Globalización y lavado de activos

P191

Combination of Sorafenib and anti-PD-1 for advanced hepatocellular carcinoma- real world experience

San-chi Chen, MD, Muh-Hwa Yang, Yee Chao

Taipei Veterans General Hospital, Taipei, Taiwan, Province of China

Correspondence:San-chi Chen ([email protected])

Journal for ImmunoTherapy of Cancer2018,6(Suppl 1):P191

Background

Advanced hepatocellular carcinoma (HCC) portends dismal progno- sis. Recently, two anti-PD-1 monoclonal antibodies have demon- strated favorable responses in HCC. Nivolumab was proved for second line treatment based on CheckMate-040, in which nivolu- mab demonstrated the objective response rate (ORR) of 15% in so- rafenib- experienced HCC. Similarly, pembrolizumab also achieved ORR of 16% in Keynote-224. However, there is still an unmet need to achieve a better response. Sorafenib that has been proved for the treatment of HCC for a decade is found to have immune modulation effect. Researches showed that sorafenib inhibited reg- ulated T cells and promoted effector T cells, especially in low dose. These data support the rationale for sorafenib to combine with immunotherapy.

Methods

We retrospectively analyzed 43 HCC patients who received the com- bination therapy of sorafenib and anti-PD-1.

Results

Among 43 patients in this cohort, mean age was 63 (+/-12) year-old, 79% were male, 49% were HBV(+) and 21% were HCV(+). The Child- Pugh Score of A, B and C were 51%, 26% and 23%, respectively. Best responses were CR in 3 patients (7%), PR in 9 (21%), SD in 7 (16%) and PD in 15 (35%); the response rate was 28% and disease control rate (DCR) 44%. Patients had no significant difference of response in etiologies, Child-Pugh Score and initiate AFP levels. Eighteen patients (42%) developed grade 1/2 toxicities and 9 (21%) grade 3/4 toxicities including 4 immune hepatitis and three skin rash. Patients who developed grade 1/2 toxicities has ORR of 50% and grade 3/4 tox- icities has ORR of 11%. Median PFS in responders and non- responders were 10.5 and 2.0 months, and median OS were 12.7 and 2.0 months, respectively. In univariate analysis, grade 1/2 tox- icity (HR 0.35) and grade 3/4 toxicity (HR 5.11) were risk factors for disease progression; Child-Push Score C and BCLC stage D were risk factors for survival.

Conclusions

Combination therapy of sorafenib and anti-PD-1 has a favorable response in patients with HCC, event in those who have been previously treated with sorafenib. The adequate dose, synergistic effect and safety of this combination need a large-scale of clinical trial to confirm.

Ethics Approval

The study was approved by Taipei Veterans General Hospital‘s Ethics Board, approval number 2017-10-005BC.

P192

A case of nivolumab-induced gastrointestinal toxicity treated with vedolizumab in the context of metastatic non-small cell lung cancer

Cynthia N. Tran, MD1, Yinghong Wang, MD, PhD2, Wenyi Luo, MD2

1_{Baylor College of Medicine, Houston, TX, USA;}2_{MD Anderson Cancer}

Center, Houston, TX, USA

Correspondence:Yinghong Wang ([email protected])

Journal for ImmunoTherapy of Cancer2018,6(Suppl 1):P192

Background

Immune checkpoint inhibitors have emerged as a novel therapeutic class for a wide variety of malignancies through their action on the im- mune system. This action promotes significant anti-tumor effect but, simultaneously, can also result in immune-related adverse events (irAEs) that may limit their use [1]. Multiple case reports and case series of lower gastrointestinal irAEs have been reported; however, the data on upper gastrointestinal tract is very sparse [2]. We herein describe a case with severe and steroid-dependent upper gastrointestinal toxicity with nivolumab treatment who eventually achieved clinical and histological remissions with vedolizumab treatment.

Methods N/A Results

A 65 year old male patient with lung cancer initially diagnosed in 2013, previously treated with pemetrexed and carboplatin regimen, was started on Nivolumab since January 2017 for progressive disease involving the left upper lung, retroperitoneal lymphadenopathy, pos- sible liver metastases, and several small brain lesions. Following six- teen cycles of nivolumab, he developed multiple episodes of severe nausea, vomiting, and abdominal cramps requiring five hospitaliza- tions total for dehydration and poor oral intake with associated weightloss. His initial EGD showed active inflammation in both the stomach and duodenum (Figure 1A, B). Due to this severe GI irAE, nivolumab was stopped even though his underlying cancer had demonstrated good response to nivolumab maintenance treatment. He was treated with multiple courses of steroid (intravenous methyl- prednisolone to oral prednisone) at each hospitalization but always developed symptomatic recurrence on prednisone taper dose at 20 mg/day. Additionally, the patient developed oral thrush and Clostrid- ium difficile infection while on steroids that required antibiotic treat- ment. Two trials of budesonide were attempted but unsuccessful. After the fifth hospitalization, he was initiated on vedolizumab infu- sion and achieved clinical remission within two weeks without fur- ther requirement of hospitalization or steroids for the following six months. His most recent EGD and biopsy after five doses of vedolizu- mab demonstrated complete resolution of active inflammation on histologic evaluation (Figure 2A, B). His lung cancer has since re- lapsed and the treatment plan is to resume nivolumab with concur- rent use of vedolizumab.

