Prior Platinum-based Chemotherapy Research Articles

Phase I Study of a B Cell-Based and Monocyte-Based Immunotherapeutic Vaccine, BVAC-C in Human Papillomavirus Type 16- or 18-Positive Recurrent Cervical Cancer

BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1 × 107, 4 × 107, or 1 × 108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2–11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway.

LKB1 mutations are not associated with the efficacy of first-line and second-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC): a post hoc analysis of the TAILOR trial

PurposeIn patients with advanced lung adenocarcinoma, the impact of LKB1 mutations on cytotoxic chemotherapy efficacy remains poorly explored. Here, we aimed at investigating the potential impact of LKB1 mutational status on chemotherapy efficacy in advanced non-small-cell lung cancer (NSCLC) patients enrolled in the TArceva Italian Lung Optimisation tRial (TAILOR) trial.MethodsThe multicenter TAILOR trial randomised patients with EGFR-wild type (wt) advanced NSCLC progressing on/after previous platinum-based chemotherapy to receive docetaxel or erlotinib. Here, we evaluated the impact of LKB1 mutational status on progression-free survival (PFS) and overall survival (OS) in patients treated with second-line docetaxel/erlotinib or during prior platinum-based chemotherapy.ResultsOut of 222 patients randomised in the TAILOR trial, left-over tumour tissues were available for 188 patients, and 120 patients with evaluable LKB1 status were included. Of them, 17 (14.17%) patients had LKB1-mutated tumours, while 103 (85.83%) had LKB1-wt disease. During second-line treatment, PFS and OS were not statistically significantly different in patients with LKB1-mutated when compared with LKB1-wt NSCLC (adjusted HR (aHR)=1.29, 95% CI 0.75 to 2.21; p=0.364 and aHR=1.41, 95% CI 0.82 to 2.44; p=0.218, respectively). Similarly, we found no significant association between LKB1 mutations and patient PFS or OS during prior first-line platinum-based chemotherapy (aHR=1.04, 95% CI 0.55 to 1.97; p=0.910 and aHR=0.83, 95% CI 0.42 to 1.65; p=0.602, respectively).ConclusionAmong advanced NSCLC patients receiving two lines of systemic therapy, LKB1 mutations were not associated with PFS or OS during second-line docetaxel or prior first-line platinum-based chemotherapy. While larger prospective trials are needed to confirm our findings, cytotoxic chemotherapy remains the backbone of investigational combination strategies in this patient population.

Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy.

Background:Immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for non-small cell lung cancer (NSCLC) patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy.Methods:The immunotherapy naïve patients with metastatic NSCLC who received anti-PD-1/PD-L1 monotherapy or combined with nab-paclitaxel after prior platinum-based chemotherapy from 2015 to 2018 in PLA General Hospital were identified. The progression-free survival, overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety were assessed.Results:Of 57 patients, 40 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel. With a median OS follow-up of 16.3 months, the nab-paclitaxel group showed significantly longer OS compared with the immune monotherapy group (median, 28.6 months versus 15.9 months, log-rank p = 0.020). When adjusted by covariates in COX proportional regression model, both the treatment group [p = 0.009, hazard ratio (HR) 0.361; 95% confidence interval (CI) 0.168–0.773] and performance status (p = 0.003, HR 0.372; 95% CI 0.192–0.721) demonstrated independent association with the longer OS from combination therapy. In addition, ORR was 23.5% (4/17) in the immune checkpoints inhibitors (ICIs) plus nab-paclitaxel group versus 13.5% (5/37) in immune monotherapy group (p = 0.439), with a DCR of 88.2% (15/17) and 59.5% (22/37) (p = 0.034), respectively. The incidence of grade 3/4 adverse events was 23.5% (4/17) in the combination group and 2.5% (1/40) in the immune monotherapy group.Conclusion:PD-1/PD-L1 inhibitor plus nab-paclitaxel resulted in significantly longer OS and higher response versus ICI single agent in metastatic NSCLC patients who have progressed after platinum-based chemotherapy. These findings need to be further explored by prospective studies.

Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: A national data base analysis

ObjectivesNivolumab is now a reference treatment for patients with advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. Little data are available on treatment approaches following discontinuation of nivolumab and on the interest of a second course of immunotherapy after nivolumab discontinuation. The aims of this study were to describe treatment pathways following nivolumab discontinuation and to describe survival following retreatment with immunotherapy. Materials and methodsThe analysis includes all patients with NSCLC recorded in a national hospital database, starting nivolumab in 2015-2016. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Patients starting a second course of PD-1 inhibitor following nivolumab discontinuation were analysed according to the duration of their initial nivolumab treatment course. Results10,452 patients were included (71 % men; mean age: 63.8 ± 9.6 years; squamous histology: 44 %). Median nivolumab treatment duration was 2.8 months [IQR :1.4–6.9]. Median OS was 11.5 months [95 %CI: 11.1–11.9]; 5118 (53.4 %) patients received post nivolumab therapy lines: 1517 (29.6 %) of these received a second course of PD-1 inhibitor, either after a treatment-free interval (resumption: n = 1127) or after intervening chemotherapy (rechallenge: n = 390). Median OS after nivolumab discontinuation was 15.0 months [13.9–16.7] in the resumption group and 18.4 months [14.8–21.9] in the rechallenge group. Median OS was significantly longer in patients with an initial nivolumab treatment duration ≥3 months. ConclusionIn this real-world setting, outcome after retreatment with a PD-1 inhibitor following a first course of nivolumab was significantly better in patients with a longer duration of initial nivolumab treatment.

Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer

ObjectivesEpidermal growth factor receptor (EGFR) exon 20 insertions comprise 4–10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment. Material and methodsTwenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1. ResultsThirteen patients received prior platinum-based chemotherapy, and three patients a first – or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6–4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1–16.4) months. ConclusionOsimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.

506P - Efficacy and safety of pegvorhyaluronidase alfa (PEGPH20; PVHA) and pembrolizumab (pembro) combination therapy in patients (Pts) with stage III/IV non-small cell lung cancer (NSCLC)

BackgroundImmunotherapy is a promising treatment option for advanced NSCLC; however, its efficacy may be limited by accumulation of hyaluronan (HA). PEGPH20 degrades tumor-associated HA and increases the efficacy of chemo- and immuno-therapeutic agents in animal models. Here we report efficacy and safety results of PEGPH20 plus pembro in a cohort of pts with Stage IIIB/IV NSCLC in the 2-cohort, phase Ib dose escalation (DE) and expansion (DX) HALO 107-101 study (NCT02563548). MethodsThis analysis included pts with advanced NSCLC and ≥1 prior platinum-based chemotherapy (DE: 1.6 µg/kg and 2.2 µg/kg of PEGPH20, 2 pts per dose) and pts with HA-high NSCLC (HA staining ≥25% of tumor surface), previously untreated or treated with 1 prior platinum-based chemotherapy (DX: 17 pts). PEGPH20 was given on days 1, 8, and 15 and pembro (DE = 2 mg/kg; DX = 200 mg) on day 1 of 21day cycles. Pts received enteric-coated aspirin (81 mg daily) for thromboembolism prophylaxis. Primary endpoints included: DE: doselimiting toxicity, recommended phase 2 dose (RP2D); DX: objective response rate (ORR). Secondary endpoints included: ORR (DE only), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. ResultsMean pt age was 68 years; 76% of pts had an ECOG PS 1, and 52% were women. The RP2D dose of PEGPH20 was 2.2 μg/kg. A total of 17 of 21 enrolled pts had evaluable tumor responses: 4 had a partial response, 8 had stable disease, and 5 had progressive disease. ORR was 24% and DCR 71%. PFS rates at 6, 12, and 18 months were 25%, 0%, and 0%, respectively, and OS rates were 62%, 47%, and 31%, respectively. Any-grade treatment-emergent adverse events (TEAEs) were reported in all pts, the most common events being muscle spasms (71%), myalgia (43%), nausea (38%), fatigue (29%), and peripheral edema (29%). Grade ≥3 TEAEs were reported in 57% of pts; 38% of pts experienced ≥1 serious adverse event (AE). There was 1 (5%) treatment-emergent thromboembolic AE. ConclusionsThe combination of PEGPH20 with pembro has an acceptable safety profile that is consistent with results from other PEGPH20 clinical trials and demonstrates activity in pts with locally advanced or metastatic NSCLC. Clinical trial identificationNCT02563548. Editorial acknowledgementMedical writing support provided by Miriam Cohen, PhD, of Paragon Medica, Knutsford, UK, supported by Halozyme Therapeutics Inc. Legal entity responsible for the studyHalozyme Therapeutics Inc. FundingHalozyme Therapeutics Inc. DisclosureE. Bertino: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Takeda. V. Lin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Halozyme Therapeutics Inc. V. Kuruvadi: Full / Part-time employment: Halozyme Therapeutics Inc. T. Heineman: Leadership role, Shareholder / Stockholder / Stock options: Halozyme Therapeutics Inc. All other authors have declared no conflicts of interest.

