ratios (HRs) for PPS accounting for platinum-sensitivity and baseline clinical covariates (i.e., measured at the time of first line therapy) were calculated using single and multivariable Cox Proportional Hazard models. Baseline covariates were included in a logistic regression model to identify predictors of platinum-sensitivity. Recursive partitioning analysis (RPA) was performed to define prognostic risk groups.
Results:
Of 657 patients, 534 had a progression date and thus included in the analysis: 162 (25%) were platinum-sensitive and 372 (75%) refractory. Fewer patients with PS 0 (32% vs. 41%) and more patients with weight loss > 5% (40% vs. 31%) were seen in the refractory group. Crude unadjusted PPS was higher in platinum-sensitive vs refractory patients (median PPS 7.5 vs. 4.3 months; HR=1.64, p <0.001, 95%CI 1.356, 1.981). A multivariable Cox model showed that baseline elevated serum lactate dehydrogenase (LDH; HR=0.66, p<0.001) and platinum-sensitivity status (HR=1.54, p<0.001) were independently associated with PPS. None of the baseline covariates predicted for platinum-sensitivity. Prognostic groups with differential PPS based on platinum-sensitivity status, gender, and LDH were identified by RPA.
Conclusion:
PPS was significantly higher for S0124 patients categorized as platinum-sensitive vs. refractory. Limitations of this work include lack of relevant clinical data at the time of progression and number and type of post-progression therapies. These data have implications for the development of ES-SCLC trials in the salvage setting. [Supported by NIH/NCI/NCTN grants to SWOG: CA180888, CA180819, and in part by Pharmacia & Upjohn, a subsidiary of Pfizer. ClinicalTrials.gov Identifier: NCT00045162]
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.10 - Lung-MAP (S1400) Lung Master Protocol: Accrual and Genomic Screening Updates (ID 3995)
14:20 - 15:50 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.
Methods:
The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.
Results:
From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.
Conclusion:
Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490Total FGFR CDK PIK3CA FGFR (15.9%) 12.9% 2.4% 0.6% CDK (18.8%) 14.6% 1.8% PIK3CA (8.8%) 6.4% Biomarker prevalence and overlap.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.03 - JAVELIN Solid Tumor: Safety and Clinical Activity of Avelumab (Anti-PD-L1) as First-Line Treatment in Patients with Advanced NSCLC (Abstract under Embargo until December 5, 7:00 CET) (ID 3717)
11:00 - 12:30 | Author(s): K. Kelly
- Abstract
- Presentation
Background:
Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody that has shown antitumour activity in various malignancies. We report safety and clinical activity of avelumab as first-line therapy in a cohort of patients with non-small–cell lung cancer (NSCLC) from a phase 1b trial (NCT01772004).
Methods:
Patients with advanced NSCLC not previously treated systemically for metastatic or recurrent disease, without an activating EGFR mutation or ALK rearrangement, and not preselected for PD-L1 expression, received avelumab 10 mg/kg IV over 1 hour Q2W until progression, unacceptable toxicity, or study withdrawal. Objective response rate (ORR) and progression-free survival (PFS) were evaluated by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0.
Results:
As of 23 Oct 2015, 145 patients had received avelumab (median 10 weeks of treatment; range 2-30) and were followed for a median of 13 weeks (range 0-31). Median age was 70 years (range 41-90), ECOG PS was 0 (31.0%) or 1 (69.0%), and tumour histology was adenocarcinoma (63.4%) or squamous (26.9%) in most patients. Eighty-two patients (56.6%) had a treatment-related (TR) AE; those occurring in ≥10% were infusion-related reaction (IRR; n=24, 16.6%) and fatigue (n=21, 14.5%). Thirteen patients (9.0%) had a grade ≥3 TRAE; only IRR and fatigue occurred in >1 patient (each n=3, 2.1%). Four patients (2.8%) had a potential immune-mediated TRAE, all grade 1-2 (pneumonitis n=3, 2.1%; hypothyroidism n=1, 0.7%). There were no treatment-related deaths. Among 75 patients with ≥3 months’ follow-up, unconfirmed ORR was 18.7% (95% CI: 10.6, 29.3) based on 1 complete response and 13 partial responses; 12 were ongoing. Thirty-four additional patients (45.3%) had stable disease as best response (disease control rate 64.0%). Updated analysis will be presented, including efficacy data with ≥3 months’ follow-up in all patients and PD-L1 analysis.
