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M. Sebastian
Moderator of
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 12
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.01 - Dual Blockade of PD-1 and C5a/C5aR Synergistically Protects against Non-Small Cell Lung Cancer Tumor Growth (ID 5261)
14:20 - 14:26 | Author(s): D. Ajona, S. Ortiz, H. Moreno, S. Vicent, L.M. Montuenga, F. Lecanda, R. Pio
- Abstract
- Presentation
Background:
Immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors has emerged as a powerful tool for the treatment of lung cancer. To further enhance the antitumor efficacy of individual treatments, numerous ongoing studies are trying to identify synergistic combinations that simultaneously block more than one immunomodulatory pathway. C5aR1 is a G protein-coupled receptor activated by C5a, an anaphylatoxin released during the activation of the complement system, a major component of innate immunity. We have previously shown in a murine model of lung cancer that pharmacological blockade of C5aR1 reduces cancer progression by reversing the immunosuppressive microenvironment. Thus, we hypothesized that a combined inhibition of C5aR1 and PD-1 may have a synergistic effect in the treatment of lung cancer.
Methods:
We characterized the immunosuppressive activity of C5aR1 and evaluated the therapeutic efficacy of the dual administration of PD-1 and C5a/C5aR1 antagonists in syngeneic non-small cell lung cancer mouse models. The RMP1-14 monoclonal antibody was used to block PD-1, and a PEG-modified L-aptamer, which binds to complement C5 and C5a, was used to inhibit the C5a/C5aR1 interaction.
Results:
Kras[G12D/+] mice deficient for C5aR (Kras[G12D/+];C5aR1[Δ/Δ]) had a lower lung tumor burden and survived longer than Kras[G12D/+];C5aR1[wt/wt] littermates. Interestingly, Kras[G12D/+];C5aR1[Δ/Δ] mice showed a significant reduction of myeloid-derived suppressor cells (MDSCs), a subpopulation of immune cells that profoundly influences the effectiveness of cancer immunotherapies. We therefore evaluated whether C5a/C5aR blockade may enhance the efficacy of anti-PD-1 therapy by reversing the immunosuppressive microenvironment. In the Kras/Tp53 mutant 393P syngeneic lung cancer model, the combination of C5a and PD-1 blockade dramatically reduced in vivo tumor growth, as compared to the effect of each treatment alone. Similarly, this combination showed a remarkable synergistic antitumor effect in Lewis lung carcinoma (3LL)-bearing mice. Survival analysis confirmed the benefit of the combined treatment. Finally, the therapeutic combination significantly diminished the in vivo metastatic capacity of the highly aggressive Lacun3 lung cancer cell line in syngeneic BALB/c mice, as compared to the effect of anti-PD-1 or anti-C5a drugs as monotherapy.
Conclusion:
Our study supports the notion that the efficacy of anti-PD-1 therapy is limited by the immunosuppressive tumor microenvironment. In this context, C5a/C5aR1 blockade concomitant to anti-PD1 therapy obliterates the resistance mechanisms mediated by MDSCs, improving antitumor immune responses. These findings provide a framework for the clinical evaluation of this therapeutic strategy.
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MA09.02 - Pembrolizumab + Carboplatin and Pemetrexed as 1st-Line Therapy for Advanced Non–Small Cell Lung Cancer: KEYNOTE-021 Cohort G (ID 5787)
14:26 - 14:32 | Author(s): C. Langer, S.M. Gadgeel, H. Borghaei, V. Papadimitrakopoulou, A. Patnaik, S. Powell, R.D. Gentzler, R.G. Martins, J.P. Stevenson, S. Jalal, A. Panwalkar, J.C. Yang, M. Gubens, L.V. Sequist, J. Fiore, J. Ge, H. Raftopoulos, L. Gandhi
- Abstract
- Presentation
Background:
Platinum doublet chemotherapy ± bevacizumab is standard first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) without genetic aberrations. Single-agent pembrolizumab exhibits robust antitumor activity in PD-L1–positive advanced NSCLC. Cohort G of the multicenter, open-label, phase 1/2 multicohort KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated the efficacy and safety of pembrolizumab + carboplatin and pemetrexed compared with carboplatin and pemetrexed in patients with treatment-naive advanced nonsquamous NSCLC with any PD-L1 expression.
Methods:
Cohort G enrollment criteria included patients with stage IIIB/IV nonsquamous NSCLC, no activating EGFR mutation or ALK translocation, no prior systemic therapy, measurable disease, ECOG performance status 0-1, and adequate tumor sample for assessment of PD-L1 status, regardless of PD-L1 expression. Patients were randomized 1:1 to 4 cycles of pembrolizumab 200 mg Q3W + carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W or carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W alone, followed by maintenance pemetrexed ± pembrolizumab. Pembrolizumab was given for ≤35 cycles. Randomization was stratified by PD-L1 expression (positive [tumor proportion score, or TPS, ≥1%] vs negative [TPS <1%]). Crossover to pembrolizumab monotherapy was allowed for eligible patients who experienced disease progression (RECIST v1.1) on chemotherapy. Response was assessed by central imaging vendor review every 6 weeks for first 18 weeks, every 9 weeks through year 1, and every 12 weeks in year 2. The primary end point was objective response rate (ORR); secondary end points included progression-free survival (PFS), duration of response, and overall survival (OS). Comparison between arms was assessed using the stratified Miettinen and Nurminen method (ORR) and stratified log-rank test (PFS, OS).
Results:
As of January 2016, 123 patients (60 in the pembrolizumab + chemotherapy arm, 63 in the chemotherapy arm) had been enrolled in cohort G. Data on ORR, duration of response, safety, and preliminary PFS and OS results will be available by August 2016.