Advanced/metastatic urothelial carcinoma of the bladder and upper urinary tract

Three important oral presentations from the ASCO 2019 congress concerning advanced and metastatic urothelial carcinoma of the urinary bladder and the upper tract are highlighted and their potential clinical implications for the improvement of systemic therapies in respective patients are discussed. Enfortumab vedotin, an antibody-drug conjugate targeting nectin‑4, demonstrated a clinically meaningful objective response rate in patients with prior platinum-based chemotherapy and checkpoint inhibition, in a phase II trial. A high unmet need in this heavily pretreated patient population combined with good tolerability and manageable safety profile support a submission to the FDA (US Food and Drug Administration) for accelerated approval. The early use of an immunotherapeutic approach via pembrolizumab in patients with metastatic urothelial carcinoma as “switch maintenance” therapy achieved an objective response rate of 22% vs. 12% in the placebo arm in a phase II trial. Pembrolizumab was shown to potentially “deepen” responses achieved with first-line chemotherapy. Moreover, switch maintenance pembrolizumab was able to significantly delay disease progression, whereby a better characterized role of switch maintenance programmed death‑1 blockade will be refined by currently ongoing phase III trials. Based on data showing that angiogenesis plays an important role in urothelial carcinoma growth and progression, a randomized, placebo-controlled phase III trial tested whether the addition of bevacizumab to gemcitabine + cisplatin combination chemotherapy is able to improve overall survival in metastatic urothelial carcinoma patients in first-line therapy. This trial was negative regarding its primary endpoint; thus, currently the standard of care remains cisplatin-based chemotherapy without the addition of biologic agents in advanced or metastatic urothelial carcinoma.

1400P - Efficacy and toxicity of combination chemotherapy with cyclophosphamide, vincristine and an anthracycline in patients with metastatic extrapulmonary neuroendocrine carcinoma

BackgroundTherapeutic options for metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma (EPNEC) after prior platinum-based chemotherapy are limited. Combination chemotherapy protocols with cyclophosphamide, vincristine and either doxorubicin/adriamycin (CAV) or epirubicin (CEV) are possible treatment options for small cell lung cancer (SCLC), however have not been systematically evaluated in EPNEC so far. The aim of this study was to analyze the efficacy and toxicity of CAV/CEV in metastatic EPNEC patients. MethodsWe reviewed the combined prospective and retrospective NEN database of our center for patients treated with CAV or CEV between January 2009 and January 2019. Histological findings of all patients were reevaluated by the investigators in order to comply with the most current WHO classification. ResultsA total of 22 patients could be identified, 19 received CAV, 3 CEV. Patients had been treated with a median of 1line of prior chemotherapy. Median proliferation rate (Ki67) was 70 %, small cell histology was present in 63.6 % of cases. Primaries were gastrointestinal (27.3 %), pancreatobiliary (22.7%), urogenital (22.7 %), head/neck (9.1 %) or unknown (18.2 %). Best response to CAV/CEV was stable disease in 3 patients, partial remission (PR) in 5, resulting in an overall response rate of 22.7 % and disease control rate of 36.4 %. Most notably, PR was observed in both 2 patients included with a prostatic primary. Of the remaining 14 patients, 12 (54.5 %) showed a progressive disease, 1 showed a mixed response and 1 was not evaluable for response. Median progression free (PFS) and overall survival (OS) after start of CAV/CEV was 2.0 and 10.0 months respectively. Significant toxicity (mainly hematotoxicity) was observed in 63.6 % of patients. ConclusionsIn this first analysis of CAV/CEV in EPNEC so far, moderate antitumor activity could be detected, most notably in patients with a prostatic primary. Despite some encouraging responses, PFS was limited and significant toxicities were observed in the majority of patients. Clinical trial identificationThe trial was approved by the institutional research ethics committee (approval S-428/2014). Legal entity responsible for the studyNational Center for Tumor Diseases (NCT) Heidelberg. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

