Lessons Learned
Palbociclib demonstrated no detectable activity in molecularly unselected and heavily pretreated patients with advanced grade 1/2 pancreatic neuroendocrine tumors.
Predictive ...biomarkers that improve patient selection should be investigated in future studies of palbociclib.
Background
Palbociclib, a CDK4/6 inhibitor, has shown in vitro activity in pancreatic neuroendocrine tumor (pNET) cell lines. Here we prospectively assessed the activity and safety of palbociclib in monotherapy in metastatic refractory pNETs.
Methods
This was a nonrandomized, open‐label, phase II study of patients with metastatic grade (G)1/2 pNETs recruited from 10 centers in Spain. Palbociclib 125 mg was orally administered once daily for 21 of 28 days until disease progression or unacceptable toxicity.
Results
Twenty‐one patients were included; 52.4% were men, and median age was 57.4 years (range, 37.4–73.4). Patients had previously received a median of three prior lines of systemic therapy (range, 1–10) for advanced disease (somatostatin analogues, 71.4%; sunitinib, 81.0%; everolimus, 47.6%; chemotherapy, 47.6%). Nineteen patients were evaluated for objective response rate (ORR), with a median follow‐up of 12.4 months (range, 7.53–19.33). No objective and confirmed responses were observed (0%); 11 (57.9%) patients had stable disease, and 6 of them lasted more than 6 months; 8 (42.1%) patients had disease progression as best response. Median progression‐free survival (PFS) was 2.6 months (95% confidence interval CI, 0–14.4) and median overall survival (OS) was 18.7 months (95% CI, 7.4–29.9; Fig. 1). Most frequent toxicities of any grade were asthenia (76.2%), neutropenia (42.9%), diarrhea (33.3%), and nausea (33.3%). Five (23.8%) patients developed G3–4 neutropenia and two (9.5%) patients developed G3–4 thrombocytopenia.
Conclusion
Lack of activity was observed with palbociclib as a single agent in molecularly unselected and heavily pretreated patients with advanced G1/2 pNETs.
In this article, we propose, based on a clinical case, the potential antitumor effect related to the inhibition of serotonin in neuroendocrine tumors (NETs). Currently, the only drug that exists for ...the symptomatic treatment of carcinoid syndrome refractory to somatostatin analogues is telotristat, based on its pivotal study, the TELESTAR trial. Based on the existing preclinical rationale, it seems that the inhibition of serotonin may have an antitumoral role in NETs. Briefly, serotonin may act as an autocrine growth factor of NETs, and it may also play an immunomodulatory role by enhancing macrophage polarization to an immunotolerant M2 phenotype. To our knowledge, this rationale for the possible antitumor effect of serotonin in NETs has not yet been published in the literature.
The treatment of choice for patients with carcinoid syndrome is based on somatostatin analogs. This brief communication presents the case of a patient with a neuroendocrine tumor who participated in the TELESTAR trial and reports on the effectiveness of telotristat ethyl for improved control of diarrhea associated with carcinoid syndrome refractory to somatostatin analogs. Moreover, the article explains the rationale for potential antitumor effects related to inhibition of serotonin synthesis in neuroendocrine tumors.
Background
Sunitinib (SUN)‐induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo‐isophosphoramide ...mustard. SUNEVO, a phase II, open‐label, single‐arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs).
Methods
Systemic treatment‐naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1.
Results
From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow‐up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression‐free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment‐related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations.
Conclusion
SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062)
Implications for Practice
Addition of hypoxia‐activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression‐free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.
The SUNEVO trial pursued the hypothesis that the hypoxia induced by sunitinib might foster the activation of the prodrug evofosfamide in patients with locally advanced or metastatic pancreatic neuroendocrine tumors. Results are reported here.
Abstract Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First‐line immunotherapy (IO)‐based combinations have improved the ...outcome of clear cell RCC patients, including that of sRCC. Real‐world data confirming the adequate first‐line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO‐based combinations within the ARON‐1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non‐sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first‐line treatment (IO + IO vs. IO + tyrosin kinase inhibitor TKI). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non‐sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6–44.2) in sRCC and 35.3 months (95%CI 30.2–40.4) in non‐sRCC patients ( p = .013). The median progression‐free survival (PFS) was longer in non‐sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first‐line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO ( p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO ( p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO‐based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted.
Patients with cancer (PC) are at high risk of acquiring COVID-19 and can develop more serious complications. Deeper understanding of vaccines immunogenicity in this population is crucial for ...adequately planning vaccines programs. The ONCOVac study aimed to comprehensively assess the immunogenicity of mRNA-1273 vaccine in terms of humoral and cellular response.