Conclusion:
The conclusion will be updated at the late-breaking submission stage.
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MA09.03 - Cisplatin/Pemetrexed + Durvalumab +/- Tremelimumab in Pts with Advanced Non-Squamous NSCLC: A CCTG Phase IB Study - IND.226 (ID 5522)
14:32 - 14:38 | Author(s): R.A. Juergens, D. Hao, S.A. Laurie, M. Mates, M. Tehfe, P. Bradbury, C. Kollmannsberger, P.M. Ellis, J.F. Hilton, P. Brown-Walker, L. Seymour
- Abstract
- Presentation
Background:
Immune checkpoint inhibitors are now established therapies in many advanced cancers. Preliminary studies suggest combining immune checkpoint inhibitors with platinum-based chemotherapy may enhance anti-tumour activity. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, ± tremelimumab (Tr), a CTLA-4 inhibitor, in combination with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract focuses on the pem / cisplatin cohort in non-squamous non-small cell lung cancer (NSCLC).
Methods:
Patients (pts) with advanced NSCLC (no prior treatment for advanced disease) who were eligible for treatment with cisplatin and pemetrexed were enrolled into one of four dose levels, regardless of tumour PD-L1 status. Concurrent with chemotherapy, dose level (DL) 0 added Du 15 mg/kg IV q3wks; DL1 added Du 15mg/kg q3wk + Tr 1mg/kg x1 dose; DL2a added Du 15mg/kg q3wk + Tr 1 mg/kg q6wk x multiple doses; DL2b added Du 15mg/kg q3wk + Tr 3 mg/kg q6wk (1 dose with cycle 1 and 2 doses with maintenance pem). Pemetrexed and Du maintenance continued after completion of 4-6 cycles of pemetrexed and cisplatin.
Results:
Twenty-four pts (median age=61 (range 37-78); 50% female, 95% ECOG PS≤1, were enrolled (5 pts to each of DL 0 and 1 and 7 pts each to DL2a and 2b). Thus far 121 cycles have been administered. The majority of drug-related adverse events (AEs) were ≤ grade 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr were mainly ≤ grade 2, the most common of which were fatigue (46%), nausea/vomiting (25%), anorexia (21%) and diarrhea (13%). Two pts (DL2a) had serious related AEs (febrile neutropenia related to chemotherapy and lung infection/pneumonitis related to both chemotherapy and Du + T (considered a DLT)). Seventeen of the 24 patients are currently evaluable for response. The provisional objective response rate is 52.9% (95% CI: 28 -77%).
Conclusion:
In this PD-1 unselected patient population, Du 15mg/kg q3w and Tr 1mg/kg (multiple doses q6w) or 3mg/kg (3 doses q6w) can be safely combined with full doses of platinum-doublet chemotherapy. Additional studies with this combination are being planned.
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MA09.04 - Discussant for MA09.01, MA09.02, MA09.03 (ID 6991)
14:38 - 14:50 | Author(s): D. Planchard
- Abstract
- Presentation
Abstract not provided
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MA09.05 - Nivolumab Alone or with Ipilimumab in Recurrent Small Cell Lung Cancer (SCLC): 2-Year Survival and Updated Analyses from the Checkmate 032 Trial (ID 4397)
14:50 - 14:56 | Author(s): M.D. Hellmann, S.J. Antonia, S. Ponce, P.A. Ott, E. Calvo, M. Taylor, N. Ready, C.L. Hann, F. De Braud, J.P. Eder, D. Jäger, P.A. Ascierto, L. Horn, A. Amin, J. Evans, V. Moreno, A. Atmaca, R.N. Pillai, J. Bhosle, P. Bono, N. Reguart, J. Schneider, P. Brossart, J. Diamond, P. Sharma, U. Lassen, C. Lin, M. Tschaika, G. Selvaggi, D.R. Spigel
- Abstract
- Presentation
Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.
Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.
Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1
Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.
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MA09.06 - Viagenpumatucel-L Bolsters Response to Nivolumab Therapy in Advanced Lung Adenocarcinoma: Preliminary Data from the DURGA Trial (ID 4650)
14:56 - 15:02 | Author(s): D. Morgensztern, W. Harb, K. Schalper, M. Price, B. Early, T. Schreiber
- Abstract
- Presentation
Background:
Viagenpumatucel-L (HS-110) is an allogeneic whole-cell vaccine, selected for high expression of adenocarcinoma tumor antigens, transfected to secrete gp96-Ig. Prior studies with HS-110 (and related gp96-Ig vaccines) have shown a correlation between increases in CD8+ tumor infiltrating lymphocytes (TIL) and tumor response. The DURGA trial was designed evaluate the combination of HS-110 and nivolumab, in an attempt to increase tumor inflammation and improve the response rates observed with nivolumab alone. Clinical Trial identifier: NCT02439450
Methods:
Patients with advanced lung adenocarcinoma who received at least one prior line of therapy were assigned to two cohorts based on baseline levels of TIL in patient biopsies: low TIL (≤10% CD8+ T cells) or high TIL (>10% CD8+ T cells). All patients received standard of care nivolumab 3 mg/kg every 2 weeks and weekly HS-110 for 18 weeks until intolerable adverse events, disease progression, or death. Each 9-patient Phase 1b cohort could be expanded to 30 patients in Phase 2 based on exhibited efficacy. The primary endpoint was safety and tolerability. Biopsies at baseline and Week 10 were used to track changes in TIL and PD-L1 staining. Peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry for detection of circulating leukocyte subsets. ELISPOT was used to track antigen-specific immune response.