1844O - Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma: Preliminary results from a multicenter phase II (REMORA) trial

1844O - Durable anti-tumor activity of the multi-targeted inhibitor lenvatinib in patients with advanced or metastatic thymic carcinoma: Preliminary results from a multicenter phase II (REMORA) trial

P2.01-24 CANOPY-2: Phase 3 Study of Canakinumab Plus Docetaxel as Second/Third Line Therapy in Locally Advanced/Metastatic NSCLC

Pembrolizumab, a PD-1 inhibitor combined with platinum-based chemotherapy is standard first-line therapy for eligible patients without a targetable mutation, stage IIIB/IV NSCLC. Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based chemotherapy and PD-1 inhibitors. Activation of inflammation and elevated baseline C-reactive protein (CRP) levels are associated with lower response/resistance to immunotherapies. Canakinumab is a high-affinity anti-IL-1β monoclonal antibody that demonstrated a significant reduction in incidence of fatal and nonfatal lung cancer in patients with increased CRP levels (CANTOS study). CANOPY-2 (NCT03626545) is a multicenter, phase 3 study evaluating safety and efficacy of docetaxel ± canakinumab in patients with squamous/non-squamous, stage IIIB-IV NSCLC. This study includes a safety run-in part (part 1 – open label) to confirm recommended phase 3 regimen (RP3R) to be used in randomized phase 3 part (part 2 – double blind, placebo-controlled). Key inclusion criteria: adult patients pretreated with one prior platinum-based chemotherapy and one prior PD-(L)1 inhibitor therapy for locally advanced/metastatic disease, either together/sequentially and then progressed; ECOG PS 0-1. In part 1, ∼9 patients will be enrolled to have at least 6 evaluable patients and ∼226 patients will be randomized (1:1, stratified by number of prior lines of therapy and histology) in part 2 to docetaxel ± canakinumab. Primary objectives: to confirm RP3R of canakinumab + docetaxel, as determined by incidence of DLTs in first 42 days of administration (part 1) and overall survival (part 2). Secondary objectives are to assess efficacy (overall response rate, disease control rate, duration of response, time to response, progression-free survival by investigator per RECIST v1.1), safety, pharmacokinetics, immunogenicity of canakinumab, and patient reported outcomes. Enrollment is ongoing. Section not applicable Section not applicable

940P - cfDNA is an acceptable but insufficient means of characterizing FGFR3 mutation in patients with metastatic urothelial cancer (mUC)

940P - cfDNA is an acceptable but insufficient means of characterizing FGFR3 mutation in patients with metastatic urothelial cancer (mUC)

1134P - Monalizumab in combination with cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck cancer (SCCHN) previously treated or not with PD-(L)1 inhibitors (IO): 1-year survival data

