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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 7405652, 3 pages https://doi.org/10.1155/2019/7405652 Case Report Excellent Response to Nivolumab and Ipilimumab in Metastatic Gastroesophageal Junction Squamous Carcinoma 1 1,2 Narayanan Sadagopan and Craig Devoe Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA Don Monti Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, The Monter Cancer Center, Lake Success, NY, USA Correspondence should be addressed to Craig Devoe; firstname.lastname@example.org Received 5 April 2019; Accepted 1 July 2019; Published 11 July 2019 Academic Editor: Raﬀaele Palmirotta Copyright © 2019 Narayanan Sadagopan and Craig Devoe. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Unresectable gastroesophageal junction (GEJ) cancers have a poor prognosis and limited treatment options. We report the case of a patient with a Siewert class III gastroesophageal junction squamous carcinoma with metastatic spread into the liver who had an exceptional response to a combination therapy of nivolumab and ipilimumab despite being programmed death-ligand 1 (PD-L1) negative, microsatellite stable (MSS), and having a low tumor mutational burden. He initially experienced disease progression on the chemotherapy regimens modiﬁed DCF and FOLFIRI resulting in limited functional status, esophageal stent placement, and feeding tube placement. After about 6 months on nivolumab and ipilimumab, he had near-complete disease resolution. He was able to return to his baseline functional status, as well as have the esophageal stent and feeding tube removed. Our case contributes to the value of exploring immunotherapy as an option for a variety of hard to treat cancers. 1. Introduction lumab and ipilimumab. Response rates were numerically lower in immunologically cold tumors . GEJ cancers are Immunotherapy with checkpoint inhibitors continues to often diagnosed with regional lymph node involvement or become a more common treatment option for a variety metastatic disease making platinum and ﬂuoropyrimidine- of cancers. Many studies have established the beneﬁtof based systemic chemotherapy the initial treatment, even if programmed cell death protein 1 (PD-1) and cytotoxic T- the patient is going to undergo a surgical resection . Tras- lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors in tuzumab is another agent often considered in metastatic GEJ the treatment of melanoma, renal cell carcinoma, and cancers as 6.0% to 29.5% may overexpress human epidermal non-small cell lung cancer [1–3]. In most other cancers, growth factor receptor 2 (HER2) . Here, we present a case the beneﬁts of immunotherapy have been limited. Reports of a patient with a GEJ squamous carcinoma who experi- of excellent immunotherapy responses in squamous cell can- enced disease progression despite two diﬀerent chemother- cers of the head and neck and primary squamous cell cancers apy regimens, who then had an exceptional response to of the skin have been accumulating . Squamous histology combination therapy of nivolumab and ipilimumab. is not a common feature in primary gastric cancer represent- ing 0.04% to 0.07% of all cases . Despite FDA immuno- 2. Case Presentation therapy approvals for GEJ cancer that overexpress PD-L1 or are found to be microsatellite instable, the majority of The patient is a 50-year-old male who presented to the oﬃce GEJ cancers do not ﬁt these criteria . The CheckMate- in April 2017 for a 50-pound weight loss over the past year, 032 study showed modest results for patients with metastatic fatigue, and diﬃculty swallowing solid foods. After initial GEJ cancer treated with nivolumab or a combination of nivo- imaging, an endoscopic ultrasound (EUS) showed a Siewert 2 Case Reports in Oncological Medicine (a) (b) Figure 1: (a) Top of mass visualized on initial esophagogastroduodenoscopy. (b) Ulcerated portion of mass visualized on initial esophagogastroduodenoscopy. (a) (b) Figure 2: (a) Baseline axial fused PET/CT from May 2017 showing increased FDG uptake. (b) Axial fused PET/CT from March 2019 showing resolution