Results:
HS-110 vaccine and nivolumab combination was well tolerated with a safety profile consistent with single-agent nivolumab. Among the 8 initial patients, only 4 had optimal biopsies which showed 2 patients with high and 2 with low TILs. PD-L1 was >1% in 3 patients. IFNγ ELISPOT assay defined 4 patients as immune responders (doubling of IFNγ-secreting cells after re-stimulation with total vaccine antigen and individual cancer antigens, IR) and 4 patients as non-immune responders (NIR). The overall response rate (ORR) was 50% in the IR patients and 0% in the NIR patients. At the time of the data cutoff, 6 patients remain alive, including the 4 IR patients, with ongoing responses for 150 to 326 days. Patients with objective response also exhibited injection site reactions and maculopapular rash consistent with HS-110 mechanism of action, decreased Myeloid Derived Suppressor Cells (MDSC) in the blood, and increased markers of activated CD8+ T cell subsets by flow cytometry (CD8+CTLA-4+, CD8+Tim3+). Although the pathology specimens were sub-optimal in the two responding patients, the limited tissue available showed lower baseline TILs in both patients.
Conclusion:
Allogeneic gp96-based vaccination may have synergistic activity in combination with immune checkpoint inhibitors.
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MA09.07 - Phase I Trial of in situ Vaccination with CCL21 Gene-Modified DC Induces Specific Systemic Immune Response and Tumor Infiltrating CD8<sup>+</sup> T Cells (ID 4917)
15:02 - 15:08 | Author(s): J.M. Lee, M. Lee, E.B. Garon, J.W. Goldman, F.E. Baratelli, D. Schaue, G. Wang, F. Rosen, J. Yanagawa, T.C. Walser, Y. Lin, S. Adams, F.M. Marincola, P.C. Tumeh, F. Abtin, R. Suh, K. Reckamp, W.D. Wallace, G. Zeng, D.A. Elashoff, S. Sharma, S.M. Dubinett
- Abstract
- Presentation
Background:
Intratumoral (IT) infiltration by activated immune effector cells is associated with a significantly better prognosis, however, tumor-associated immune suppression commonly occurs in non-small cell lung cancer (NSCLC). CD8[+ ]T cell or dendritic cell (DC) infiltration is an independent favorable prognostic indicator. CCL21 is a lymphoid chemokine that chemoattracts both lymphocytes and DC. Our aim was to investigate anti-tumor specific systemic immune responses and tumor-infiltrating CD8[+] T cells (CD8[+] TIL) in NSCLC patients in response to in situ vaccination via IT administration of autologous DC transduced with a replication-deficient adenoviral (Ad) vector expressing the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we conducted a phase I trial and evaluated safety and immune responses following in situ vaccination.
Methods:
Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10[6], 5 x 10[6], 1 x 10[7], or 3 x 10[7] dendritic cells/injection) by CT- or bronchoscopic-guided IT injection (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8[+ ]T cells by immunohistochemistry (IHC).
Results:
Twenty-five percent (4/16) of patients had stable disease at day 56 follow-up by RECIST criteria. Median survival was 3.9 months. Four possible vaccine-related grade 1 adverse events (AE) occurred in 3 patients with no clear association to dose or schedule; the AE included flu-like symptoms, blood-tinged sputum after each injection, nausea, and fatigue. ELISPOT assays revealed 38% (6/16) of patients had systemic responses against tumor associated antigens (TAA). Tumor CD8[+] T cell infiltration was induced in 54% of subjects (7/13; 3.4 fold average increase in the number of CD8[+ ]T cells per mm[2]). Patients with increased intratumoral CD8[+ ]T cells following vaccination showed significantly increased PD-L1 mRNA expression (p=0.02).
Conclusion:
Intratumoral vaccination with Ad-CCL21-DC was well-tolerated and resulted in 1) induction of systemic tumor antigen-specific immune responses and 2) enhanced tumor CD8[+ ]T cell infiltration. DC-CCL21 in situ vaccination may be a promising approach to induce tumor CD8[+ ]T cell infiltration in combination with checkpoint inhibitor therapy.
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MA09.08 - Discussant for MA09.05, MA09.06, MA09.07 (ID 7048)
15:08 - 15:20 | Author(s): L. Petruželka
- Abstract
- Presentation
Abstract not provided
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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)
15:20 - 15:26 | Author(s): E. Angevin, J. Strickler, C. Weekes, R. Heist, D. Morgensztern, X. Fan, O. Olyaie, M. Motwani, D. Afar, L. Naumovski, 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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MA09.10 - A NaPi2b Antibody-Drug Conjugate Induces Durable Complete Tumor Regressions in Patient-Derived Xenograft Models of NSCLC (ID 5769)
15:26 - 15:32 | Author(s): D. Bergstrom, N. Bodyak, A. Yurkovetskiy, L. Poling, M. Yin, M. Protopopova, M. Devit, L. Qin, D. Gumerov, E. Ter-Ovanesyan, R. Mosher, T. Lowinger
- Abstract
- Presentation
Background:
The sodium-phosphate transporter NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug conjugate (ADC) development in this disease. However, NaPi2b is also expressed at high levels in type II alveolar cells, raising the potential for normal tissue toxicity with this approach. XMT-1536 is an ADC comprised of a humanized antibody against NaPi2b and approximately 15 auristatin-derived payload molecules per antibody conjugated via a multivalent hydrophilic polymer (Fleximer). The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin-derivative that is capable of bystander effect killing.
Methods:
The anti-tumor activity of XMT-1536 was evaluated in seven patient-derived xenograft models of NSCLC adenocarcinoma, chosen for high NaPi2b-expression and representing a spectrum of oncogenic driver mutations prevalent in NSCLC adenocarcinoma (including tumors without oncogenic drivers). The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study.