Conclusions

Immune checkpoint inhibitors, such as nivolumab, have emerged as treatment for a variety of malignancies [1].

Their use can be associated with various immune-related adverse events (irAEs) involving the upper gastrointestinal tract which is not commonly seen [2]. This case scenario showed that vedolizumab can provide steroid-sparing therapeutic effect to achieve clinical and histological remission even in cases that failed multiple steroid courses with good safety profile.

References

1. Postow M, Callahan M, Wolchock J. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015; 33:1974-1982.

2. Abdel-Rahman O, El Halawani H, Fouad M. Risk of gastrointestinal compli- cations in cancer patients treated with immune checkpoint inhibitors: A meta-analysis. Immunotherapy, 2015; 7:1213-1217.

Ethics Approval

Institutional Review Board protocol is exempted at the University of Texas MD Anderson Cancer Center for single case report.

Consent

This study was granted waiver for consent.

P193

Exceptional response of MSH6-null castration-resistant prostate cancer patient with myelophthisic pancytopenia to

pembrolizumab

Panagiotis Vlachostergios, MD, PhD, Julia T. Geyer, MD, Ana M. Molina, MD, David M. Nanus, MD, Himisha Beltran, MD, Scott T. Tagawa, MD, Panagiotis J. Vlachostergios, MD, PhD

Weill Cornell Medicine, New York, NY, USA

Correspondence:Scott T. Tagawa ([email protected])

Journal for ImmunoTherapy of Cancer2018,6(Suppl 1):P193

Background

Metastatic castration-resistant prostate cancer (mCRPC) remains lethal despite recent advances in AR-directed therapies. Myelophthisis is not rare in advanced PC and often limits chemotherapeutic options. The tissue-agnostic activity of the anti-programmed cell death-1 (PD-1) in- hibitor pembrolizumab in tumors harboring mismatch-repair (MMR) de- fects may offer an important therapeutic option in such patients. Methods

We describe a MMR-deficient mCRPC patient with widespread metas- tases involving the bone marrow causing myelophthisis, who responded to immune checkpoint inhibition with pembrolizumab. Results

A 74 year old man initially presented in 1999 with early prostate can- cer, Gleason 4+3 = 7 underwent prostatectomy and salvage radiation but had PSA recurrence 9 years later. He was started on combined androgen blockade with leuprolide and bicalutamide to which he responded (PSA nadir <0.1 ng/ml) for 7 months, but then experienced PSA and radiologic progression with osseous metastases. He received consecutively sipuleucel-T, abiraterone, enzalutamide, 177Lu-J591, Radium-223 and docetaxel for his mCRPC. However he had further dis- ease progression with diffuse osseous, lymph node and visceral (bilateral lung, solitary liver, bilateral adrenal) metastases and a rising PSA level at 2,048 ng/ml. Due to persistent pancytopenia (WBC: 3.2 x103/uL, Hb: 7.5 g/dl, PLT: 30 x103/uL) a bone marrow biopsy was performed. Hematoxylin and eosin staining revealed extensive metastatic PC (PSMA +, synaptophysin+, ERG–). Additionally, whole exome tumor sequencing was performed and disclosed somatic loss of MSH2 and MSH6. Germline mutation testing (father with multiple myeloma) showed a pathogenic

Fig. 1 (abstract P192).Pathology of stomach and duodenum pre vedolizumab

Fig. 2 (abstract P192).Pathology of stomach and duodenum post vedolizumab

germline MSH6 mutation [c.2731C>T (p.Arg911*)]. The patient started pembrolizumab which he tolerated well. After 14 months on treatment, he has demonstrated complete PSA response (0.1 ng/ml) and complete resolution of soft-tissue (visceral and lymph node) metastases and CBC recovery (3.5 x103/uL, Hb: 11.8 g/dl, PLT: 132 x103/uL).

Conclusions

This is the first report of very good and durable response to immune checkpoint inhibition in a mCRPC patient with biallelic MSH6 inacti- vation who had extensive disease and myelophthisis. Personalized therapy of advanced PC with pembrolizumab in the context of MMR deficiency can be effective in the bone marrow.

Ethics Approval

The patient consented to participate in the Precision Medicine proto- col at Weill-Cornell Medicine (WCM). The study was approved by our Institutional Review Board and Ethics Committee (WCM / New York- Presbyterian IRB protocol #: 1305013903).