of increased FDG uptake. in November due to severe nausea/vomiting and dehydra- class III gastroesophageal junction mass extending from the top of the gastric folds to the body of the stomach tion. He underwent multiple esophagogastroduodenoscopies (Figure 1), multiple bulky nearby lymph nodes with the larg- (EGDs) later in November resulting in balloon dilatation and est lymph node being 5 cm, and a T3 N3 staging by the EUS liquid nitrogen cryotherapy for a near-complete GEJ obstruc- criteria. Biopsy of the gastric mass revealed it was a high- tion and eventually had an esophageal stent placed. He also had a percutaneous endoscopic gastrostomy (PEG) tube grade carcinoma with glandular, neuroendocrine, and squa- mous diﬀerentiation. The tumor cells stained positive for placed around this time since he could not tolerate eating the tumor markers pancytokeratin AE1/AE3, synaptophysin, by mouth. CT imaging in December showed worsening p40, and CDX2 and did not overexpress HER2. An MRI in metastatic disease in the liver. early May showed a 9 mm liver metastasis. He began Based on the early data of CheckMate-032, the unique treatment in May with modiﬁed DCF (docetaxel 40 mg/m squamous histology of this patient’s cancer, and the recent 2 2 cisplatin 40 mg/m , and 5-ﬂuorouracil 2000 mg/m ). Foun- successes of PD-1 inhibition in other squamous carcinomas dation One genomic alterations demonstrated the gene of the skin and head and neck, his treatment was switched locations SMARCA4 P319fs 7 and TP53 splice site 375 to the oﬀ-label use of ipilimumab and nivolumab in Decem- +1G>A which were not actionable. Molecular markers for ber 2017. Due to his weakened condition and the known high PD-L1 and microsatellite instability were negative, and the concern for immune-related adverse events with the dual tumor mutation burden was low (4 mutations/megabase). checkpoint blockade, the ﬁrst 2 cycles were given with a In August, after he completed 6 cycles of modiﬁed DCF, reduced dose of ipilimumab at 1 mg/kg and nivolumab at chemotherapy was switched to FOLFIRI (leucovorin calcium, 3 mg/kg. When he demonstrated good tolerance, this was 5-ﬂuorouracil, and irinotecan hydrochloride) due to mild dis- followed by 4 cycles of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg. Also, at this time, he received 14 radiation treat- ease progression on CT imaging and extreme fatigue from the modiﬁed DCF. Despite showing some initial response to the ments to the GEJ for obstruction. Over the next several FOLFIRI on imaging, his FOLFIRI was held after 6 cycles months, he began to feel better, and his esophageal stent Case Reports in Oncological Medicine 3 be to further investigate whether squamous histology is a was removed at the end of March, as his scans showed improvement of the GEJ mass and metastatic hepatic lesions. feature in gastric cancer that indicates better response to His treatment was modiﬁed to monthly maintenance of nivo- immunotherapy. Our case contributes to the value of explor- ing immunotherapy as an option for a variety of hard to lumab at a ﬁxed dose of 480 mg starting in May 2018, and by June, he could eat without vomiting and was able to return to treat cancers. work full time. His PEG tube was removed in July. Later that month, a PET scan showed resolution of ﬂuorodeoxyglucose (FDG) avidity in the GEJ, abdominal lymph nodes, and near Conflicts of Interest total resolution in the hepatic metastases. He showed incred- ible improvement on ipilimumab and nivolumab with the The authors declare that there is no conﬂict of interest main adverse eﬀect being mild thyroiditis. His CT scan in regarding the publication of this paper. November 2018 shows resolution of all visible disease, and a PET/CT scan in March 2019 was negative for the uptake of FDG isotope at all sites of disease (Figure 2). He will References remain on monthly maintenance with nivolumab 480 mg  F. S. Hodi, S. J. O'Day, D. F. McDermott et al., “Improved sur- until the end of the 2019. vival with ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711– 3. Discussion 723, 2010.  