Results:
At the 3 mg/kg dose, XMT-1536 was active in 6/7 models: complete tumor regression in 3 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 3 of the 4 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60. The antibody component of XMT-1536 is cross-reactive with cynomolgus NaPi2b with similar affinity as human NaPi2b. XMT-1536 was well tolerated up to 5 mg/kg (4294 mg/m[2] auristatin payload equivalents), the highest dose tested. There was no body weight loss, no clinical observations attributable to XMT-1536, and no evidence of neutropenia. On pathology, there was minimal mixed inflammatory cell infiltrate in the lung in 1 high dose animal at each necropsy time point, but no evidence of significant lung toxicity. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.
Conclusion:
These results indicate XMT-1536 can achieve durable tumor regressions in murine patient-derived NSCLC adenocarcinoma models at doses associated with good tolerability in cynomolgus monkey, and support evaluation of XMT-1536 in patients with NSCLC.
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MA09.11 - Efficacy and Safety of Necitumumab and Pembrolizumab Combination Therapy in Stage IV Nonsquamous Non-Small Cell Lung Cancer (NSCLC) (ID 4712)
15:32 - 15:38 | Author(s): B. Besse, P. Garrido, J. Puente, A.B. Cortot, M.E. Olmedo, M. Pérol, M. Gil, G.Y. Chao, J. Shahidi, J. Bennouna
- Abstract
- Presentation
Background:
Trials of anti-EGFR necitumumab and anti-PD1 pembrolizumab demonstrate the anti-tumor activity of each agent in NSCLC.
Methods:
Single-arm, multicenter Phase 1b study to investigate effectiveness and safety of necitumumab combined with pembrolizumab in patients with Stage IV NSCLC (NCT02451930). In Part A, escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W. In the absence of dose limiting toxicity, Part B (expansion cohort) was planned with necitumumab 800 mg in 27 squamous and 27 nonsquamous NSCLC patients. Major eligibility criteria included: progression after ≥1 platinum-based chemotherapy, and ECOG PS 0-1. Study objectives were to evaluate tolerability and ORR by RECIST 1.1. PD-L1 status was centrally assessed using PD-L1 IHC 22C3 pharmDx assay (considered negative, weak positive, strong positive if <1%, 1-49%, ≥50% of tumor cells were stained, respectively).
Results:
The interim analysis population includes 34 nonsquamous patients (median age 61 years, 68% men, 21% never smokers, PD-L1 status: negative, 50% [17/34]; positive weak/strong, 15% [5/34]/15% [5/34]; unknown 21% [7/34[BJ1] ]). Median follow-up was 6.0 months. Ten patients (29.4%) had PR (confirmed and unconfirmed) (PRs by PD-L1 status: negative, 18% [3/17]; positive weak/strong, 60% [3/5]/40% [2/5]; unknown status, 2 patients). DCR was 67.6%. PFS rate at 6 months was 55.1% (95% CI, 36.2-70.6); median PFS was 6.9 months (95% CI, 2.7-NR). Most common Grade ≥3 AEs were skin rash (9%), hypomagnesemia (9%), VTE (9%) and increased lipase (9%); 1 patient died due to an AE (respiratory tract infection). Five patients (14.7%) discontinued therapy because of an AE. Figure 1
Conclusion:
Safety profile corresponds to individual profiles for both drugs, with no additive toxicities. These preliminary data suggest activity of this combination in a pretreated nonsquamous NSCLC population, irrespective of PD-L1 status.
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MA09.12 - Discussant for MA09.09, MA09.10, MA09.11 (ID 7082)
15:38 - 15:50 | Author(s): C.S. Baldotto
- Abstract
- Presentation
Abstract not provided
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SC10 - Squamous Cell NSCLC (ID 334)
- Event: WCLC 2016
- Type: Science Session
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:D.R. Gandara, M. Sebastian
- Coordinates: 12/05/2016, 16:00 - 17:30, Strauss 3
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SC10.01 - Genetic Alterations as Potential Therapeutic Targets (ID 6637)
17:10 - 17:30 | Author(s): R.K. Thomas
- Abstract
Abstract not provided
Information from this presentation has been removed upon request of the author.