Consent

Consent was received.

P194

Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis

Yinghong Wang, MD, PhD1_{, Hamzah Abu-Sbeih, MD}1_{, Diana Wiesnoski}1_,

Beth Helmink, MD PhD1, Vancheswaran Gopalakrishnan, MPH, PhD1, Kati Choi, MD2_{, Hebert DuPont, MD}3_{, Zhi-Dong Jiang}3_{, Michael T. Tetzlaff, MD}

PhD1, Jennifer A. Wargo, MD, MMSc1, Robert Jenq, MD1

1_{Univ of Texas MD Anderson Cancer center, Houston, TX, USA;}2_Baylor

College of Medicine, Houston, TX, USA;3Univ of Texas School of Public Health, Houston, TX, USA

Correspondence:Yinghong Wang ([email protected])

Journal for ImmunoTherapy of Cancer2018,6(Suppl 1):P194

Background

Background: Immune checkpoint inhibitors (ICIs) can lead to a severe immune-mediated colitis (IMC), which is treated with immunosuppressive therapy that is associated with significant morbidity. Pre-clinical models demonstrated that patients who develop IMC have differential bacterial sig- natures in their gut microbiome and that targeting specific bacterial-taxa may abrogate such toxicities.[1-4] Herein, we report the first reported case series of two-patients with refractory IMC successfully treated with FMT. Methods

Methods: Included two-patients had a refractory IMC that was treated with FMT (50 grams). Clinical courses and immunohistochemical analysis of the colonic mucosa are detailed in Figures 1-7. Stool microbiome prior to and post-FMT was assessed via 16S sequencing (Figures 8-9). Results

Results: Patient-1: a 50-year-old female with metastatic urothelial car- cinoma received combined CTLA-4 and PD-1 blockade. Two-weeks after treatment initiation, she developed CTCAE grade_≥2 IMC. Infec- tious workup was negative. Colonoscopy demonstrated severe ulcer- ation. She received corticosteroids, infliximab and vedolizumab for 3 months, but her symptoms and ulcers persisted. She then received a single-FMT via colonoscopy with complete resolution of symptoms and healed ulcers within 2 weeks. Prior to FMT, analysis in the co- lonic mucosa demonstrated high-density of CD8+ and low-density of CD4+ FoxP3+ T-cells. Post-FMT, CD8+ T-cell decreased and CD4+ FoxP3+ increased. Patient-2: a 78-year-old male with prostate cancer received ipilimumab. Three-months after treatment initiation, he de- veloped grade_≥2 IMC. Infectious etiologies were excluded. Colonos- copy confirmed IMC. His symptoms and mucosal ulcerations persisted despite corticosteroids, infliximab and vedolizumab for 5 months. Then he received the first-FMT with partial response, how- ever, after the second-FMT he had complete resolution of symptoms and ulcers. The density of all T-cell subtypes decreased post-FMT with persistence of CD4+ FoxP3+ cells. Principal coordinates analyses demonstrated the similarity to the donor microbiome most notice- ably immediately post-FMT, but later deviated away, still, distinct

from pre-FMT. At time of IMC diagnosis, patient-1 had a predomin- ance of Clostridia and absence of Bacteroidia and Verrucomicrobiae and patient-2 had a predominance of Gammaproteobacteria (pre- dominantly Escherichia). Immediately post-FMT, donor FMT-derived bacteria colonized the intestines of patient-1 (~75%) with abundance of Akkermansia that later decreased with expansion of Bifidobacter- ium. In patient-2, there was a notable increase in Blautia, Bacteroides and Bifidobacterium species post-FMT and a decrease in Escherichia. Conclusions

Conclusion: These cases provide provocative and novel evidence that refractory IMC could be treated successfully with FMT, which recon- stitutes the gut microbiome with relative increase in the proportion of regulatory T cells within the colonic mucosa.

References

Dubin, K., et al., Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. Nat Commun, 2016. 7: p. P341 *Corresponding author email: [email protected]. Vetizou, M., et al., Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science, 2015. 350(6264): p. 1079-84.3. Chaput, N., et al., Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol, 2017. 28(6): p. 1368-1379.4. Wang, F., et al.,

Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA- 4 blockade. Proc Natl Acad Sci U S A, 2018. 115(1): p. 157-161.5. Borody, T.J. and A. Khoruts, Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol, 2011. 9(2): p. 88-96.

Ethics Approval

This study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center (PA18-0372)

Consent

Enrolled patients signed consent for the treatment protocol (CIND17-0036, CIND17-0058).

Fig. 1 (abstract P194).See text for description.

Fig. 3 (abstract P194).See text for description.

Fig. 4 (abstract P194).See text for description.

Fig. 5 (abstract P194).See text for description.