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- I. Svane
- T. Powles
1144O - Phase III randomized controlled trial of adjuvant chemoimmunotherapy in patients with resected primary lung cancer (ID 1273)
- H. Kimura
Abstract
Background
Adoptive cellar immunotherapy is not widely approved as a treatment option for cancer treatment. The preliminary results from our phase III, randomized controlled trial (RCT) of adjuvant chemoimmunotherapy for lung cancer indicated significant advantages in patients receiving immunotherapy. Here we report the final results and long-term analysis of this RCT.
Methods
A hundred and three postsurgical non-small-cell lung cancer patients were randomly designated to receive either chemoimmunotherapy (group A, immunotherapy arm, n = 51) or chemotherapy (group B, control arm, n = 52). The immunotherapy consisted of adoptive transfer of autologous activated killer T cells and dendritic cells obtained from regional lymph nodes of the patients.
Results
The 2- and 5-year overall survival (OS) rates were 96·0% and 69.4% in group A and 64·7% and 45.1% in group B, respectively. The hazard ratio (HR) was 0.451 (0.235∼0.807) by multivariate analysis. The 2- and 5-year recurrence-free survival rates were 70.0% and 57·9% in group A and 43.1% and 31.4% in group B, respectively. P values of Log-rank test between groups were 0.0059. Subgroup analysis for the OS between treatment groups indicated males (HR, 0·474), adenocarcinoma patients (HR, 0·479), stage III cancer patients (HR, 0·399), and those who did not receive preoperative chemotherapy (HR, 0·483) had lower HRs than those in the other groups. Immunological analysis of cell surface markers in regional lymph nodes of subjects receiving immunotherapy indicated that the CD8+/CD4+ T-cell ratio was elevated in survivors.
Conclusions
Non-small-cell lung cancer patients benefited from adoptive cellular immunotherapy as an adjuvant to surgery. Immunological analysis of cell surface markers indicated cytotoxic T cells were essential for a favorable chemoimmunotherapy outcome.
Clinical trial identification
The University Hospital Medical Information Network in Japan (UMIN: 000007525).
Legal entity responsible for the study
Chiba Cancer Center, Japan
Funding
None
Disclosure
All authors have declared no conflicts of interest.
1135O - Phase 1b/2 Study (SCORES) assessing safety, tolerability, and preliminary anti-tumor activity of durvalumab plus AZD9150 or AZD5069 in patients with advanced solid malignancies and squamous cell carcinoma of the head and neck (SCCHN) (ID 1719)
- E. Cohen
Abstract
Background
Anti-tumor activity of durvalumab (D), a programmed death ligand (PDL1) blocking antibody, may be enhanced by overcoming intratumoral immune suppression. The selective Generation 2.5 antisense oligonucleotide STAT3 inhibitor AZD9150 (STATi), a small molecule CXCR2 inhibitor AZD5069 (CX2i), and CTLA4 inhibitor tremelimumab (T) are in evaluation.
Methods
Part A, dose escalation in solid tumors, evaluated STATi + (D or D+T) and CX2i + (D or D+T) for safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose. Part B, dose expansion in SCCHN, tested STATi (3 mg/kg)+D and CX2i (40 mg BID)+D in PDL1 pretreated/naive pts and as monotherapy for Objective Response Rate (ORR) and Disease Control Rate (DCR).
Results
Part A showed STATi+D and CX2i+D as safe and tolerable combinations with confirmed partial responses (cPR) in multiple tumor types and 2 confirmed complete responses (cCR) in breast and prostate cancer (>64 weeks [wks] on treatment). STATi+DT had a cPR in sarcoma at 12 wks. In Part B (STATi+D reported here), the PDL1 naive arm had 25% ORR (4 cPR, 1 unconfirmed PR (uPR); 3 Human Papilloma Virus negative and 2 unknown), 45% DCR (9/20) was observed at 12 wks, and 30% of pts (6/20) remain on treatment at 25 wks. One cPR pt is unconfirmed CR at data cut off. In the PDL1 pretreated arm, 1 pt had complete metabolic response and 1 pt had uPR; 20% DCR (3/15) was observed at 12 wks. Safety and tolerability were confirmed for STATi+D in SCCHN pts, with manageable and reversible adverse events of thrombocytopenia and liver enzyme increases (for each, Grade 3/4 in 3.4% of 58 pts dosed); 2 STATi+D related discontinuations occurred.
Conclusions
Initial ORR and DCR data suggest enhanced antitumor activity results from combining a PDL1 antagonist (D) with an agent targeting immunosuppression in the tumor microenviornment (STATi) compared to PDL1 monotherapy. The combination may prove to provide a tolerable and effective option for patients with recurrent/metastatic SCCHN in the naive and PDL1-pretreated setting and other solid tumor types being studied.
Clinical trial identification
NCT02499328
Legal entity responsible for the study
AstraZeneca PLC
Funding
AstraZeneca
Disclosure
E.E. Cohen: Consulted for AstraZeneca, Bristol-Myers Squibb, Human Longevity, Merck, Merck Serrano, and Pfizer. Received expenses for travel or accommodation from AstraZeneca, Merck, and Pfizer. Holds stock in Human Longevity, Inc. D.S. Hong: Received grants from Bayer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirati, Ignyta, Merck, Daichi-Sanko, and Eisai. Travel expenses were provided by MiRNA and LOXO. Consulted for Bayer, Baxter, and Guidepoint Global. He founded Oncoresponse. T. Wise Draper: Received funding for investigator-initiated studies from Bristol-Myers Squibb and Merck. D. Schrijvers: Participated in studies sponsored by Cougar, Janssen, and Bayer. Served on the advisory board of Janssen and Bayer Belgium. Spoken at events organized by Janssen and Bayer Belgium. R. Mesia Nin: Served an advisory role for AstraZeneca, Merck SL, Bayer, and Bristol. Received conference honoraria from Bristol and Merck SL. M.L. Scott, P. Lyne, P. McCoon, C.E. Cook: Employee of, and owns stock in, AstraZeneca. G. Mugundu: Employee of AstraZeneca and owns stock in AstraZeneca and Pfizer. M.M. Mehta: Employed by AstraZeneca. U. Keilholz: Received speaker honoraria, and served on advisory boards, for AstraZeneca, Merck, MSD, Pfizer, Novartis, and Innate. Participates in research sponsored by AstraZeneca and Merck. All other authors have declared no conflicts of interest.
Invited Discussant 1144O and 1135O (ID 5835)
- T. Powles
1136O - Nivolumab and ISA 101 HPV vaccine in incurable HPV-16+ cancer (ID 2757)
- B. Glisson
Abstract
Background
Vaccines directed against Human Papilloma Virus (HPV) do not generally mediate regression of invasive cancer. To test the hypothesis that the efficacy of vaccine-induced T cells may be amplified through treatment with immune checkpoint antibodies, we conducted a phase II trial of ISA 101, a synthetic long-peptide HPV-16 vaccine, and nivolumab in pts with incurable HPV-16+ cancer.
Methods
Tumors were HPV-genotype 16 by Cervista HPV16/18. Patients were ECOG PS 0-1 with up to one prior regimen for recurrence. ISA101 100 mcgs/peptide was given Days 1, 22, 50. Nivolumab 3 mg/kg was given iv every 2 wks beginning day 8 for up to one year. Imaging was obtained baseline, 11 wks and every 6 wks thereafter. The primary objective was assessment of overall response rate (ORR) targeting 30%. Secondary objectives: tolerability, PFS, OS. A Simon two stage design required response in 2/15 first stage and 5/25 in second stage.
Results
The trial accrued 24 patients; 22 with oropharynx cancer (OPC) and 1 pt each with anal and cervical cancer. 18 pts (75%) had progression within 6 mos of prior platin and 1 was platin-naïve. 12 pts (50%) had prior cetuximab. Treatment was frontline for recurrence in 10/24 and second line in 14/24. ORR is 33% (8/24): 1 CR, 7 PR (1 unconfirmed), 3(13%) SD, 13 (54%) PD. ORR in OPC pts is 36% (8/22). 6/8 pts with PR progressed within 6 mos of prior platin. Median duration of response 30.1+ wks (6- 49+ wks); 5/8 pts with PR remain in response. Median PFS is 2.7 mos [95% CI 2.3-8.0 mos] and median OS is not reached with median follow up time among censored pts 8.6 mos. PFS rate at 6 mos: 33%, [16-52%] OS rate at 6 mos 74%, [51-87%] . Toxicity: grade 3 transaminase and grade 4 lipase elevation in 1 pt each, grade 1-2 toxicity: fever (5 pts), injection site reaction (6 pts), transaminase elevation, fatigue, nausea (3 pts each).
Conclusions
The primary endpoint was met and ORR of 36% in OPC pts compares favorably to 16% for nivolumab monotherapy in p16+ OPC pts in Checkmate 141 (Ferris RL et al N Engl J Med 2016; 375:1856). These data suggest that the efficacy of vaccine-induced T cells can be augmented by anti-PD-1 therapy, mitigating the influence of an immunosuppressive microenvironment. Our findings merit confirmation in a larger randomized trial. Correlation of efficacy outcomes with immunoprofiling of tumors will be presented.
Clinical trial identification
NCT02426892
Legal entity responsible for the study
U T M D Anderson Cancer Center
Funding
U T M D Anderson Cancer Center
Disclosure
S. van der Burg, C. Melief: Employed by ISA Pharmaceuticals Inc. All other authors have declared no conflicts of interest.
1137O - Interim analysis of the phase 3 ADAPT trial evaluating rocapuldencel-T (AGS-003), an individualized immunotherapy for the treatment of newly-diagnosed patients with metastatic renal cell carcinoma (mRCC) (ID 5493)
- R. Figlin
Abstract
Background
Rocapuldencel-T is an investigational immunotherapy formulated with RNA isolated from the patient's tumor to program autologous dendritic cells with tumor-specific antigens. It is administered chronically via intradermal injection to activate a tumor-specific memory T-cell response.
Methods
The Phase 3 ADAPT trial was designed to evaluate overall survival (OS) of rocapuldencel-T in combination (Combo) with standard-of-care (SOC) for the treatment of newly diagnosed mRCC as compared to SOC alone (Control). It included adults with synchronous, clear cell mRCC who were eligible for nephrectomy at 107 sites across North America, Europe and Israel.
Results
462 patients were randomized 2:1 from February 2013 - October 2015. In February 2017, an interim analysis by the Independent Data Monitoring Committee after 75% of the targeted number of 290 events (deaths) prompted a recommendation to stop the trial because the OS hazard ratio was greater than the pre-defined futility boundary (0.98) for the 3rd interim assessment. However, in consultation with investigators and the FDA, the sponsor has continued the trial due to the still maturing survival data, the mechanism of action of rocapuldencel-T, which involves the induction of long-term memory immune responses, and its’ safety profile. The median duration of follow-up was 20 months and more than half the patients in both treatment groups were still alive. Data from the first third of patients randomized (n = 154), and, therefore the longest follow up time and least censored data (44%), suggest a potential survival benefit for the combination worthy of further assessment. Additionally, a statistically significant correlation was observed between the increase in the number of rocapuldencel-T induced memory T cells (CD8+/CD28+/CD45RA-) and OS in patients for whom data has been analyzed and 7 doses of rocapuldencel-T has been administered (n = 114). Updated long-term response and immune data will be presented.
Conclusions
The ADAPT trial is ongoing to further assess the long-term effects of this well-tolerated individualized immunotherapy.
Clinical trial identification
NCT01582672
Legal entity responsible for the study
Argos Therapeutics
Funding
Argos Therapeutics
Disclosure
R. Figlin: Institution receives research funding. C. Nicolette, M. Debenedette, T. Monesmith, W. Tan, S. Leland: Employee of Argos Therapeutics. N. Tannir: Grants and/or personal fees and non-financial support from Bristol-Myers Squibb, Exelixis, Nektar, Pfizer, Argos, Calithera, Epizyme, Miranti, outside the submitted work. All other authors have declared no conflicts of interest.
Invited Discussant 1136O and 1137O (ID 5836)
- H. Gogas