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SC10.02 - EGFR Mutations in Indian Patients with Squamous Cell NSCLC (ID 6638)
16:00 - 16:20 | Author(s): K. Prabhash
- Abstract
- Presentation
Abstract not provided
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SC10.03 - Anti-EGFR Monoclonal Antibodies in Squamous Cell NSCLC (ID 6639)
16:20 - 16:40 | Author(s): R. Pirker
- Abstract
- Presentation
Abstract:
Patients with advanced squamous NSCLC receive first-line chemotherapy with a platin-based doublet. Combining first-line chemotherapy with EGFR-directed monoclonal antibodies has been studied as a strategy to improve outcome of these patients. Anti-EGFR monoclonal antibodies inhibit EGFR-mediated signal transduction and may also act via immunological mechanisms. Several monoclonal antibodies have been studied within clinical trials and data from phase III trials are available for cetuximab and necitumumab (for review see ref. 1). Two randomized phase III trials compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced NSCLC (2, 3). The FLEX trial demonstrated improved overall survival for cetuximab added to chemotherapy in patients with advanced NSCLC and enriched for EGFR expression in their tumors (2). The hazard ratio was 0.87 (p=0.044), median survival times were 11.3 months and 10.1 months, and 1-year survival rates were 47% and 42%, respectively. For patients with squamous cell carcinomas (n=347), the hazard ratio was 0.80 and median survival times were 10.2 months and 8.9 months, respectively. The BMS 099 trial failed to show an improvement in progression-free survival for cetuximab added to carboplatin plus paclitaxel in unselected patients with advanced NSCLC (3). A meta-analysis based on individual patient data from four randomized trials demonstrated a survival benefit for chemotherapy plus cetuximab compared to chemotherapy alone (4). The hazard ratio was 0.88 (95% CI 0.79-0.97; p=0.009). The benefit was greater in patients with squamous NSCLC in whom a hazard ratio of 0.77 (95% CI 0.64-0.93) was seen. Necitumumab has also been studied in combination with first-line chemotherapy in two phase III trials (5, 6). The SQUIRE trial assessed cisplatin plus gemcitabine with or without necitumumab in 1,093 patients with advanced squamous NSCLC (5). Necitumumab was intravenously administered at a dose of 800 mg on days 1 and 8 of every 21 days and was planned to be continued after the end of chemotherapy until disease progression or intolerable toxicity. Necitumumab improved the outcome of chemotherapy. The hazard ratio was 0.84 (95% CI 0.74-0.96; p=0.012). Median survival times were 11.5 months and 9.9 months, and 1-year survival rates were 47.7% and 42.8% for the chemotherapy-plus-necitumab arm and chemotherapy arm, respectively. Progression-free survival and response rates were also improved with the combined treatment. Grade ≥3 adverse events more frequently seen with chemotherapy plus necitumumab compared to chemotherapy were skin rash and hypomagnesemia. Based on these results, necitumumab has been approved as first-line therapy of squamous NSCLC in combination with gemcitabine and cisplatin. In contrast to the SQUIRE trial, the INSPIRE trial was prematurely stopped after enrolment of 634 patients because an interim analysis showed increased thrombo-embolic events and a lack of survival benefit for the combined treatment (6). Research has also focussed on the characterization of predictive biomarkers. Immunohistochemical EGFR protein expression and EGFR FISH positivity were of particular interest. In the FLEX trial, immunohistochemical EGFR expression of tumor cells was prospectively assessed by means of the DAKO pharmDx[TM] kit (7). Membrane staining intensity was divided into no staining, weak staining (1+), intermediate staining (2+), and strong staining (3+). The fractions of cells at the various staining intensities were determined. An immunohistochemistry score (IHC) based on both intensity and frequency of staining was then used for further analysis on the association between EGFR expression levels and clinical outcome. Patients were divided into those with high (IHC score ≥200) and those with low (IHC score <200) EGFR expression. High EGFR expression was seen in 31% of the patients. Among patients with high EGFR expression, patients treated with chemotherapy plus cetuximab had prolonged survival compared to those treated with chemotherapy alone. The hazard ratio was 0.73 (95% CI 0.58–0.93; p=0.011), median survival times were 12.0 and 9.6 months, and 1-year survival rates were 50% versus 37%. Among patients with low EGFR expression, survival times were not different between the two treatment arms. The treatment interaction between EGFR expression levels and treatment effect was statistically significant (p=0.04). The survival benefit achieved by the addition of cetuximab to chemotherapy in patients with high EGFR expression was seen across most subgroups including all major histological subgroups. Among patients with squamous NSCLC and high EGFR expression, the hazard ratio was 0.62 (0.43-0.88) in favour of cetuximab plus chemotherapy compared to chemotherapy alone. The survival benefit by the addition of cetuximab to chemotherapy in patients with high EGFR expression was achieved without an increase in toxicity. In summary, patient selection based on EGFR expression levels resulted in a clinically meaningful improvement in the risk benefit assessment of platinum-based first-line chemotherapy plus cetuximab in patients with advanced NSCLC (7). The SWOG S0819 biomarker validation study indicated that EGFR FISH positivity predicted benefit from cetuximab, particularly in patients with squamous NSCLC (8). Similarly, the benefits from necitumumab appeared to be greater in patients with EGFR FISH positivity or high EGFR expression (5, 9-10). References 1. Pirker R et al. Curr Opin Oncol 2015, 27, 87-93 2. Pirker R et al. Lancet 2009, 373, 1525-31 3. Lynch TJ et al. J Clin Oncol 2010, 28, 911-7 4. Pujol JL et al. Lung Cancer 2014, 83, 211-8 5. Thatcher N et al. Lancet Oncol 2015, 16, 763-74 6. Paz-Ares L et al. Lancet Oncol 2015, 16, 328-37 7. Pirker R et al. Lancet Oncol 2012, 13, 33-42 8. Herbst R et al. J Thorac Oncol 2015, 10, S795 9. Hirsch F et al. J Thorac Oncol 2015, 10, S797 10. Paz-Ares L et al. Ann Oncol 2016, 27, 1573-9
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SC10.04 - Second-Line Therapy and Beyond in Squamous Cell NSCLC (ID 6640)
16:40 - 17:00 | Author(s): T. Vavala, S. Novello
- Abstract
- Presentation
Abstract:
Lung cancer is the leading cause of cancer-related mortality worldwide with 1.59 million deaths in 2012 and, with an estimated 1.8 million new lung cancer cases, it accounts for about 13% of total cancer diagnoses[1]. Non-small cell lung cancer (NSCLC) represents around 85% of all lung cancers with the majority of patients in advanced stages of the disease when diagnosed. Squamous cell carcinoma (SqCC) is the second most common histology in NSCLC accounting for 20-30% of cases[2]. Compared to the most frequent advanced lung adenocarcinoma, for which targeted therapies are available in case of presence of actionable mutations, treatment options for advanced lung SqCC have not changed with the same vividness in the last decade. But, to date, we can definitely say that also for these patients, the research has made progresses and new therapeutic scenarios are now open. Docetaxel and erlotinib were the only standard second-line treatment options for lung SqCC until, in December, 2014, the US Food and Drug Administration (FDA) approved ramucirumab (an anti-VEGFR-2 antibody) in combination with docetaxel, for the treatment of metastatic NSCLC patients who progressed during or after a platinum-based chemotherapy. In March 2015 nivolumab (an immune-checkpoint-inhibitor) was approved, for treatment of patients with metastatic SqCC, who progressed during or after a platinum-based chemotherapy and pembrolizumab (another immune-checkpoint-inhibitor) was approved in October, in the same setting of patients but whose tumors expressed PD-L1 (evaluated with the approved specific companion diagnostic, the PD-L1 IHC-22C3 pharmDx test). Finally, in April 2016, afatinib (an EGFR tyrosine-kinase inhibitor) was approved for treatment of patients with metastatic SqCC progressing after a platinum-based chemotherapy[3][,[4],[5],[6]]. It has been suggested that SqCC patients treated with docetaxel had a poorer survival compared to non-SqCC patients hypothesizing that docetaxel may be less effective in squamous compared with non-squamous lung cancer[7]. This was also evidenced in the phase III study (REVEL), in which squamous and non-squamous NSCLC patients were treated with docetaxel with or without ramucirumab: an OS benefit was seen with ramucirumab-docetaxel in the whole population (10.5 vs 9.1 months, HR 0.86, 95% CI 0.75–0.98, p = 0.023). In those patients who presented squamous cell histology (25%) the OS benefit, when treated with ramucirumab-docetaxel, was 9.5 months (4.4–17.6) vs 8.2 months (3.6–14.9, HR: 0.88, 95% CI 0.69–1.13) in placebo-docetaxel subgroup, while in those with non-squamous disease a better OS was described (11.1 months, Interquartile Range, IQR 5.3–24.3) in the ramucirumab-docetaxel group, vs 9.7 months (4.4–19.6) in the control group (HR 0.83, 95% CI 0.71–0.97), however it needs to be noted that subgroup analyses in this study were not pre-planned[4]. In LUX-Lung 8, a phase III study of second-line afatinib vs erlotinib, which enrolled squamous patients only, OS was 7.9 vs 6.8 months (HR 0.81, 95% CI 0.69–0.95, p = 0.007), in the afatinib subgroup vs erlotinib one[7]. Survival benefits highlighted in these studies when compared to older studies with docetaxel, while statistically significant, evidenced modest developments in the treatment of advanced-stage SqCC, as a consequence, novel therapeutic approaches have been considered and well accepted in the oncology community as well as largely awaited. Research on tumor immunosurveillance led to the development of PD-1 immune-checkpoint-inhibitors, such as nivolumab and pembrolizumab, and the PD-L1 inhibitors atezolizumab (MPDL3280A), durvalumab (MEDI4736) and avelumab (MSB0010718C)[8]. Nivolumab produced response rates equal to 15 to 17% with a median OS of 8.2 to 9.2 months, in phase I and II trials, among previously treated patients with advanced SqCC[5]. Then in the phase III CheckMate 017, Nivolumab induced a median OS of 9.2 months (95% CI, 7.3-13.3) vs 6 months (95% CI, 5.1-7.3) with docetaxel. The results in the docetaxel group were worst than expected. The risk of death was 41% lower with nivolumab than with docetaxel (HR, 0.59; 95% CI, 0.44-0.79; p < 0.001)[5]. PD-L1 expression is largely debated and its specific influence in the squamous population still needs further elucidations, since a total of 83% of the patients who underwent randomization (225 of 272 patients) in this trial had quantifiable PD-L1 expression and PD-L1 was assessed on archival tumor tissue, which may not have reflected its real status at the time of treatment[5]. SqCC is considered the tumor with the second highest amount of molecular aberrations, (eg, FGFR1 amplification, PIK3K3 abnormalities, DDR2 mutations), providing a plausible explanation about heterogeneity of treatment responses and efficacy results in the second-line setting[9]. However, despite the identification of those specific molecular alterations, progress in targeting oncogenic drivers in SqCC still runs behind adenocarcinoma. There is a need to develop predictive and specific molecular biomarkers, that might identify subgroups of patients with lung SqCC that are most likely to benefit from targeted treatments or immunotherapic approaches. In this context Pilotto et al. elaborated a project with the aim to evaluate the molecular profile of resected SqCC in order to identify those immunologic pathways and molecular aberrations potentially able to estimate the probability of disease recurrence (prognostic factors) and to characterize novel biomarkers, whose targeting with specific drugs could potentially limit the oncogenic potential and change the natural history of this disease (predictive factors). Preliminary results of this study were consistent with literature data: several molecular alterations might be identified [PIK3CA, MET, FGFR3, DDR2, FRS2, CDKN2A, SMAD4, PD-L1] and some of them might impact on the biological behavior of SqCC contributing in the determination of patients prognosis[10]. These data will be further presented at WCLC this year. In conclusion, as more treatment options turn out to be available for patients, it will become essential to tailor those choices on patient’s unique molecular characteristics and his own needs, identifying the best sequence of treatments, especially in the era of rising healthcare costs and longer lifespan of advanced lung cancer patients. References [1] WHO Statistics. http://www.who.int/mediacentre/factsheets/fs297/en/ [Accessed on 21 August , 2016]. [2] Travis WD. Pathology of lung cancer. Clin Chest Med 2011; 32: 669–92. [3] Garon EB et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665–73. [4] Brahmer J et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 2015; 373(2):123-35. [5] FDA approves Keytruda for advanced non-small cell lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm [Accessed on 21 August , 2016]. [6] Soria JC et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial Lancet Oncol 2015; 16: 897–907. [7] LE Ang Y et al. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. OncoTargets and Therapy 2016:9 3187–3195. [8] Melosky B et al. Pointed Progress in Second-Line Advanced Non–Small-Cell Lung Cancer: The Rapidly Evolving Field of Checkpoint Inhibition. J Clin Oncol 2016;34:1676-1688. [9] The Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489(7417): 519–525. [10] S. Pilotto et al. Analyzing prognostic outliers to unravel biologically and clinically relevant molecular and immunologic pathways: a model from resected squamous cell lung carcinoma (R-SQCLC). Poster presented at 58 Annual Meeting of the Italian Cancer Society helded in Verona on 5-8 September 2016.
