ABSTRACTS

FGF- R inhibition, a biomarker driven alternative in second line metastatic urothelial cancer

Introduction

Fibroblast growth factor (FGF) signaling contributes to tumorigenesis in a wide variety of tumor types. In metastatic urothelial cancer (mUC), mutations of the FGF receptor can be found in about 20% of cases. This abstract discusses two phase III trials currently recruiting UC patients in Belgium using the FGF-R targeting agents rogaratinib (BAY-1163877) and erdafitinib (JNJ-42756493).

Materials and methods

The protocols of both studies were analyzed to identify targeted unmet medical needs in the treatment of mUC.

Results

Erdafitinib is a strong pan-FGF-R inhibitor that showed significant inhibition of proliferation in preclinical trials. In a large phase I study (N=187) of mUC patients with FGF-R aberrations, overall response rate (ORR)was 40%, 70% in higher doses. The most frequent adverse events (AE) were hyperphosphatemia, dry mouth, asthenia and stomatitis. The current randomized open label phase III trial(NCT03390504) compares single agent erdafitinib to chemotherapy (investigators choice) in patients with prior anti-PD(L)1 treatment in one cohort and to pembrolizumab in patients without prior anti-PD(L)1 treatment in the second cohort. The primary endpoint is overall survival (OS).

Rogaratinib is a strong pan-FGF-R targeting TKI that also showed strong inhibition of cell growth in preclinical models. Two phase I trials have studied rogaratinib. Tolerance was good with hyperphosphatemia, fatigue and gastro-intestinal symptoms as main AEs. As with other FGF-R inhibitors, retinal disorder is a treatment limiting toxicity. The current open label study randomizes mUC patients to rogaratinib and second line chemotherapy (docetaxel, paclitaxel or vinflunin) in patients with tumors expressing FGF-R mutations or high mRNA load. The phase II part will randomize 58 patients in each arm, the study is planned to continue in a phase III after a futility analysis. Primary endpoint in phase II is ORR, in phase III OS.

Conclusions

Treatment of mUC patients after progression on platinum based chemotherapy and eventually checkpoint inhibitors is an unmet need. Both rogaratinib and erdafitinib are effective in targeting FGF-R mutations in a subgroup of patients and have shown high ORR in phase I studies. Phase III trials are open to recruitment and offer mUC patients a biomarker-based alternative to poorly active second line cytotoxic therapy.

The safety of anti-PD1 therapy in a case of paraneoplastic immune disease: a case report

Cancer-associated thrombotic microangiopathy is a group of disorders defined by microvascular thrombosis, thrombocytopoenia and ischaemic end-organ damage. Rarely, it may be a manifestation of the malignancy itself or a side effect of its therapy.

We report on a 64-year-old male, diagnosed in 2017 with a T1N1M0 squamous cell carcinoma of the pyriform sinus treated by radio-chemotherapy (cisplatin + 70 Gy). The patient was hospitalised six months after the completion of the treatment, while he was still in complete remission, for fatigue and an altered general status. Laboratory results revealed haemolytic anaemia, thrombocytopenia, a negative coombs test, LDH 537, undetectable haptoglobin and acute renal insufficiency requiring haemodialysis. Investigations showed presence of schistocytes, a normal ADAMTS13 activity and absence of ADAMTS13 inhibition. A kidney biopsy confirmed the diagnosis of thrombotic microangiopathy and plasmapheresis was initiated which lead to a partial resolution of the thrombocytopenia and other microangiopathy factors. A PET-CT scan revealed multiple secondary lesions in the lungs along with the lymph nodes. A lymph node biopsy was performed and showed metastatic squamous cell carcinoma which confirmed the probable paraneoplastic nature of the disease. We conducted a literature review that revealed that when the thrombotic microangiopathy is cancer-associated it is necessary to treat the underlying disease. It was therefore decided to discontinue the plasmapheresis and treat with anti-PD1 antibody therapy (nivolumab). A PET-scan revealed progression after three cycles of nivolumab and we decided to stop the treatment, however we did not observe recurrence of the thrombotic microangiopathy.

Despite the debate about immunotherapy in active autoimmune diseases, this case demonstrates the safety of anti PD-1 therapy in case of a paraneoplastic immune disease.

Renal cell carcinoma with TFE3 rearrangement at Xp11.2

Renal cell carcinoma with TFE3 (Transcription Factor for immunoglobulin heavy-chain enhancer 3) rearrangement at Xp11.2 is a distinct subtype manifesting an indolent clinical course in children, with recent reports suggesting a more aggressive entity in adults. This subtype is morphologically heterogeneous and can be misclassified as clear cell or papillary renal cell carcinoma (RCC). RCCs with TFE3 rearrangement account for only approximately 1% of adult RCCs and may be clinical aggressive tumor.