H. J. Hammers, E. R. Plimack, J. R. Infante et al., “Safety and The patient’s clinical course signiﬁcantly changed from eﬃcacy of nivolumab in combination with Ipilimumab in decreasing functional status and worsening tumor burden metastatic renal cell carcinoma: the CheckMate 016 study,” to near-complete resolution following treatment with nivo- Journal of Clinical Oncology, vol. 35, no. 34, pp. 3851–3858, lumab and ipilimumab. Since he also received radiation therapy during the initial part of the immunotherapy treat-  M. D. Hellmann, T. E. Ciuleanu, A. Pluzanski et al., “Nivolu- ment, it is diﬃcult to deﬁnitively say what role the radia- mab plus ipilimumab in lung cancer with a high tumor muta- tion played in terms of the abscopal eﬀect. The radiation tional burden,” The New England Journal of Medicine, vol. 378, likely contributed to the improvement of the patient’s GEJ no. 22, pp. 2093–2104, 2018. mass, but the continued improvement of nonradiated met-  H. A. Qureshi and S. M. Lee, “Immunotherapy approaches astatic lesions in the months following the conclusion of beyond PD-1 inhibition: the future of cellular therapy for head the radiation therapy points to the substantial role of nivo- and neck squamous cell carcinoma,” Current Treatment lumab and ipilimumab. Options in Oncology, vol. 20, no. 4, 2019. Interestingly, the patient’s tumor was PD-L1 negative,  J. A. González-Sánchez, R. Vitón, E. Collantes, and J. A. had a low tumor mutational burden, and was MSS giving it Rodríguez-Montes, “Primary squamous cell carcinoma of the features suggestive that cancer would be less likely to respond stomach,” Clinical Medicine Insights: Oncology, vol. 11, 2017. to immunotherapy. Immunotherapy biomarkers is an area  C. S. Fuchs, T. Doi, R. W. Jang et al., “Safety and eﬃcacy of where there is still a signiﬁcant room for improvement to pembrolizumab monotherapy in patients with previously determine which patients will beneﬁt from therapy. In this treated advanced gastric and gastroesophageal junction can- case, the rare squamous histology may have played a role cer: phase 2 clinical KEYNOTE-059 trial,” JAMA Oncology, given the recent success of immunotherapy in squamous cell vol. 4, no. 5, article e180013, 2018. cancers of the head and neck. It is possible that squamous  Y. Y. Janjigian, J. Bendell, E. Calvo et al., “CheckMate-032 cells have a feature that makes them more susceptible to study: eﬃcacy and safety of nivolumab and nivolumab plus immunotherapy. Alternatively, a PD-L1-positive status has ipilimumab in patients with metastatic esophagogastric can- some inherent variability. Some tumors may constitutively cer,” Journal of Clinical Oncology, vol. 36, no. 28, pp. 2836– 2844, 2018. express PD-L1 while others only express it when T-cells inﬁltrate the tumor . Thus, it is possible that the lack  S. Kasper and M. Schuler, “Targeted therapies in gastroesoph- of T-cell inﬁltrate during sampling resulted in a false- ageal cancer,” European Journal of Cancer, vol. 50, no. 7, pp. 1247–1258, 2014. negative PD-L1 status for our patient. While the exact mech- anism of PD-L1 negative tumor response to nivolumab may  N. Boku, “HER2-positive gastric cancer,” Gastric Cancer, vol. 17, no. 1, pp. 1–12, 2014. be unknown, our patient who switched to only nivolumab after 6 cycles of combination immunotherapy continued to  A. Ribas and S. Hu-Lieskovan, “What does PD-L1 positive or show improvement. negative mean?,” The Journal of Experimental Medicine, vol. 213, no. 13, pp. 2835–2840, 2016. In conclusion, our case is an example of an exceptional response to immunotherapy in a patient who was running out of options after failing two chemotherapy regimens. He went from gastric tube feeds and an esophageal stent to keep his esophagus from collapsing to returning to his usual activ- ities of daily living. His GEJ cancer responded spectacularly to immunotherapy despite having biomarkers suggestive of a poor response. 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Case Reports in Oncological Medicine – Hindawi Publishing Corporation
Published: Jul 11, 2019
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