We conducted a prospective, single-center study including patients with solid tumours treated with cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), immunotherapy (IT) or chemotherapy (CT). Patients were enrolled previously to vaccination with mRNA-1273. We also involved health care workers (HCW) to serve as a control group. We took blood samples before first dose administration (BL), after first dose (1D), and after second dose (2D). The primary objective was to compare the rate and magnitude of T cell response after second dose whereas safety and humoral response were defined as secondary objectives. We also collected patient reported outcomes after both the first and second vaccine dose and a six-month follow-up period to diagnose incident COVID-19 cases was planned.
The rate of specific anti-S serologic positivity (anti-S IgG cut-off point at 7,14 BAU/mL) was significantly higher in HCW compared to PC after 1D (100% versus 83.8%; p = 0.04), but similar after 2D (100% versus 95.8%; p = 0.5). This difference after 1D was driven by PC treated with CT (100% versus 64.5%; p = 0.001). Cellular response after 2D was significantly lower in PC than in HCW for both CD4+ (91.7% versus 59.7%; p = 0.001) and CD8+ (94.4% versus 55.6%; p < 0.001) T cells. We found a difference on pre-existing CD4+ T cell response in HCW comparing to PC (36% and 17%, p = 0.03); without difference in pre-existing CD8+ T cell response (31% and 23%, p = 0.5). After excluding patients with pre-existing T cell response, PC achieved even lower CD4+ (50.9% versus 95.5%, p < 0.001) and CD8+ (45.5% versus 95.5%, p < 0.001) T cell response compared with HCW. Regarding safety, PC reported notably more adverse events than HCW (96.6% versus 69.2%, p < 0.001).
We demonstrated that PC showed a similar humoral response but a lower T cell response following two doses of mRNA-1273 vaccination. Further studies are needed to complement our results and determine the implication of low T cell response on clinical protection of PC against COVID-19.
•Cancer patients showed lower humoral response after one dose of mRNA-1273 vaccine.•Humoral response achieves similar levels after full vaccination.•Cellular response was significantly lower in cancer patients compared to controls.
Tyrosine Kinase Receptors in Oncology Esteban-Villarrubia, Jorge; Soto-Castillo, Juan José; Pozas, Javier ...
International journal of molecular sciences,
11/2020, Letnik:
21, Številka:
22
Journal Article
Recenzirano
Odprti dostop
Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations ...of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.
Clear cell renal cell carcinoma (ccRCC) is the seventh most frequently diagnosed tumor in adults in Europe and represents approximately 2.5% of cancer deaths. The molecular biology underlying renal ...cell carcinoma (RCC) development and progression has been a key milestone in the management of this type of tumor. The discovery of Von Hippel Lindau (
) gene alterations that arouse in 50% of ccRCC patients, leads the identification of an intracellular accumulation of HIF and, consequently an increase of VEGFR expression. This change in cell biology represents a new paradigm in the treatment of metastatic renal cancer by targeting angiogenesis. Currently, there are multiple therapeutic drugs available for advanced disease, including therapies against VEGFR with successful results in patients´ survival. Other tyrosine kinases' pathways, including PDGFR, Axl or MET have emerged as key signaling pathways involved in RCC biology. Indeed, promising new drugs targeting those tyrosine kinases have exhibited outstanding efficacy. In this review we aim to present an overview of the central role of these tyrosine kinases' activities in relevant biological processes for kidney cancer and their usefulness in RCC targeted therapy development. In the immunotherapy era, angiogenesis is still an "old guy" that the medical community is trying to fight using "new bullets".
Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the ...splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
Despite being infrequent tumors, the incidence and prevalence of pancreatic neuroendocrine tumors (P-NETs) has been rising over the past few decades. In recent years, rigorous phase III clinical ...trials have been conducted, allowing the approval of several drugs that have become the standard of care in these patients. Although various treatments are used in clinical practice, including somatostatin analogues (SSAs), biological therapies like sunitinib or everolimus, peptide receptor radionuclide therapy (PRRT) or even chemotherapy, a consensus regarding the optimal sequence of treatment has not yet been reached. Notwithstanding, sunitinib is largely used in these patients after the promising results shown in SUN111 phase III clinical trial. However, both prompt progression as well as tumor recurrence after initial response have been reported, suggesting the existence of primary and acquired resistances to this antiangiogenic drug. In this review, we aim to summarize the most relevant mechanisms of angiogenesis resistance that are key contributors of tumor progression and dissemination. Furthermore, several targeted molecules acting selectively against these pathways have shown promising results in preclinical models, and preliminary results from ongoing clinical trials are awaited.
PDF