Herein, we describe the case of a 17-year-old woman who presented for lumbar and abdominal pain for 3 months. Abdominal CT revealed small liver lesions, retroperitoneal lymphadenopathies, lytic bone lesion L3 confirmed by the PET CT Scan.

A biopsy of a retroperitoneal lymph node revealed a clear/granular cell tumor, with psammoma calcifications with diffuse expression of CD10, focal expression of PAX8 suggesting a renal carcinoma associated with the Xp11.2 translocation/TFE3 rearrangement.

Patient was started on Sunitinib and Denosumab with a good response but one year later we documented a progressive disease so that the patient was included in a clinical trial with a VEGF inhibitor and angiopoïetin II inhibitor. Four cycles later, we documented again a progressive disease with peritoneal carcinomatosis and ascitis. Consequently, a third line therapy with nivolumab was started with good partial response but the treatment was stopped because of nivolumab induced hepatitis. The disease kept on progressing and a fourth line with Cabozantinib was prescribed and PET-FDG showed a mixed response. The patient is still receiving Cabozantinib with dose reduction due to toxicity. The natural history of renal-cell carcinoma associated with TFE3 rearrangement at Xp11.2 is not well described because the tumor type is so rare. The question is whether these patients should be treated the same way as RCCs without molecular alteration.

Incidence and prognosis of biliary tract and gallbladder cancers in an academic hospital

Introduction

Biliary tract and gallbladder cancers are rare tumors with a poor prognosis (except ampulla). There is a variation in the evolution of the incidence around the world. According to Belgian Cancer Registry, the number of hepatobiliary cancers increases every year since 2004.

Material and Methodology

A retrospective study was performed. Patients with cholangiocarcinoma, ampulla or gallbladder cancers who were diagnosed at CHU UCL Namur site Godinne between 1997 and 2017 were included in this analysis. The evolution of the incidence was evaluated by the Mann-Kendall method on 7 periods of 3 years. We calculated the survival of these patients by the Kaplan Meier method and we determined prognostic factors by the logrank test.

Results

Between 1997 and 2017, we report an incidence of 128 patients in our center. Twenty percent were ampulla, 77% cholangiocarcinoma including 38% intrahepatic, 16% hilar and 23% extrahepatic. Last 3% corresponded to gallbladder cancer. According to the Mann-Kendall test, the evolution of the incidence of these cancers increases significantly with a slope of Sen of 7 corresponding to 7 additional new cases for each successive 3-year period (p=0.003). Our population consisted of 52% males with an average age of 68.6±11.9 years. Forty-five percent smoked, 14% consumed more than 3 units of alcohol a day, 8% had cirrhosis and 20% were diabetic. Regarding treatments, 34% had surgery, 59% received chemotherapy and 26% only supportive care. The average BMI was 26.4±5.6kg/m². The one-year overall survival was 52.0±4.7%. Poor prognosis factors were age and metastatic disease (p<0.001). The ampulla had a better prognosis with a one-year overall survival of 75.1%±9.8% compared to cholangiocarcinoma intrahepatic, hilar and extrahepatic with respectively 38.0±7.4%, 38.6±12.5% and 51.9±9.6% (p<0.001 for all). Finally, intrahepatic cholangiocarcinoma had a lower progression-free survival than the extrahepatic cholangiocarcinoma with a hazard ratio of 2.33 (p=0.001), however survival was identical.

Conclusion

Incidence of biliary tract and gallbladder cancers increases in our center. Further investigations are needed to determine the reasons for this increase. Although new therapies are emerging, these cancers still have a poor prognosis. Determining risk factors could help to develop preventive approach.

Hemophagocytic lymphohistiocytosis, an unusual initial presentation of a gastric adenocarcinoma with an unusual exclusive bone marrow metastasis

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening condition caused by an excessive chaotic immune activation. It can be primary or secondary to a trigger such as an auto-immune disease, an infectious process or a malignancy. It is usually associated with hematological malignancies and less frequently with solid tumors. This medical emergency has variable presentations lacking pathognomonic clinical and laboratory findings. The prognosis is usually dismal and is associated with high mortality rates.