Conclusion:
First-line avelumab monotherapy showed clinical activity and was well-tolerated in patients with EGFR-wildtype/ALK-negative NSCLC unselected for PD-L1 expression. A phase 3 trial of avelumab vs platinum-doublet in first-line NSCLC is in progress. *Proposed nonproprietary name.
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OA10 - EGFR Mutations (ID 382)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
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OA10.01 - Comprehensive Genomic Profiling and PDX Modeling of EGFR Exon 20 Insertions: Evidence for Osimertinib Based Dual EGFR Blockade (ID 4375)
11:00 - 12:30 | Author(s): K. Kelly
- Abstract
Background:
EGFR exon 20 insertion mutations (EGFRex20ins) comprise a subset of EGFR activating alterations relatively insensitive to 1[st] and 2[nd] generation EGFR-TKIs. Comprehensive genomic profiling (CGP) integrated with PDX modeling may identify new EGFR-inhibition strategies for EGFRex20ins.
Methods:
EGFRex20ins and co-occurring genomic alterations were identified by hybrid-capture based CGP performed on 14,483 consecutive FFPE lung cancer specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. An EGFRex20ins(N771_P772>SVDNP)/EGFR-amplified tumor (24 copies) from this cohort was implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid]Il2rg[tm1Wjl]/SzJ (NSG) mice for tumor growth inhibition studies (TGI) with vehicle, erlotinib (50 mg/kg PO daily), osimertinib (25 mg/kg PO daily), and osimertinib (25 mg/kg PO daily) plus cetuximab (10 mg/kg IV, 2x/week) administered for 21 days.
Results:
CGP identified 263/14,483 cases (1.8%) with EGFRex20ins, which represent 12% (263/2,251) of EGFR activating mutations in this series. 90% (237/263) were NSCLC-adenocarcinoma, 9% (23/263) were NSCLC-NOS, and 1% (2/263) were sarcomatoid carcinoma. Over 60 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%); 6% (15/263) harbored EGFR A763_Y764insFQEA, an EGFRex20ins typically sensitive to erlotinib. Among EGFRex20ins cases, EGFR-amplification occurred in 22% (57/263). Putative co-occurring driver alterations including EGFR (ex19del and L858R), Her2, MET and KRAS tended to be mutually exclusive, occurring only in 5% (12/263) of cases. The most common co-occurring alterations affected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%). Average tumor mutation burden was low (mean 4.3 mutations/Mb, range 0-40.3 mutations/Mb). Clinical outcomes to 1st and 2nd generation EGFR-TKIs were obtained for a subset of cases with various EGFRex20ins, and 0/6 patients had responses. However, robust TGI was observed with combination osimertinib and cetuximab in a highly EGFR-amplified PDX model with a conserved EGFRex20ins (N771_P772>SVDNP) not associated with response to earlier generation EGFR-TKI, and was superior to vehicle, erlotinib or osimertinib alone (D21 mean tumor size 70 mm[3] vs. 1000, 800, 225 mm[3] respectively; p-values all <0.001).
