Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy

Immune checkpoint inhibitors; Metastatic renal carcinoma; Second-line treatmentInhibidors del punt de control immunitari; Carcinoma renal metastàtic; Tractament de segona líniaInhibidores del punto de control inmunitario; Carcinoma renal metastásico; Tratamiento de segunda líneaBackground: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. Patients and methods: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. Results: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. Conclusion: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.This work was supported by Pfizer, S.L.U. (Madrid, Spain). Pfizer, S.L.U. provided an unrestricted research grant with drug funding and drug supply to conduct the study (no grant number)

Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Already natural low levels of pro-apoptotic proteins BIM and PUMA in tolerant cell lines were insufficient to inhibit Bcl-xL as this anti-apoptotic protein showed a slow decay curve after Dinaciclib-induced protein synthesis disruption. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS

Quality of Life and Utility in Patients with Metastatic Soft Tissue and Bone Sarcoma: The Sarcoma Treatment and Burden of Illness in North America and Europe (SABINE) Study

The aim of the study was to assess health-related quality of life (HRQoL) among metastatic soft tissue (mSTS) or bone sarcoma (mBS) patients who had attained a favourable response to chemotherapy. We employed the EORTC QLQ-C30, the 3-item Cancer-Related Symptoms Questionnaire, and the EQ-5D instrument. HRQoL was evaluated overall and by health state in 120 mSTS/mBS patients enrolled in the SABINE study across nine countries in Europe and North America. Utility was estimated from responses to the EQ-5D instrument using UK population-based weights. The mean EQ-5D utility score was 0.69 for the pooled patient sample with little variation across health states. However, patients with progressive disease reported a clinically significant lower utility (0.56). Among disease symptoms, pain and respiratory symptoms are common. This study showed that mSTS/mBS is associated with reduced HRQoL and utility among patients with metastatic disease

Phase II randomized study of Plitidepsin (Aplidin), alone or in association with L-carnitine, in patients with unresectable advanced renal cell carcinoma

This randomized phase II study evaluated two schedules of the marine compound Plitidepsin with or without co-administration of L-carnitine in patients with renal cell carcinoma. Patients had adequate performance status and organ function.The primary endpoint was the rate of disease control (no progression) at 12 weeks (RECIST).Other endpoints included the response rate and time dependent efficacy measures.The trial also assessed the efficacy of L-carnitine to prevent Plitidepsin-related toxicity. The two regimes given as 24 hour infusion every two weeks showed hints of antitumoral activity. Disease control at 12 weeks was 15.8% in Arm A (5mg/m2, no L-carnitine) and 11,1% in Arm B (7mg/m2 with L-carnitine). Two partial responses were observed in Arm A (19 patients), none in Arm B (20 patients). Both schedules had the same progression-free interval (2.1 months).The median overall survival was 7.0 and 7.6 months.The safety profile was similar in both arms of the trial and adverse events were mainly mild to moderate (NCI CTC version 2.0). Increasing the dose to 7mg/m2 did not increase the treatment efficacy but the incidence of transaminase and CPK elevations and serious AEs. Coadministration of L-carnitine did not prevent muscular toxicity or CPK-elevation associated with Plitidepsin

The importance of being dead: cell death mechanisms assessment in anti-sarcoma therapy

Cell death can occur through different mechanisms, defined by their nature and physiological implications. Correct assessment of cell death is crucial for cancer therapy success. Sarcomas are a large and diverse group of neoplasias from mesenchymal origin. Among cell death types, apoptosis is by far the most studied in sarcomas. Albeit very promising in other fields, regulated necrosis and other cell death circumstances (as so-called "autophagic cell death" or "mitotic catastrophe") have not been yet properly addressed in sarcomas. Cell death is usually quantified in sarcomas by unspecific assays and in most cases the precise sequence of events remains poorly characterized. In this review, our main objective is to put into context the most recent sarcoma cell death findings in the more general landscape of different cell death modalities

Recent therapeutic advances in urothelial carcinoma : A paradigm shift in disease management

Altres ajuts: Pfizer.Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the administration of platinum-based chemotherapy followed by observation. Despite moderate to high response rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic developments including the paradigm shift of first-line maintenance therapy with avelumab after response or stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease

Effectivity of pazopanib treatment in orthotopic models of human testicular germ cell tumors

Background: Cisplatin (CDDP) resistance in testicular germ cell tumors (GCTs) is still a clinical challenge, and one associated with poor prognosis. The purpose of this work was to test pazopanib, an anti-tumoral and anti-angiogenic multikinase inhibitor, and its combination with lapatinib (an anti-ErbB inhibitor) in mouse orthotopic models of human testicular GCTs. Methods: We used two different models of human testicular GCTs orthotopically grown in nude mice; a CDDP-sensitive choriocarcinoma (TGT38) and a new orthotopic model generated from a metastatic GCT refractory to first-line CDDP chemotherapy (TGT44). Nude mice implanted with these orthotopic tumors were treated with the inhibitors and the effect on tumoral growth and angiogenesis was evaluated. Results: TGT44 refractory tumor had an immunohistochemical profile similar to the original metastasis, with characteristics of yolk sac tumor. TGT44 did not respond when treated with cisplatin. In contrast, pazopanib had an anti-angiogenic effect and anti-tumor efficacy in this model. Pazopanib in combination with lapatinib in TGT38, an orthotopic model of choriocarcinoma had an additive effect blocking tumor growth. Conclusions: We present pazopanib as a possible agent for the alternative treatment of CDDP-sensitive and CDDP-refractory GCT patients, alone or in combination with anti-ErbB therapies

Clinical Study Quality of Life and Utility in Patients with Metastatic Soft Tissue and Bone Sarcoma: The Sarcoma Treatment and Burden of Illness in North America and Europe (SABINE) Study

The aim of the study was to assess health-related quality of life (HRQoL) among metastatic soft tissue (mSTS) or bone sarcoma (mBS) patients who had attained a favourable response to chemotherapy. We employed the EORTC QLQ-C30, the 3-item CancerRelated Symptoms Questionnaire, and the EQ-5D instrument. HRQoL was evaluated overall and by health state in 120 mSTS/mBS patients enrolled in the SABINE study across nine countries in Europe and North America. Utility was estimated from responses to the EQ-5D instrument using UK population-based weights. The mean EQ-5D utility score was 0.69 for the pooled patient sample with little variation across health states. However, patients with progressive disease reported a clinically significant lower utility (0.56). Among disease symptoms, pain and respiratory symptoms are common. This study showed that mSTS/mBS is associated with reduced HRQoL and utility among patients with metastatic disease