Here we report the case of a 45-year-old male patient, previously healthy, who presented with alteration of general status and high-grade fever. Laboratory investigations showed a pancytopenia, with grade IV neutropenia, grade II normocytic anemia and grade III thrombocytopenia. The peripheral smear didn’t reveal any abnormal immature cells, schistocytes, nor evidence of leukoerythroblastic reaction. The fibrinogen was low. The bilirubin was increased with a grade III elevation of transaminases and a grade II elevation of cholestatic liver enzymes. The lactate dehydrogenase (LDH) was 10 times more than the upper limit of normal. The ferritin was quite elevated (12598 ng/mL) and there was a hypertriglyceridemia of 750 mg/dL. The clinical and biological findings were consistent with the diagnosis of HLH which was confirmed by a bone marrow biopsy revealing erythro-phagocytocytic changes. There was also a bone marrow infiltration by carcinoma cells; the immunohistochemistry profile was compatible with a gastro-intestinal primary. The radiological and endoscopic investigations concluded for a newly diagnosed gastric adenocarcinoma, initially presenting with exclusive bone marrow metastasis leading to hemophagocytic lymphohistiocytosis. There were no other associated metastatic sites as usually seen in generalized gastric carcinomas. The clinical condition deteriorated despite the urgent initiation of a standard treatment of HLH. The patient passed away after multi-organ failure.

HLH is an aggressive syndrome. Clinicians must be aware of this rare entity that may be the initial presentation of a certain triggering disorder. The treatment consists of stopping the inflammatory cascade via the HLH treatment protocol followed by the appropriate treatment of the underlying trigger.

A case report of a psoriasis flare-up during treatment with an immune-checkpoint inhibitor

Introduction

With the emerging use of immunotherapy, we see an increase in new immune related side-effects. Dermatologic toxicities, like maculopapillary rash and pruritus, are among the most frequent side effects. We report a case of a patient who developed a more infrequent side-effect on immune-checkpoint inhibition.

Case-report

A 62-year old women was diagnosed with a pT3bN1a melanoma of the left thigh (stage IIIc). Adjuvant treatment with Nivolumab (3mg/kg) was initiated. After two cycles of Nivolumab, the patient developed characteristic skin lesions on her lower legs. She was referred to a dermatologist who diagnosed her with psoriasis vulgaris. Local therapy with Betamethasone-Calcipotriol cutaneous foam was applied and Nivolumab was continued. Re-evaluation after 2 weeks showed a regression of the lesions. A thorough anamnesis revealed that the patient had comparable lesions in the past, that were diagnosed as Psoriasis. The history of psoriasis was not mentioned before the start of Nivolumab, due to full recovery after PUVA therapy in the past.

Conclusion

Flare-up of psoriasis is an infrequent side-effect of immune-checkpoint inhibition. The pathogenesis is not clear, but it might involve up-regulation of T-helper cells. This case emphasizes the importance of a thorough anamnesis and a multidisciplinary approach when confronted with immune-related toxicities. These remarks will only become of more importance with the emerging use of immunotherapy. This is highlighted by the growing amount of case reports that are appearing every year in the literature about different types of immune related toxicities.

Case report of myopericarditis in a patient treated with an immune checkpoint inhibitor

Introduction

Treatment with PD(L)-1 blockers, a type of immune checkpoint inhibitors, implies an increase in T-cell toxicity, which carries the risk of harmful immune-related effects in all organs. The reported incidence of cardiotoxicity related with PD(L)-1 blockers is 1%, with half of the cases being fatal. Recently this spectrum of side effects is gaining more attention. We report a case of a patient with myopericarditis during treatment with Pembrolizumab, a PDL-1 antagonist.

Case-report

A 54-year old woman with a stage 4 malignant melanoma presented with acute diffuse chest and back pain at the emergency department. Since 1 month, treatment had been switched from Dabrafenib and Trametinib to Pembrolizumab because of disease progression. At presentation, clinical examination was reassuring, high-sensitive troponin T was mildly elevated but non-evolutive and ECG was normal. The patient was initially sent home from the emergency department – without consultation of an oncologist or cardiologist – but later represented with increased and mainly inspiratory chest pain. Transthoracic echocardiography at 8 hours after initial presentation showed a limited pleural effusion. Also diffuse ST elevation was then apparent on ECG, as typically seen in pericarditis. The patient was admitted and treated with acetylsalicylic acid and IV corticosteroids. Two days after admission, we noted a marked elevation of hs-troponin T, suggestive for myocardial involvement. The patient was asymptomatic at that moment. ST-elevation on ECG and Hs-troponine T decreased during the following week and no symptoms of heart failure or arrhythmia were noted. Cardiac magnetic resonance imaging one week after treatment showed diffuse contrast captation of the pericard and a focal area of myocardial oedema, confirming myopericarditis.

Conclusion

This case report illustrates a mild form of immune checkpoint inhibitor related cardiotoxicity. The case exposes the importance of primary health care workers being informed of possible immunotherapy related side effects, so that early recognition and consultation with specialists is improved. Since the use of immunotherapy is emerging, close cooperation between oncologists and cardiologists is recommended for prevention, treatment and follow-up of patients with (possible) cardiotoxicity.