Conclusion:
Diverse EGFRex20ins were detected in 12% of EGFR-mut NSCLC. Available clinical outcomes data demonstrated lack of response to 1[st] and 2[nd] generation EGFR-TKIs. Identification of co-occurring EGFR-amplification in 22% of cases led to testing of a dual EGFR blockade strategy with an EGFR monoclonal antibody and osimertinib, which demonstrated exceptional tumor growth inhibition in an EGFRex20ins PDX minimally responsive to erlotinib. These findings can rapidly be translated into an ongoing clinical trial of osimertinib and necitumumab.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-053 - Role of KRAS Mutation Status in NSCLC Patients Treated on SWOG S0819, a Phase III Trial of Chemotherapy with or without Cetuximab (ID 6113)
14:30 - 15:45 | Author(s): K. Kelly
- Abstract
Background:
The S0819 phase III study of chemotherapy and bevacizumab (by patient/physician choice) with or without cetuximab in NSCLC showed no benefit from the addition of cetuximab, either overall or within the EGFR FISH-positive subset. Secondary analysis suggested an overall survival benefit in EGFR FISH-positive squamous cell carcinoma (SCC) (Herbst WCLC 2015, Hirsch ASCO 2016). In colorectal cancer (CRC), benefit from EGFR monoclonal antibodies such as cetuximab is limited to patients with RAS wild type (WT) tumors; however, in NSCLC, previous studies have not been sufficiently powered to make this determination. We prospectively incorporated KRAS mutation testing in S0819 to determine whether it predicts cetuximab efficacy. Since KRAS mutations are rare in SCC, we focused this analysis on nonSCC.
Methods:
KRAS mutation status was determined using the Therascreen KRAS test (Qiagen), conducted in a CLIA-certified diagnostic laboratory at the UC Davis Comprehensive Cancer Center. This test is FDA-approved for KRAS diagnostics in metastatic CRC, and identifies 6 mutations at codon 12 (G12A,D,R,C,S,V) plus G13D.
Results:
KRAS mutation status was available for 448 nonSCC patients, and mutations were identified in 150 cases (33%). Amino acid substitutions matched the expected distribution for a NSCLC population, with 52% harboring G12C and 17% with G12V. No significant differences were observed between KRAS-mut and WT populations for PFS (HR=1.15 (0.94-1.42); p=0.18) or OS HR=1.10 (0.89-1.37); p=0.39). Furthermore, no differences in outcomes between arms were observed based on KRAS mutation status (Table). The KRAS WT, EGFR FISH+ molecular subset (hypothetically the most likely subgroup to benefit from cetuximab) showed no statistical differences in outcomes between arms. Figure 1
Conclusion:
Determination of KRAS mutation status did not identify a subgroup of nonSCC patients with differential outcome from addition of cetuximab to front-line chemotherapy. In contrast to CRC, cetuximab does not appear to confer benefit to patients with KRAS-WT nonSCC NSCLC.
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P3.02b - Poster Session with Presenters Present (ID 494)
- 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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P3.02b-052 - Afatinib with or without Cetuximab for First-Line Treatment of EGFR-Mutant NSCLC: Interim Safety Results of SWOG S1403 (ID 5798)
14:30 - 15:45 | Author(s): K. Kelly
- Abstract
Background:
Afatinib is used as first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC), however resistance invariably develops. To attempt to delay resistance and improve survival, we are conducting a randomized Phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722).
Methods:
Previously untreated patients with EGFR exon 19 deletion or L858R point mutation are randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks (afat/cetux) or afatinib 40mg PO daily (afat). Dose reductions are performed for grade 3-4 or intolerable or medically concerning grade 2 adverse events (AEs) per CTCAE v4.0. The Phase II primary endpoint is progression-free survival and the Phase III primary endpoint is overall survival. Here we review the safety data after enrollment of the first 53 patients.
