Abstract 5584: PHY906(YIV-906), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Immune checkpoint blockade therapy: anti-PDL1, anti-PD1, anti-PD1/CTLA4 against melanoma
0
Citation
0
Reference
10
Related Paper
Abstract:
Abstract Immune checkpoint blockade therapy has recently been recognized as a breakthrough in cancer treatment. Currently the FDA has approved Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD1) and Nivolumab (anti-PD1), and Atezolizumab (anti-PDL1) for the treatment of several types of cancers, including melanoma. However, colitis and diarrhea are commonly found in these immunotherapies, particularly in anti-PD1/CTLA4 therapy. PHY906(YIV-906) is inspired by the Huang Qin Tang, which was first described in Chinese texts 1800 years ago for the treatment of numerous gastrointestinal symptoms. Consistent preparations of PHY906 could be manufactured apart 10 years. In animal studies, PHY906 can increase the anti-tumor activity of a broad spectrum of chemotherapies while promoting damaged intestinal tissue recovery via mutliple targets. Several clinical results suggest that PHY906 had potential to increase the therapeutic index of cancer treatments (chemotherapy, radiation) by prolonging life and improving patient quality of life. We hypothesize that PHY906 can reduce diarrhea caused by anti-PD-L1, anti-PD1, and/or in combination with CTL4 without compromising their anti-tumor activity. We studied the effect of PHY906 in combination with anti-PDL1, anti-PD1, anti-CTLA4 and anti-PD1/CTLA4, using subcutaneously implanted B16F10 melanoma in Black B16 mice. Results indicated that PHY906 enhanced the anti-tumor activity of anti-PD1, anti-PDL1, or anti-PD1/CTLA4; but not anti-CTLA4 alone, in vivo. In addition, PHY906 did not compromise the action of anti-PD-L1 in brain implanted B16 tumor. PHY906 in combination with all of the antibodies had no impact of body weight change or different type of blood cells counts. PHY906 reduced mRNA expression of several inflammation markers, including TNFa, MCP1, ICAM, IL2, in ileum or colon tissues following anti-PD1 or anti-CTLA4 treatment. In cell culture, PHY906 was found to have modulation effect on Indoleamine 2,3-dioxygenase (IDO) which is a key resistance factor to immune checkpoint blockade therapies. Overall, PHY906 can increase the therapeutic index for anti-PDL1, antiPD1, or anti-PD1/CTLA4 in against melanoma. We are planning to initiate a clincal trial to determine if PHY906 could enhance the therapeutic index of anti-PD1/CTLA4 for the treatment fo melanoma in patient. This work was supported by grant (1PO1CA154295-01A1) from National Cancer Institute (NCI), NIH, USA. Dr. Yung-Chi Cheng is a fellow of National Foundation for Cancer Research (NFCR), USA. Citation Format: Wing Lam, Zaoli jiang, Xue han, Shwu-Huey Liu, Lieping Chen, YungChi Cheng. PHY906(YIV-906), an adjuvant based on a 1800-year-old Chinese medicine, enhanced the anti-tumor activity of Immune checkpoint blockade therapy: anti-PDL1, anti-PD1, anti-PD1/CTLA4 against melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5584. doi:10.1158/1538-7445.AM2017-5584Keywords:
Immune checkpoint
Atezolizumab
For patients with advanced melanoma, the combination of ipilimumab and nivolumab yields better responses than ipilimumab alone. However, the two-drug combination is much more likely to cause side effects than the monotherapy.
Cite
Citations (1)
Cost utility analyses of oncology treatments are most commonly performed using partitioned survival models, applying health state utilities to progression-free and progressive disease and relative to a specific line of therapy. The objective of this study was to assess utility values across treatments and lines of treatment using data in advanced melanoma for two immuno-oncology agents, nivolumab and ipilimumab. Utility values from 1st line (1L) and 2nd line (2L) advanced melanoma populations treated with nivolumab and ipilimumab were extracted from three randomised controlled clinical trials: CheckMate-067 (1L nivolumab and 1L ipilimumab), CheckMate-037 (2L nivolumab) and MDX010-20 (2L ipilimumab). Visual assessment of QoL over time as well as comparisons of baseline and change from baseline values were performed using summary statistics. Baseline values for 1L and 2L were similar for nivolumab (0.80 vs 0.75, p=0.001) and ipilimumab (0.79 vs 0.81, p=0.123). Across all lines of therapy nivolumab use resulted in improvements in utility whilst patients remained progression free. Ipilimumab treatment regimens showed initial declines in utilities in the first 3 months followed by improvements over the remainder of time on treatment. The change in utility from baseline to 12 months was similar for 1L and 2L nivolumab (0.050 v 0.047, p=0.930). Both these changes were greater than that observed for 1L ipilimumab at 12 months (0.035, p=0.533 v 1L nivolumab and p=0.767 v 2L nivolumab). 2L ipilimumab results were limited to short term follow-up, however utility values were comparable to 1L ipilimumab at 5 months (-0.023 v 0.014, p=0.091). The quality of life of patients on immune-based therapies appears to be independent of therapy line. Furthermore, economic modelling in an immune-oncology setting should reflect that quality of life looks to be a function of time on treatment.
Cite
Citations (0)
Recent studies suggest that combining nivolumab with ipilimumab is a more effective treatment for melanoma patients, compared to using ipilimumab or nivolumab alone. However, treatment with these immunotherapeutic agents is frequently associated with increased risk of toxicity, and (auto-) immune-related adverse events. The precise pathophysiologic mechanisms of these events are not yet clear, and evidence from clinical trials and translational studies remains limited. Our retrospective analysis of ~7700 metastatic melanoma patients treated with ipilimumab and/or nivolumab from the FDA Adverse Event Reporting System (FAERS) demonstrates that the identified immune-related reactions are specific to ipilimumab and/or nivolumab, and that when the two agents are administered together, their safety profile combines reactions from each drug alone. While more prospective studies are needed to characterize the safety of ipilimumab and nivolumab, the present work constitutes perhaps the first effort to examine the safety of these drugs and their combination based on computational evidence from real world post marketing data.
Cite
Citations (25)
Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.
Cite
Citations (3,067)
ABSTRACTMetastatic melanoma has less frequency, but considered as the most dreaded cancer. The combination of nivolumab & ipilimumab is proving their mettle in treating metastatic melanoma. The patients when administered with the combination of nivolumab & ipilimumab have shown improved median progression free survival, objective response rate and overall survival rate compared with nivolumab and ipilimumab monotherapy. The combination shrinks the tumor cells by attacking different checkpoints viz. CTLA-4 and PD-L1, respectively. The combination treatment reveals reduced disease progression and suggests nivolumab's non-cross resistant nature. The median progression free survival in "nivolumab plus ipilimumab" group has shown an increase of 66.7% and 296.6% in comparison to nivolumab and ipilimumab monotherapy. The other parameter viz. objective response rate improvement is equivalent to almost 14% and 38.6% when compared to nivolumab and ipilimumab monotherapy, respectively.KEYWORDS: Checkpoint inhibitorsmedian progression free survivalmetastatic melanomametastasizenivolumab AcknowledgementsThis research work was funded by the Institutional Fund projects under grant no. (IFPDP-111-22). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Deanship of Scientific Research, Jeddah, Saudi Arabia.Disclosure statementNo potential conflict of interest was reported by the author(s).Author contributionsConceived and designed the study or experiments: MW RKM AJ AA AHM SH (Steve Harakeh) AH SF RP SHh (Shafiul Haque). Performed the experiments/Collected the data: MW RKM AJ AA. Analyzed the data: MW RKM AJ AA. Contributed reagents/materials/analysis tools: AHM SH AH SF RP SHh. Wrote the paper: MW RKM AJ AA AHM SH AH SF RP SHh. All authors reviewed the manuscript.Additional informationFundingThis research work was funded by the Institutional Fund projects under grant no. (IFPDP-111-22). Therefore, the authors gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Deanship of Scientific Research, Jeddah, Saudi Arabia
Combination therapy
Cite
Citations (0)
Abstract Background: Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors. We performed a meta-analysis to evaluate the efficacy and treatment-related adverse events (TRAEs) of nivolumab-ipilimumab combination therapy in cancer treatment. Methods: We examined data from PubMed, Web of science, EBSCO and Cochrane library. Eleven articles fulfilled our criteria, which we divided into 3 groups; nivolumab and ipilimumab versus ipilimumab, nivolumab and ipilimumab versus ipilimumab and nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) versus nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1). We measured the complete response (CR), partial response (PR), objective response rate (ORR) and TRAEs in any grade and grade 3 or higher. Results: Compared with ipilimumab alone, the combined immunotherapy had better CR (RR: 4.89, p <0.001), PR (RR: 2.75, p <0.001), and ORR (RR: 3.31, p <0.001). The overall effect estimate favored the combined immunotherapy group in terms of the ORR (RR: 1.40, p <0.001) and PR (RR: 1.50, p <0.001) than nivolumab alone. Finally, N1I3 showed better PR (RR: 1.35, p =0.006) and ORR (RR: 1.21, p =0.03) than N3I1. The incidence of any TRAEs was similar between the both groups (RR: 1.05, p =0.06). However, the incidence of serious adverse events (grade 3 or higher) were lower in group N3I1 than group N1I3 (RR: 1.51, p <0.001). Conclusion: This meta-analysis showed that the curative effect of nivolumab plus ipilimumab was better than that of ipilimumab or nivolumab monotherapy. In the combination group, N1I3 combination was more effective than N3I1. Although the side effects were slightly increased in group N1I3, the overall safety was acceptable.
Cite
Citations (0)
Atezolizumab
Cite
Citations (0)
Introduction: The immune checkpoint inhibitors, including nivolumab, and targeted agents have dramatically improved the outcome for patients with unresectable advanced melanoma.Areas covered: This is a narrative review of the published evidence on nivolumab in metastatic melanoma.Expert opinion: In ipilimumab pre-treated patients (CheckMate 037), nivolumab was associated with a higher response rate and a longer duration of response when compared to chemotherapy. In previously untreated patients, nivolumab improves survival when compared to chemotherapy (CheckMate 066) or to ipilimumab (CheckMate 067). The combination of nivolumab and ipilimumab also improves survival when compared to ipilimumab (CheckMate 067). CheckMate 067 was not designed to compare the nivolumab–ipilimumab combination to nivolumab alone. A modified regimen using a lower dose of ipilimumab in combination with standard dose nivolumab is better tolerated than nivolumab in combination with standard dose ipilimumab (CheckMate 511).In patients with previously untreated metastatic melanoma, the anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab improve survival when compared to ipilimumab. Nivolumab is equally active in BRAF mutated and BRAF wild type melanoma. The optimal sequence of checkpoint inhibitors and BRAF/MEK inhibitors in BRAF mutated patients has not been established.
Combination therapy
Cite
Citations (3)
Abstract To describe the treatment patterns of nivolumab and ipilimumab in Japan, a retrospective observational study was conducted in melanoma patients who received nivolumab and ipilimumab sequentially. Patients who received nivolumab and ipilimumab in combination were excluded from this study. Efficacy was evaluated by the Response Evaluation Criteria in Solid Tumors ( RECIST ) in terms of the overall response rate ( ORR ), progression‐free survival ( PFS ), and disease control rate ( DCR ). Overall survival ( OS ) was also evaluated. Safety was assessed by the Common Terminology Criteria for Adverse Events ( CTCAE ). The treatment for all 68 patients enrolled involved switching from nivolumab to ipilimumab in 61 patients and switching from ipilimumab to nivolumab in seven patients. Switching occurred because of progressive disease in 55 patients and adverse events in eight patients. The median number of ipilimumab doses was three. Ipilimumab treatment achieved an ORR and DCR of 4.9% and 21.3%, respectively, and the median OS from start of ipilimumab was 7.0 months. During the study period, no new safety signals were noted. Independent factors which were indicative of poor prognosis for PFS were high neutrophil‐to‐lymphocyte ratio ( NLR ) and high C‐reactive protein ( CRP ) levels before ipilimumab treatment. An evaluation over a washout period indicated that no significant relationship existed with efficacy or safety. For the sequential administration of nivolumab and ipilimumab in Japanese melanoma patients, switch from nivolumab to ipilimumab was common, and the major reason for switching was progressive disease. The major prognostic factors for ipilimumab PFS after nivolumab were NLR and CRP before ipilimumab treatment.
Cite
Citations (15)
Patients with metastatic melanoma whose disease progresses on ipilimumab can clearly derive benefit from subsequent anti-programmed death-1 (PD-1). However, patients experience heterogeneous outcomes with ipilimumab, including rapid or delayed progression, and it is unclear whether patterns of ipilimumab progression influence subsequent clinical responses to anti-PD-1. We retrospectively reviewed data from 116 patients with metastatic melanoma who progressed on ipilimumab and were subsequently treated with pembrolizumab. The study objectives were to determine whether progression-free survival (PFS) with ipilimumab was associated with PFS, objective response rate (ORR), and clinical benefit rate (CBR; ORR + stable disease) with pembrolizumab. Patients with PFS ≥90 days after treatment with ipilimumab generally had superior outcomes with subsequent pembrolizumab treatment compared with patients with PFS <90 days (ORR, 49% vs. 35%, P = 0.12; CBR, 66% vs. 46%, P = 0.03). Patients with prolonged ipilimumab benefit (PFS ≥ 180 days) had excellent outcomes with pembrolizumab compared with rapid progressors (PFS < 45 days; ORR, 55% vs. 25%; CBR, 80% vs. 25%; median PFS, 249 vs. 50 days). Using logistic regression models, PFS with ipilimumab was independently correlated with response to pembrolizumab (odds ratio, 1.22; 95% CI, 1.02-1.51). This study shows that prolonged PFS with ipilimumab predicts excellent outcomes with subsequent pembrolizumab treatment, offering valuable prognostic information for clinicians. Cancer Immunol Res; 4(7); 569-73. ©2016 AACR.
Cite
Citations (20)