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)
11:30 - 11:36 | Author(s): M. Sebastian
- Abstract
- Presentation
Background:
ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.
Methods:
Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.
Results:
In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).
Conclusion:
Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.02 - Clinical Research Platform into Molecular Testing, Treatment, Outcome (CRISP): A Prospective German Registry in Stage IV NSCLC AIO-TRK-0315 (ID 5911)
11:06 - 11:12 | Author(s): M. Sebastian
- Abstract
- Presentation
Background:
Treatment in non-small cell lung cancer is quickly evolving and new agents make it to the routine practice at a rapid pace. Whether outcome and PRO data generated in clinical trials with often narrow inclusion and exclusion criteria will hold up in the routine practice is of high interest, especially due to the increasing costs of new drugs. Therefore registry data are of ever increasing importance to patients, physicians and reimbursement institutions.
Methods:
Therefore, we have started a prospective, clinical registry for patients with metastatic non-small cell lung cancer. The purpose of CRISP is to set up a national clinical research platform to document representative data on molecular testing, sequences of systemic therapies and other treatment modalities, course of disease in patients with advanced or metastatic NSCLC in Germany not amenable to curative treatment. A particular focus is on molecular biomarker testing of patients before the start of first-line treatment. The data shall be used to assess the current state of care and to develop recommendations concerning topics that could be improved. PRO assessment will provide large-scale data on quality of life and anxiety/depression for real-life patients in routine practice. In addition, two questionnaires (concerning individual quality of life and patient-caregiver communication) will be validated in German patients with metastatic NSCLC. Furthermore CRISP will set up a decentral tissue annotation for future collaborative, investigational scientific biomarker testing.
Results:
This study will be carried out in up to 150 representative cancer centers in all therapeutic sectors in Germany. More than 8000 patients will be recruited and followed up to a maximum of 3 years, respectively until death. The first patients have been included as of December 2015. As of yet, 82 centers have been initiated, 211 patients have been recruited. Preliminary data will be presented at the meeting in terms of molecular test rates, demographic data as well as treatment stratification in the 1[st] line setting.
Conclusion:
The registry CRISP will be the first to present representative real life data, covering all treatment settings of patients with NSCLC in Germany. ClinicalTrials.gov Identifier: NCT02622581 CRISP is supported by Grants from AstraZeneca GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Bristol-Myers Squibb GmbH & Co. KGaA, Celgene GmbH, MSD Sharp & Dohme GmbH, Novartis Pharma GmbH, and Pfizer Pharma GmbH.
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OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:O.T. Brustugun, S. Lu
- Coordinates: 12/07/2016, 14:20 - 15:50, Stolz 2
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OA23.04 - Discussant for OA23.01, OA23.02, OA23.03 (ID 6966)
14:50 - 15:05 | Author(s): M. Sebastian
- Abstract
- Presentation
Abstract not provided
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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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P2.06-016 - Phase 2 Study of Ramucirumab plus Weekly Docetaxel in Stage IV NSCLC Following Progression after Platinum-Based Chemotherapy (ID 4614)
14:30 - 14:30 | Author(s): M. Sebastian
- Abstract
Background:
Ramucirumab, a human IgG1 monoclonal antibody, binds to vascular endothelial growth factor (VEGF) receptor 2, competing with VEGF-A, -C and –D and thereby preventing receptor activation and angiogenesis. The phase 3 REVEL trial demonstrated the addition of ramucirumab to docetaxel improved survival in patients with stage IV NSCLC following progression after platinum-based chemotherapy, independent of histology. The approved dose of docetaxel in NSCLC patients after progression on prior platinum-based chemotherapy is 75 mg/m2 every 3 weeks. The most common toxicity associated with this dosing regimen is myelosuppression, specifically neutropenia. In order to reduce the incidence of myelosuppression, various weekly docetaxel dosing regimens have been evaluated. These studies have suggested that weekly docetaxel can provide better tolerability with at least similar efficacy. This phase 2, single arm, open-label study (JVDN; NCT02831491) is designed to assess a potential reduction in the rate of grade ≥3 neutropenia and febrile neutropenia with weekly docetaxel in combination with ramucirumab, as compared to historical safety data from the REVEL trial. This study will also assess safety and efficacy of ramucirumab with weekly docetaxel in patients who received prior immunotherapy for NSCLC.
Methods:
Study JVDN includes patients (n=50) with stage IV NSCLC, with measurable disease and ECOG performance status 0-1 who have experienced disease progression from one prior platinum-based therapy which may have included bevacizumab. Prior immunotherapy for NSCLC is permitted. Patients will receive the approved ramucirumab dose regimen for NSCLC (10mg/kg IV) on day 1 every 3 weeks, followed by weekly docetaxel (35 mg/m2 IV) on days 1, 8 and 15 every 4 weeks. Treatment may continue until disease progression or a criterion for discontinuation is met. The primary endpoint is to assess safety, as measured by the rate of grade ≥3 neutropenia (CTCAE v4.0). Secondary endpoints for all patients include the rate of treatment-emergent febrile neutropenia, overall safety, pharmacokinetics (ramucirumab), and efficacy. Additional secondary endpoints of safety and efficacy will be assessed in patients who did or did not receive prior immunotherapy. An exploratory endpoint is to assess the association between biomarkers with safety and clinical outcomes. The primary and final analyses will occur after 31 and 50 patients, respectively, have completed ≥12 weeks of treatment to determine if grade ≥3 neutropenia and febrile neutropenia are reduced with the investigational weekly docetaxel treatment as compared to historical safety data from REVEL.