BackgroundMonalizumab is a first in class immune checkpoint inhibitor targeting Natural Killer Group 2A (NKG2A), which is expressed as a heterodimer with CD94 on subsets of Natural Killer (NK), γδ T and tumor-infiltrating CD8+ T cells (André et al. Cell 2018). The NKG2A ligand, HLA-E, is upregulated in cancer, including SCCHN. NKG2A blockade promotes innate anti-tumor immunity mediated by NK and CD8+ T cells and enhances human NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) induced by cetuximab. This dual targeting could provide greater antitumor activity than cetuximab alone. MethodsThe multicenter phase II trial tested the combination of monalizumab and cetuximab in pts with R/M SCCHN. Pts received monalizumab 10mg/kg q2weeks and cetuximab according to the label until disease progression or unacceptable toxicity. Pts were required to be progressing after platinum-based chemotherapy and to have received ≤2 prior lines of therapy in the R/M setting. Previous treatment with IO was allowed. The primary endpoint was Overall Response Rate (ORR) per RECIST. ResultsAll 40 pts received prior platinum-based chemotherapy, 18 (45%) prior IO and 5 (13%) prior cetuximab. ORR was 27.5% [95% confidence interval: 16-43] with 11 confirmed responses (1 complete + 10 partial) observed in both IO naive 36% [20-57] and IO pretreated pts 17% [6-39]. As of April 17, 2019, with a median follow-up of 17 months (mo), in all pts, IO naïve and IO pretreated pts respectively, median duration of response was 5.6, 5.3 and 5.6mo, PFS was 4.5, 3.9 and 5.1mo and OS was 8.3, 7.8 and 12.8mo. The 12mo OS estimate is 44% [31-63]. No new safety signal emerged. Pre and post treatment tumor biopsies were collected and RNA seq analyses are ongoing. ConclusionsIn a cohort of 40 patients of heavily pretreated SCCHN patients, monalizumab and cetuximab combination demonstrated high response rate, good duration of response, and promising PFS and OS as well as good safety profile. An additional R/M SCCHN cohort of 40 patients who received both platinum-based chemotherapy and IO is being enrolled in this study. Clinical trial identificationNCT02643550. Legal entity responsible for the studyInnate Pharma. FundingInnate Pharma. DisclosureR.B. Cohen: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Innate Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genocea; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck. M.R. Posner: Advisory / Consultancy: Merck; Advisory / Consultancy: Cel-Sci; Shareholder / Stockholder / Stock options: Promedior; Licensing / Royalties: Bet Isreal-Deaconess Médical Centre, Arizona Stat. J.R. Bauman: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer. C. Even: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Innate Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genocea; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Heat; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Alkermes; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Arrys; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Honoraria (self), Advisory / Consultancy: Cantargia; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Xencor. E. Saada-Bouzid: Advisory / Consultancy: AstraZeneca. T. Seiwert: Honoraria (self): Aduro biotech; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self): Celgene; Honoraria (self): Innate; Honoraria (self): Loxo Oncology; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self): Nanobiotix; Research grant / Funding (institution): Jounce. F. Calmels: Shareholder / Stockholder / Stock options, Full / Part-time employment: Innate Pharma. R. Zerbib: Shareholder / Stockholder / Stock options, Full / Part-time employment: Innate Pharma. P. André: Shareholder / Stockholder / Stock options, Full / Part-time employment: Innate Pharma. A. Boyer-Chammard: Shareholder / Stockholder / Stock options, Full / Part-time employment: Innate Pharma. J. Fayette: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy: Innate Pharma; Honoraria (self), Advisory / Consultancy: Biogen. All other authors have declared no conflicts of interest.

SWOG S1400C (NCT02154490)—A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration–Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)

ObjectiveLung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities. MethodsPatients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressed after at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment. ResultsA total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n = 32) were as follows: CCND1, 81% (n = 26); CCND2, 9% (n = 3); CCND3, 6% (n = 2); and CDK4, 3% (n = 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% [95% confidence interval (CI): 0%–15%]), both with CCND1 amplification. Twelve patients had stable disease (38% [95% CI: 21%–54%]). The median progression-free survival was 1.7 months (95% CI: 1.6–2.9 months) and the median overall survival was 7.1 months (95% CI: 4.2–12.5). ConclusionPalbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.

Abstract CT171: Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors

Abstract Background: Nivolumab monotherapy results in limited responses (19-25%) in thoracic tumors, therefore the potential exists to design combination strategies to improve tumor response. Evidence exists to suggest that antiangiogenic agents have the potential to stimulate the immune system. Several pilot trials combined inhibitors of PD-1/PD-L1 and VEGFR in renal cell carcinoma, and the combinations outperformed either single agent. However, none of the combinations were well tolerated at full doses of the drugs. Therefore, it is desirable to explore immunotherapy and antiangiogenic agent combinations that have lower toxicity. Vorolanib is structurally similar to the antiangiogenic agent sunitinib but was designed to improve the safety profile without compromising efficacy. Preclinically, vorolanib had comparable anti-tumor activity to sunitinib, and toxicokinetic analyses suggested a very high safety window. Methods: NCT03583086 is a multi-institutional, phase I/II study of nivolumab and vorolanib in patients with thoracic tumors who failed at least one prior line of chemotherapy. The primary objective of phase I is to determine the maximum tolerated dose. Dose escalation uses a standard 3+3 design with three dose levels of vorolanib (200, 300, and 400 mg once-daily) and 240 mg nivolumab every two weeks. Phase II evaluates efficacy of the combination among five cohorts: immunotherapy naïve non-small cell lung cancer (NSCLC), NSCLC patients that have progressed (primary refractory and acquired resistance) on immunotherapy, thymic carcinoma, and small cell lung cancer (SCLC) patients with progression on prior platinum-based chemotherapy. Primary refractory is defined as radiographic progression of disease within 12 weeks after initiation of checkpoint therapy; acquired resistance includes achieving radiographic partial or complete response, or stable disease for at least 12 weeks followed by radiographic disease progression. Enrollment to phase II will use a Simon two-stage design for each cohort. Exploratory objectives will be performed to quantify changes in the innate and adaptive immune responses after treatment. Mass cytometry will be used to monitor serial changes in multiple immune markers on individual circulating cells in the blood. Changes in each marker will be correlated with response using the Lasso-based elastic net method. Single cell gene expression analysis from peripheral blood samples collected prior to and at the end of treatment will be performed and correlated with response to combination therapy in order to improve our understanding of the biology behind systemic changes to this treatment. Enrollment to phase I is ongoing; 7 patients have been enrolled, including 3 in dose cohort 1 and 4 in dose cohort 2. Thus far, a dose-limiting toxicity of elevated liver function tests possibly related to nivolumab and vorolanib was observed in one patient enrolled in dose cohort 2. Citation Format: Jennifer G. Whisenant, Katy Beckerman, Hossein Borghaei, Taofeek Owonikoko, Jyoti Patel, Yu Shyr, Kimberly Harrow, Chris Liang, Allison Holzhausen, Heather Wakelee, Leora Horn. Phase I/II study to evaluate the safety and preliminary activity of nivolumab in combination with vorolanib in patients with refractory thoracic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT171.