Results:
53 patients were registered as of June 30, 2016, and safety has been assessed in 47 (23 treated with afat/cetux and 24 with afat, see Table). Grade 1-2 rash occurred in 71% of patients receiving afat/cetux and 63% of patients on afat. Grade 3 rash was noted in 22% of patients on afat/cetux. Fatigue was more common in the combination arm; all occurrences were grade 1-2. Grade 1-2 diarrhea and other gastrointestinal AEs were comparable between the two arms. There were similar numbers of dose reductions for AEs on each arm. Three patients discontinued treatment due to AEs: 2 on the afat/cetux arm due to hyperglycemia and accumulated side effects and 1 on the afat arm due to weight loss and diarrhea. Figure 1
Conclusion:
In this randomized trial of afat/cetux versus afat, treatment was tolerable in both arms of the study. Skin toxicity appears to be worse with the combination however other AEs are similar between the two groups. Enrollment to this trial is ongoing.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-056 - Interim Results From the Phase I Study of Nivolumab + nab-Paclitaxel + Carboplatin in Non-Small Cell Lung Cancer (NSCLC) (ID 4127)
14:30 - 15:45 | Author(s): K. Kelly
- Abstract
Background:
Chemotherapy, including nab-paclitaxel, plus an immune checkpoint inhibitor has demonstrated antitumor activity in patients with metastatic breast cancer (mBC) and NSCLC. Here, results from the 2 lung cohorts of the phase I nivolumab + nab-paclitaxel in pancreatic cancer (± gemcitabine), NSCLC (+ carboplatin), and mBC safety trial are presented.
Methods:
Enrollment in the lung cohorts (C and D) was initiated in two sequential parts: Dose-limiting toxicity (DLT) evaluation was done in Part 1 prior to treatment arm expansion in Part 2. Chemotherapy-naive patients with stage IIIB/IV NSCLC received 4 cycles of nab-paclitaxel 100 mg/m[2] D 1, 8, 15 + carboplatin area under the curve (AUC) 6 D 1 + nivolumab 5 mg/kg D 15 (starting in cycle 1 [Arm C] or cycle 3 [Arm D]) of each 21-day cycle; nivolumab continued as monotherapy from cycle 5. Primary endpoints were DLTs (Part 1), and grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation (Parts 1 and 2). Patients who received ≥ 2 nivolumab cycles and remained on study for 14 days after the last nivolumab dose or discontinued due to DLT prior to completing 2 nivolumab cycles were considered DLT-evaluable. Key secondary endpoints include safety, PFS, OS, and ORR.
Results:
As of May 25, 2016, 21 patients have enrolled in Arm C (18 nivolumab-treated); most were aged ≥ 65 years (57.1%) and female (71.4%), 33.3% had ECOG PS 0, 42.9% and 33.3% had adenocarcinoma and squamous cell carcinoma, respectively. No DLTs were reported (5 DLT-evaluable patients). The most common grade 3/4 AEs in Arm C (all patients) were neutropenia (28.6%), anemia (19.0%), and hypokalemia (14.3%); gastrointestinal disorders (11.1%) were the most frequent grade 3/4 immune-related AE in nivolumab-treated pts. Seven patients (5 nivolumab-treated) discontinued treatment (majority due to progressive disease [PD]). Of the 18 nivolumab-treated patients, 9 had a PR, 8 had stable disease, and data is pending in 1 patient; tumor shrinkage (baseline to nadir) ranged from 3% to 83%. The median PFS (n = 4 with PD or death; nivolumab-treated) was 7.3 months (treatment duration, 0.7 - 9.4 months). Eight patients have enrolled in Arm D (4 nivolumab-treated); 1 DLT (pneumonitis) was reported in 4 DLT-evaluable patients.