Results:
Not applicable
Conclusion:
Not applicable
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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-110 - ROS1 Translocation as a Bystander Mutation in T790M EGFR Mutated NSCLC (ID 4105)
14:30 - 14:30 | Author(s): M. Sebastian
- Abstract
Background:
Non small cell lung cancer comprises a number of subtypes that are defined by genetic alterations in terms of oncogenic driving mechanisms that constitute groundwork for the development of targeted therapy. EGFR mutations, as well as ROS1 translocations are two well described genetic alterations with prognostic and therapeutic implications and almost mutually exclusive occurance. Activating mutations in the EGF receptor gene are found in approximately 10% of european patients and large clinical trials with anti EGFR–kinase inhibitors set EGFR-TKIs as the gold standard of treatment. However treatment failure obligatory occurs within 8–13months and T790M gatekeeping mutation is found in approximately 60% as the resistance mechanism. 3rd generation TKI Osimertinib is a highly active treatment option in these patients. Furthermore ROS1 rearrangements are found in approximately 1-2% with various rearrangement partners. First clinical trials confirmed it´s pivotal role in NSCLC tumorigenesis as pharmacologic inhibition leads to tumor regression and durable response rates. We present a case report of a 74year old, ECOG 1 female patient, formerly smoker (15py), presenting with a relapsed, formerly stage II classified, metastatic L858R EGFR mutated adenocarcinoma, that progressed after 11months on Erlotinib therapy and harbored a T790M mutation as well as a bypassing ROS1 translocation. We initiated Osimertinib therapy and performed a short term radiologic evaluation after 4 weeks on the 3rd generation TKI.
Methods:
Tumor biopsies were obtained after clinical and radiologic findings of progressive disease and were analyzed by FISH for ROS1 and ALK (split fish technique), cMET (FISH) and EGFR (Therascreen EGFR-test by Qiagen). PET CT scans were performed before initiation of and 4 weeks after continuous Osimertinib therapy.
Results:
Molecular analysis revealed a T790M gatekeeping mutation, in addition a ROS1 (45% of vital tumor cells) translocation was detected. PET CT scans after Erlotinib failure confirmed metastatic and progressive disease with hypermetabolic and enlarged lymph nodes in the mediastinum and widespread tumor lesions juxtaposed to the pleural cavity at the right hemithorax with infiltration of the osseus thoracic wall. 4 weeks after initiation of Osimertinib therapy, repeated PET CT scans showed a partial remission of tumor burden with a concomitant complete resolution of pathologic glucose uptake.
Conclusion:
This is a rare case describing a tumor progress after acquired EGFR TKI resistance harboring a T790M mutation in addition to a ROS1 rearrangement. After one month of treatment with Osimertinib we found a metabolic CR indicating that ROS1 rearrangement had no clinical significance in this situation.
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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-091 - Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC (ID 4735)
14:30 - 14:30 | Author(s): M. Sebastian
- Abstract
Background:
Preclinical studies demonstrated that local radiotherapy (RT) acts synergistically with RNActive[® ]vaccines to increase tumor-infiltrating immune cells and enhance anti-tumor effects. BI 1361849 (CV9202) is an immunotherapeutic cancer vaccine comprising optimized mRNA constituents (RNActive[®]) encoding six NSCLC-associated antigens. Here we report clinical outcomes and immune response data of a phase Ib study, employing local RT and BI 1361849 in advanced NSCLC.
Methods:
Patients (Pts) with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) were enrolled in three cohorts based on histological and molecular NSCLC subtypes (non-squamous vs. squamous vs. EGFR-mutated NSCLC). Pts received two initial vaccinations with BI 1361849 prior to local RT to the primary tumor or a metastatic lesion (four consecutive daily fractions of 5 Gy), followed by further vaccinations until start of another treatment. Maintenance Pemetrexed (mP) and EGFR-TKIs were continued according to the label. Primary endpoint was safety; secondary endpoints included objective response, PFS and OS. Cellular and humoral immune responses were measured ex vivo by multifunctional intracellular cytokine staining, IFN-γ ELISpot, and ELISA in pre- and post-treatment blood samples.
Results:
26 pts were enrolled. 15 pts received mP, two received EGFR TKIs. Most frequent AEs were mild to moderate injection-site reactions and flu-like symptoms. Two pts experienced BI 1361849-related grade 3 AEs (fatigue, pyrexia). No BI 1361849-related SAE or grade 4 AE was reported. Interim results indicate one confirmed PR in a patient receiving mP and SD in 13/25 evaluable pts (52%, 8 pts on mP, 3 pts without maintenance therapy, 2 pts on EGFR-TKI), with two pts showing remarkably long-lasting disease stabilization of up to 72 and 54 weeks, respectively. Shrinkage of lesions outside the irradiated field of ≥15% occurred in 7 pts, all but one receiving mP. Longitudinal assessment of tumor response allows for further insight into patterns of progression. BI 1361849 was capable of eliciting antigen-specific immune responses in the majority of the patients including both cellular and humoral immune responses.
Conclusion:
BI 1361849 elicits antigen-specific immune responses and can be safely combined with local RT and mP treatment. Shrinkage of non-irradiated lesions and prolonged disease stabilization was observed in a subset of pts, mainly in combination with mP. Final clinical outcomes and analyses of cellular and humoral immune responses will be presented.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (ID 4452)
09:05 - 09:15 | Author(s): M. Sebastian
- Abstract
- Presentation
Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.
Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.
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