Derazantinib (DZB) provides antitumor efficacy regardless of line of therapy in patients (pts) with FGFR2-fusion positive advanced intrahepatic cholangiocarcinoma (iCCA).

e15607 Background: FGFR2 fusions are prevalent in 13-22% of iCCA and known oncogenic drivers. DZB is a kinase inhibitor with potent pan-FGFR activity. In a non-comparative Phase 2a study, DZB was administered to 29 pts with FGFR2-fusion positive advanced, inoperable iCCA, either as first-line (1L) (n = 2), 2L (n = 13), 3L (n = 10), 4L (n = 2) or 5L therapy (n = 2). The objective response rate (ORR) with DZB was 21%, disease-control rate (DCR) 83% and median PFS 5.7 months (Mazzaferro et al. 2018 BJC). Data from biliary tract cancer studies suggest decreasing treatment effects of chemotherapy with increasing lines of treatment. Here, we present a post-hoc analysis of outcomes of pts treated with DZB in 1L/2L (n = 15) compared to pts treated post-2L (n = 14). Methods: Pts received 300 mg DZB QD PO. Eligibility criteria included locally confirmed, positive testing of FGFR2 fusion expression (FISH or NGS), ECOG PS 0-1. Objective responses were determined using RECIST 1.1. Disease control rate was defined as CR, PR or SD. Results: The mean age of pts treated in 1L/2L was 66y and 55y in post-2L; 73% were females in 1L/2L and 50% in post-2L treatment; other demographic variables were balanced between groups (87% vs 86% of liver target lesions, median baseline lesion size of 97.5 mm vs 109.5 mm, ECOG PS0 was 60% vs 71%). Of 15 1L/2L group pts, 12 (80%) had prior platinum-based chemotherapy as compared to all 14 pts in the post-2L group. In the 1L/2L and post-2L groups, ORR was 20% and 21%, DCR was 80% and 86%, and a reduction in sum of the largest diameter of target lesions was observed in 60% and 64% of pts, respectively. Median PFS was 5.5 mo (95% CI, 1.9-11.9) and 6.2 mo (3.6-9.2) for the 1L/2L and post-2L groups, respectively. Types of drug-related adverse events were similar in 1L/2L and post-2L. Conclusions: Anti-tumor efficacy of DZB in iCCA patients measured either by ORR, DCR, tumor shrinkage or PFS was numerically similar irrespective of treatment line. These data suggest that DZB is an effective treatment option that can be applied early in the treatment continuum of iCCA patients or at later stages to offer anti-tumor efficacy and disease control. Clinical trial information: 01752920.

Infigratinib in upper tract urothelial carcinoma vs urothelial carcinoma of the bladder and association with comprehensive genomic profiling/cell-free DNA results.