Conclusion:
These results demonstrate that the combination of nivolumab with nab-paclitaxel/carboplatin is tolerable and has promising antitumor activity in patients with NSCLC. Updated results will be presented at the meeting. (NCT02309177)
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P3.02c-102 - Safety and Tolerability of Abemaciclib Combined with LY3023414 or with Pembrolizumab in Patients with Stage IV NSCLC (ID 4625)
14:30 - 15:45 | Author(s): K. Kelly
- Abstract
Background:
Currently, treatment options are limited for patients with advanced and/or metastatic NSCLC particularly after initial treatment. In a prior phase 1 study, abemaciclib, a CDK4 & 6 inhibitor, demonstrated single-agent anti-tumor activity when dosed orally on a continuous schedule, with an acceptable safety profile in patients with previously treated metastatic NSCLC (NCT01394016). PI3kinase is an escape pathway after CDK inhibition in tumor models and aberrant immunity is a hallmark of cancer, providing the rationales to combine abemaciclib with PI3K and with checkpoint inhibitors. An ongoing Phase 1b multicenter, open-label, 3+3 dose-escalation trial with an expansion phase is investigating abemaciclib in combination with multiple single-agent options in metastatic NSCLC (NCT02079636). Here we report preliminary results for two arms of the study.
Methods:
In Part D, abemaciclib was administered orally on a continuous schedule every 12 hours (q12h) in combination with the PI3K/mTOR inhibitor, LY3023414, at 100, 150, or 200 mg q12h. In Part E, abemaciclib was administered in combination with the anti-PD-1 antibody, pembrolizumab (200 mg I.V. infusion q3 weeks). Patients with late stage NSCLC and 1-3 prior therapies without central nervous system metastasis were treated until disease progression or other discontinuation criteria were met. Primary endpoints for each cohort included safety/tolerability and identification of the recommended phase 2 dose. Safety assessments followed the Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0). Parts D and E began enrolling patients on April 13, 2015 and April 29, 2016, respectively.
Results:
As of August 24, 2016, Parts D and E escalation included, respectively, 22 [male (64%)/Caucasian (77%)/stage IV (91%)/adenocarcinoma (91%)] and 6 patients [male (33%)/Caucasian (100%)/stage IV (67%)/adenocarcinoma (100%)]. ECOG PS was ≤1 in both cohorts. In Part D, 1 patient on dose level-2 (DL-2) experienced a dose limiting toxicity (DLT) (G4 thrombocytopenia). Evaluation of additional dose levels is ongoing. Seventeen patients (77%) experienced ≥1 treatment-related emergent adverse event (TRAE). Common TRAEs were nausea (50%), diarrhea (50%), vomiting (36%), fatigue (32%), and decreased appetite (27%). In Part E, no DLTs or deaths occurred in the two dosing cohorts evaluated. Four patients (67%) experienced ≥1 TRAE with 75% G1/2. Common TRAEs included fatigue (50%), diarrhea and proteinuria, (33%, each).
Conclusion:
The majority of previously treated advanced/metastatic NSCLC patients administered abemaciclib with LY3023414 or with pembrolizumab had manageable and tolerable adverse events, similar to those of the single agents.
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PC02 - By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV (ID 324)
- Event: WCLC 2016
- Type: Pro Con
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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PC02.03 - Contra Chemotherapy (ID 6597)
14:30 - 15:45 | Author(s): K. Kelly
- Abstract
Abstract:
By 2030 Chemotherapy will Remain Standard of Care for the Majority of Patients with NSCLC Stages I-IV: Contra Chemotherapy Cytotoxic chemotherapy has undeniably provided benefit for our patients with non-small cell lung cancer (NSCLC). However its nondiscriminatory application based on general tumor biology principles and not on the underlying biology of lung cancer has hampered its ability to dramatically improve survival and cures for lung cancer. Over the last twenty years we have seen multiple examples of how molecular characterization of lung tumors coupled with advances in drug development, have led to astonishing improvements in cancer outcomes. Hence, it is time to set a course toward abandoning chemotherapy. In addition to their superior efficacy, targeted therapies and immunotherapy have milder toxicity profiles compared to chemotherapy that all patients appreciate. We have already made significant progress in this quest. Our journey began with the discovery of EGFR (epidermal growth factor receptor) mutations and their exquisite sensitivity to EGFR-TKI (tyrosine kinase inhibitors). This observation was confirmed in the landmark IPASS trial that demonstrated the superiority of EGFR-TKIs over platinum-based chemotherapy for the first line treatment of patients whose tumors