However, Regorafenib is very poorly tolerated with a Grade 3/4 drug related adverse event rate of 54%, mostly due to hand-foot skin reactions, fatigue and diarrhea, resulting in frequent dose reductions and discontinuations and a general reluctance among GI oncologists to administer it. P502 In vitro and in vivo RRx-001 synergy with regorafenib and in vivo attenuation of regorafenib-induced toxicity Bryan Oronsky, MD PhD 1, Tony Reid, MD PhD 2, Corey Carter, MD 2, 2, Pedro Cabrales, PhD 3 1 EpicentRx Inc, La Jolla, CA, United States 2 EpicentRx, Inc., La Jolla, CA, United States 3 University of California San Diego (UCSD), La Jolla, CA, United States Correspondence: Christopher Larson ( the Phase 3 CORRECT study, which led to the approval of the multi-kinase inhibitor, Regorafenib, in 3rd/4th line metastatic colorectal cancer, the OS was 6.4 months and the PFS was 1.9 months compared to an OS of 5.0 months and a PFS of 1.7 months for placebo. The study CA-XLI-6 was approved by the CRO's Ethics Board under IACUC approval number 19-015.9. With further development, dietary NEAA deprivation may become the promising foundation for a broad spectrum of cancer therapies. Our data supports the use of dietary NEAA deprivation to improve the efficacy of anti-PD-1 or anti-PD-L1 immunotherapy for colorectal cancer without noticeable side effects. We found 1) On day 24 post tumor implantation, NEAA-deprived diet FTN203 significantly reduced tumor growth when used alone, compared to the group fed with Teklad ENVIGO (by 81%, P=0.0054, unpaired t-test after Welch correction) and COMPLETE (by 81%, P=0.013), respectively 2) The efficacy of FTN203 is comparable with that of anti-PD-1 or anti-PD-L1 in tumor growth and median survival 3) FTN203 did not negate the efficacy of anti-PD-1 or anti-PD-L1 immunotherapy antibody when combined 4) FTN203 significantly improved the efficacy of anti-PD-1 by further reducing the tumor growth (by 80% on day 26, P=0.046) and increasing the median survival (by 5 days or 14%, Log-rank test P= 0.031), against the combo of COMPLETE and anti-PD-1 5) None of the mono or combo treatments caused body weight loss.
Each of these diets was used alone or combined with anti-PD-1 antibody (i.p., twice per week for 2 weeks) or anti-PD-L1 antibody (i.v., twice per week for 2 weeks). After tumor size-based randomization, these diets were provided to mice ad libitum throughout the whole test.
Both COMPLETE and FTN203 have the same nutritional structures, contain 17% w/w protein equivalent, and are isocaloric.
Three diets were tested, including a natural rodent diet Teklad ENVIGO Global 16% Protein Rodent Diet (control 1), a formulated NEAA-complete diet COMPLETE (control 2, using amino acid mix in place of protein), and a formulated NEAA-deprived diet FTN203 (treatment, using amino acid mix in place of protein). In this study, we tested the effects of NEAA-deprived diets and checkpoint inhibitor anti-PD-1 and anti-PD-L1 in colon cancer using syngeneic mouse model (Balb/c) bearing tumors of mouse colorectal cancer cell line CT-26. It is not clear whether dietary NEAA deprivation could be combined with immunotherapy for better safety-efficacy profiles. However, deprivation of NEAAs could negatively impact the immune activation, an essential process for immunotherapy, because fast cell proliferation poses a higher demand for building blocks such as NEAAs. Dietary deprivation of select (NEAAs) can slow down the growth of multiple solid tumors in mice, creating a new non-drug strategy in cancer treatment. Biomarkers, Immune Monitoring, and Novel Technologies P501 Dietary deprivation of non-essential amino acids improves anti-PD-1 immunotherapy in murine colon cancer Zehui Li, PhD, Grace Yang, PhD, Shuang Zhou, PhD, Xin Wang, MD, PhD, Xiyan Li, PhD Filtricine, Inc., Santa Clara, CA, United States Correspondence: Xin Wang ( Xiyan Li ( cells require outside supply of some non-essential amino acids (NEAAs) to survive.
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