4510 Background: Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitor with significant activity in patients (pts) with advanced or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations [Pal et al 2018]. Given the distinct biologic characteristics of upper tract UC (UTUC) and urothelial carcinoma of the bladder (UCB), we sought to determine if infigratinib had varying activity in these settings. Methods: Eligible pts had mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy, unless contraindicated. Pts received infigratinib 125 mg orally daily (3 wks on/1 wk off). Overall response rate (ORR: CR+PR) and disease control rate (DCR; CR+PR+SD) were characterized in UCB and UTUC pts. Comprehensive genomic profiling was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA). Blood was collected for cell-free (cf)DNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer. Results: 67 pts were enrolled; the majority (70.1%) had received ≥2 prior antineoplastic therapies. ORR was 25.4% and DCR was 64.2%. In the 8 pts with UTUC, 1 CR and 3 PRs were observed (ORR 50%); the remainder had a best response of SD (DCR 100%). UTUC pts were predominantly 2nd line (62.5%), with only 2 (25%) showing response to previous treatment. In pts with UCB, 13 PRs were observed (ORR 22%), and 22 pts had a best response of SD (DCR 59.3%). Notable differences in genomic alterations between cohorts included a higher frequency of FGFR3-TACC3 fusions (12.5% vs 5.8%) and FGFR3 R248C mutations (50% vs 11.5%), and a lower frequency of FGFR3 S249C mutations (25% vs 59.6%) in UTUC vs UCB. Consistent with previous reports [Sfakianos et al 2016], UTUC pts had a differential frequency of alterations in HRAS, CDKN2B and ARID1A. Sufficient cfDNA yield was obtained in UTUC and UCB pts and a comprehensive comparison of these data will be presented. Conclusions: Differences in cumulative genomic profile were observed between UCB and UTUC in this FGFR3-restricted experience, underscoring the distinct biology of these diseases. Results with infigratinib in UTUC support a planned phase III adjuvant study predominantly in this population. Clinical trial information: NCT01004224.

RNAseq and DNA whole-exome sequence analysis reveal novel response signatures to IO treatment in muscle invasive bladder cancer (MIBC) patients.

4558 Background: Objective: To examine in a cohort of anti-PD-(L)1 immune checkpoint inhibitors (ICP) treated urothelial cancer patients a strategy combining treatment outcomes with molecular alterations, pathways, and immune/tumor microenvironment features to determine potential responder and rapid-progression signatures. Methods: De-identified clinical history and treatment outcomes were collected on 109 MIBC patients treated with ICP agents. Archived FFPE samples from these patients were obtained and processed for mRNAseq, exome-seq, tumor mutation burden (TMB), microsatellite instability (MSI) and mutation panel testing. Comprehensive tumor/immune profiling is being analyzed in the context of ICP treatments and RECIST 1.1 outcomes. A 60 gene MIBC 4-typer expression subtyper and other response associated predictors are used to stratify and identify positive/negative ICP response indicators. Results: 109 patients were identified (median age 75, 64% male, 78% white, 17% black). 74% of patients had received prior platinum-based chemotherapy, and 12% had received 2 or more prior lines of therapy. At initiation of ICP, 28% of patients had hemoglobin < 10, 30% had liver metastases, and 59% had ECOG performance status > 0. Mutation analysis of the first 66 patients showed TP53 (n = 34, 52%), FGFR (n = 17, 26%), CDKN2A (n = 13, 20%) and RB1 (n = 12, 18%) as the top alterations. No patients (0/8) with known pathogenic mutations in FGFR3 (S249C and TACC3-fusion) responded to ICP. Of patients with T2 staging prior to ICP (37/66), overall survival was markedly shorter (2.7 years) in those possessing FGFR3 mutations (n = 6/37) compared to that for FGFR3 WT patients (5.7 years, n = 31/37; p = 0.045). Further analyses of molecular features relative to treatment outcomes are ongoing to characterize response signatures. Conclusions: Our preliminary cohort of patients with pathogenic FGFR3 alterations showed 0% favorable response to ICP. We are expanding on this observation with further comprehensive molecular analyses and retrospective treatments/outcomes data. We anticipate identifying expression signatures that reflect ICP patient responder/non-responder signatures that may aid in future therapy decisions.

Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer.