harbor these mutations (1). On the heels of this therapeutic advancement came the discovery of ALK (anaplastic lymphoma kinase) gene rearrangements and the replacement of doublet chemotherapy with an ALK-TKI in patients with ALK positive tumors (2). To date actionable driver mutations are found in at least 50% of patients with adenocarcinoma (3) and inhibitors to all of these mutations are in clinical development with the hope that they will have similar success as their predecessors. Of particular interest is developing inhibitors to KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) because it is the most frequent driver mutation occurring in approximately 20-25% of tumors. Today there is optimism that we will achieve this goal given it is the focus of the Stand Up To Cancer (SU2C) lung cancer dream team initiative and several novel agents are in development including direct KRAS therapy. Driver mutations are typically identified in patients who are never smokers, light former smokers or have a lengthy quit time. The remaining groups of patients’ (i.e. current smoker or recent former smokers) have a different biology that has been successfully exploited with immunotherapy. Immune checkpoint inhibitors have replaced single agent docetaxel as the standard of care for second line treatment of lung cancer for all histological subtypes of NSCLC (4-6). Most recently the KEYNOTE-024 a randomized trial of pembrolizumab versus doublet chemotherapy for untreated patients with advanced NSCLC whose tumor have > 50% PD-L1 (programmed death-ligand 1) IHC (immunohistochemistry) expression met its primary progression-free survival (PFS) endpoint and also improved overall survival (7). This will represent a new standard of care for approximately 25% of patients and will serve as the backbone for immune combinations. We are anxiously awaiting the results of a randomized trial of a PD-1 (programmed cell death protein 1) inhibitor plus a CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitor versus platinum-based chemotherapy that is expected to report out in mid 2017. A similar study is actively accruing patients. The preliminary results on this dual immune combination were very promising and if positive would increase the number of patients receiving upfront immune therapy over chemotherapy (8). Additionally, there are numerous immune combinations involving drugs that target immune evasion and even more drugs that stimulate the immune system including cellular therapies that are being evaluated. The success of targeted therapy and immunotherapy in the advanced setting has quickly led to their evaluation in earlier stages of disease. There is a lot of enthusiasm for combining immunotherapy with radiation for patients with locally advanced lung cancer given the well-known immune modulatory effects of radiation. Moreover the bar for replacing weekly low dose concurrent chemotherapy with immunotherapy is low. In the adjuvant setting our Asian colleagues designed and conducted two randomized phase III trials in patients whose tumors have an EGFR sensitizing mutation to replace chemotherapy with an EGFR-TKI. Accrual is completed and we are awaiting the results. In regard to immunotherapy, enrolling phase III trials are evaluating immune checkpoint inhibitors as maintenance therapy but the pursuit of immunotherapy as a replacement for chemotherapy will follow. Beyond treatment of lung cancer, on the horizon is the exploration of targeted agents and immunotherapy as preventive agents. It is important to emphasize that our current and future success is the consequence of many factors: 1) the exponential advances in technology that has driven the science and drug development 2) rapid trial accrual and 3) regulatory authorities’ responsiveness to bringing efficacious treatments to patients as quickly as possible. This momentum is what will lead us to replacing chemotherapy for lung cancer. With 20%+ of patients with driver mutations and 25% of all NSCLC with high PD-L1 already benefiting from non-chemotherapy treatment, we are well on our way to ousting chemotherapy in NSCLC by 2030. References Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma. N Engl J Med 2009, 361:947-57. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013, 368:2385-94. Vigneswaran J, Tan YH, Murgu SD, et al. Comprehensive genetic testing identifies targetable genomic alterations in most patients with non-small cell lung cancer, specifically adenocarcinoma, single institute investigation. Oncotarget 2016, 7:18876-86. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373:123-35. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015, 373: 1627-39. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016, 387:1540-50. MERCK press release, July 2016 Hellman MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001).