8514 Background: Recent progress in genomic profiling of small cell lung cancer (SCLC) has demonstrated that a high proportion of SCLC harbor mutations in cell cycle-related genes and RICTOR amplification. With the recent introduction of cell-cycle altering small molecules, AZD1775 (WEE1 inhibitor), AZD2811 (aurora kinase B inhibitor) and mTOR1/2 inhibitor (AZD2014), biomarker-driven umbrella study is being conducted in relapsed SCLC. Methods: This is a phase II umbrella trial study with multiple monotherapy arms in resistant SCLC who has failed prior platinum-based chemotherapy and known genomic profile from pre-designed screening study of SUKSES-S (Small cell lung cancer Umbrella Korea StudiES, NCT02688894). Patients with MYC family amplification or co-alteration in CDKN2A and TP53 were allocated to SUKSES-C (AZD1775 arm, NCT02593019); RICTOR amplification to SUKSES-D (AZD2014 arm, NCT03106155). Otherwise, patients were randomly assigned to non-biomarker specific arms, SUKSES-N1 (AZD1775 arm, NCT02593019) or SUKSES-N3 (AZD2811 arm, NCT03366675). Each cohort was designed as Simon 2-stage scheme. Results: Patients allocated to SUKSES-C (n = 7) & N1 (n = 24) showed no objective response rate and stable disease was observed in 3 patients (42.9%) and 6 patients (25.0%), respectively. The median progression-free survival (PFS) was 1.28 months (95% confidential interval [CI] 1.18–not available [NA]) and 1.21 months (95%CI 1.15-2.33), respectively. SUKSES-D (n = 4) showed no objective response as well as no stable disease with PFS of 1.25 months (95%CI 0.98-NA). SUKSES-N3 (n = 15) showed no objective response with 5 stable disease (33.3%) and PFS of 1.61 months (95%CI 1.18-NA). For the safety record, adverse events (AEs) grade≥3 were observed as follows: SUKSES-C & -N1 (n = 1, 3.2%), -D (n = 3, 75.0%), -N3 (n = 9, 60%). Notably, neutropenia (grade≥3) was frequently observed (n = 8, 53.3%) in AZD2811 arm including a case of septic shock. Conclusions: SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development. Clinical trial information: NCT02593019, NCT03106155, NCT03366675.

PCN90 AN ECONOMIC EVALUATION OF NIVOLUMAB FOR THE TREATMENT OF ADVANCED NON-SMALL CELL LUNG CANCER (ANSCLC) AFTER PRIOR CHEMOTHERAPY IN CHINA

To assess the value of nivolumab in the treatment of aNSCLC [squamous (SQ) and non-squamous (NSQ)] after prior platinum-based chemotherapy in adults without EGFR/ALK mutations in China. Partitioned survival models were developed to evaluate lifetime costs and benefits of nivolumab versus docetaxel by histological subtype (SQ and NSQ) from the Chinese healthcare payer’s perspective. The models considered three health states (progression-free; progressive disease; dead) over a 20-year time horizon. Clinical data were derived from pivotal phase-III clinical trials (CheckMate017; CheckMate057; CheckMate078). Parametric functions to extrapolate survival data beyond the trial follow-up period were selected based on best fit. Health state utilities were calculated from EQ-5D-3L data using Chinese tariffs. Health-care resource utilisation and unit costs were obtained from database analysis, systematic literature review, clinician opinion and public information. Sensitivity analyses explored the robustness of results to uncertainty surrounding assumptions and inputs. Nivolumab was associated with incremental survival (1.235 and 1.330 LYs) and quality of life (0.873 and 0.902 QALYs) benefit at additional cost (¥198,228 and ¥144,248) compared with docetaxel in SQ and NSQ aNSCLC, respectively. Due to a favorable safety profile, AE management costs were lower for nivolumab than docetaxel (¥94 vs. ¥4,928 across histologies), while patients receiving nivolumab incurred lower subsequent treatment costs versus those receiving docetaxel (SQ: ¥23,034 vs. ¥56,474; NSQ: ¥23,020 vs. ¥56,389). Sensitivity analyses determined that drug acquisition costs were a key model driver across histologies. It is the first economic evaluation undertaken for nivolumab in the Chinese context. Nivolumab was associated with substantial survival and quality of life benefits at incremental cost compared with docetaxel in aNSCLC. Given a traditional healthcare payer perspective was adopted for the analyses the true economic benefit of nivolumab may be underestimated since not all treatment benefits and costs of relevance to society have been captured.

Italian Cohort of Nivolumab Expanded Access Program in Squamous Non-Small Cell Lung Cancer: Results from a Real-World Population.

Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program. Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information. The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2-9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy (n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression (n = 65). In the overall population, the rate of any-grade and grade 3-4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths. To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials. Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials.