Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma.

INTRODUCTION: Combination immune checkpoint inhibitors (ICI) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGF-R-TKI), including pembrolizumab/axitinib, are approved for first-line treatment of metastatic renal cell carcinoma (mRCC). Pembrolizumab/axitinib is associated with superior progression free survival (PFS), objective response rate (ORR), and overall survival over sunitinib. However, to date, the activity and safety of pembrolizumab/axitinib in later lines of therapy has not been reported. MATERIALS AND METHODS: Clinical data of consecutive patients receiving pembrolizumab/axitinib in the second-line or beyond for mRCC at Yale-New Haven Hospital were retrospectively collected. Best objective response was assessed using RECIST 1.1 criteria. Kaplan-Meier function was used to analyze survival. RESULTS: Thirty-eight patients were included. Median age was 64, 92.1% had clear cell mRCC, 18.4% had sarcomatoid dedifferentiation; 94.7% had prior ICI and 39.5% had prior VEGF-R-TKI. Pembrolizumab/axitinib was administered as second-line therapy in 21 (55.5%) patients, third-line in 5 (13.2%) and beyond in 12 (30.2%). Adverse events (AEs) occurred in 86.8% of patients. Grade 3-4 AEs attributed to pembrolizumab and axitinib were seen in 18.4% and 6.4% of patients, respectively. No grade 5 AEs occurred. At a median follow up of 17.1 months, median PFS was 9.7 months (95% CI, 4.1-15.3). Amongst 36 response evaluable patients, the ORR was 25.0% (all partial) and disease control rate (including stable disease for at least 6 months) was 66.6%. The most frequent treatment sequence was first-line nivolumab/ipilimumab followed by second-line pembrolizumab/axitinib (n = 17, 44.7%); among this cohort, median PFS with pembrolizumab/axitinib was 11.1 (95% CI, 8.4-13.7) months, with an ORR of 31.4%. CONCLUSION: Combination pembrolizumab/axitinib among previously treated mRCC patients has activity, with AE rates comparable to those reported in the first line. Prospective studies evaluating ICI-VEGF-R-TKI combinations beyond first-line are warranted to identify the most beneficial treatment sequencing in mRCC.

Current Understanding and Management of Intraductal Carcinoma of the Prostate.

PURPOSE OF REVIEW: This review will discuss current understanding and management approaches of Intraductal carcinoma of the prostate (IDC-P). IDC-P is a histological finding characterized by neoplastic cells that expand but do not invade prostate ducts. RECENT FINDINGS: The presence of IDC-P on a prostate biopsy is almost always associated with an invasive disease component and is independently associated with worse clinical outcomes in both early and late disease. These tumors are enriched for mutations in homologous DNA recombination repair (HRR) leading to high genomic instability. Multiparametric MRI with targeted biopsy may aid in diagnosis. Given the poor clinical outcomes associated with this histologic entity, its presence in biopsies should warrant consideration of aggressive management.

Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma.

Adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) has been studied for patients with advanced metastatic cancers (primarily melanoma) for decades and has changed significantly during that period. Treatment with TIL includes ex vivo cell activation and expansion followed by re-infusion of these cells into the patient. After cell infusion, patients receive Interleukin-2 (IL-2). Objective response rates up to 52% have been seen in patients with metastatic melanoma. Efforts to improve TIL therapy include better selection and expansion of tumor-reactive lymphocytes, optimization of IL-2 or other T cell activating cytokine dosing, and, potentially, genetic manipulation of the immune cell product. Here we describe methods involved in the collection, expansion, and treatment with TIL for patients with metastatic melanoma.

Novel Targets and Precision Medicine for Prostate Cancer-Part 2: Tumor Profiling and Personalized Therapy in Patients With Castration-Resistant Prostate Cancer.

Despite advances in the treatment of castration-resistant prostate cancer (CRPC), options remain limited and non-curative; thus, prostate cancer remains one of the deadliest cancers in men. The discovery of novel therapeutic targets is needed to improve outcomes for men with metastatic CRPC. Precision/personalized medicine creates new opportunities to discover these targets. With an increase in the use of next-generation sequencing and tumor profiling, potentially clinically relevant tumor mutations are being identified. Here, we review the current use of and future direction for genetic testing and tumor profiling in patients with metastatic CRPC.

Integrating Novel Targets and Precision Medicine Into Prostate Cancer Care-Part 1: The Non-Androgen-Targetable Pathways in Castration-Resistant Prostate Cancer.

Prostate cancer is the second most common cause of cancer-related death in men. Although the overall survival of patients with metastatic prostate cancer has improved with the addition of second-generation hormone therapy, most men will develop progressive disease, eventually leading to death. Novel therapeutic mechanisms are needed to improve treatments and outcomes in patients with metastatic prostate cancer. Biomarker-driven treatments such as targeted therapies and immuno-oncologic agents are currently under investigation, and may lead to less toxicity and better outcomes for these patients. Here, we review the current use and future direction of these novel therapeutic targets.

Current Status and Future Directions of Immunotherapy in Renal Cell Carcinoma.

PURPOSE OF REVIEW: Renal cell carcinoma (RCC) was recognized as an immunologically sensitive cancer over 30 years ago. The first therapies to affect the course of RCC were cytokines (interferon alfa-2B and interleukin-2). Subsequently, drugs that inhibit HIF (hypoxia-inducible factor)/VEGF (vascular endothelial growth factor) signaling demonstrated overall survival advantages (tyrosine kinase inhibitors and mTor inhibitors). RECENT FINDINGS: In the last 3 years, the immune checkpoint inhibitors (ICIs) have become the standard of care treatments in the first and second lines for RCC. Emerging data show that combinations of ICI, HIF signaling inhibitors, and cytokines are potentially powerful regimens. How to combine and sequence these types of therapies and how to integrate new approaches into the management of RCC are now the key questions for the field. Treatment of RCC is likely to change dramatically in the next few years.

Be careful of the masquerades: differentiating secondary myelodysplasia from myelodysplastic syndromes in clinical practice.

In patients suspected to have myelodysplastic syndrome (MDS), especially in those patients without cytogenetic abnormalities or blast excess, accurate morphologic review by an expert hematopathologist and meticulous exclusion of other secondary causes of myelodysplasia are vital to establish the diagnosis. Errors in diagnosis can lead to dangerous consequences such as the administration of hypomethylating agents, lenalidomide, or even the use of intensive chemotherapy or allogeneic hematopoietic cell transplantation in patients who do not have an underlying MDS or even a malignant hematopoietic process. Additionally, beyond the possible harm and lack of efficacy of such therapies if the diagnosis of MDS is erroneous, the secondary myelodysplasia and resultant cytopenias are not likely to resolve unless the underlying etiology is identified and addressed. Discriminating a malignant process such as MDS from non-malignant secondary myelodysplasia can be quite challenging, and community hematologists/oncologists should consider referral to specialized physicians (both clinical experts and experienced hematopathologists) if there is any doubt regarding the diagnosis. In this article, we present a representative case series of patients from our own practice who posed diagnostic dilemmas and propose a systematic approach for assessment for secondary causes of myelodysplasia.

Coronary Vasospasm and Bowel Ischemia in a Patient with Metastatic Gastrointestinal Carcinoid.

We describe a case of a 60-year-old female with a history of metastatic carcinoid disease with liver involvement who developed coronary vasospasm and mesenteric ischemia. The carcinoid syndrome is known for its cardiac involvement most well characterized by fibrous tissue deposits on the endocardium.(1,2) Case reports of coronary artery vasospasm have been previously described and hypothesized to be mediated by vasoactive amines and polypeptides synthesized by the tumor.(3-9) Intestinal ischemia is another reported complication of the carcinoid syndrome and is hypothesized to have a similar mechanism to that of the coronary vasospasm.(10-17) We have reviewed the literature and describe a case of coronary vasospasm and mesenteric ischemia in a patient on octreotide therapy. This is the first case in which we have identified concurrent coronary vasospasm and mesenteric ischemia in a patient with carcinoid disease.

Filoviruses require endosomal cysteine proteases for entry but exhibit distinct protease preferences.

Filoviruses are enveloped viruses that cause sporadic outbreaks of severe hemorrhagic fever [CDC, MMWR Morb. Mortal. Wkly. Rep. 50:73-77, 2001; Colebunders and Borchert, J. Infect. 40:16-20, 2000; Colebunders et al., J. Infect. Dis. 196(Suppl. 2):S148-S153, 2007; Geisbert and Jahrling, Nat. Med. 10:S110-S121, 2004]. Previous studies revealed that endosomal cysteine proteases are host factors for ebolavirus Zaire (Chandran et al., Science 308:1643-1645, 2005; Schornberg et al., J. Virol. 80:4174-4178, 2006). In this report, we show that infection mediated by glycoproteins from other phylogenetically diverse filoviruses are also dependent on these proteases and provide additional evidence indicating that they cleave GP1 and expose the binding domain for the critical host factor Niemann-Pick C1. Using selective inhibitors and knockout-derived cell lines, we show that the ebolaviruses Zaire and Cote d'Ivoire are strongly dependent on cathepsin B, while the ebolaviruses Sudan and Reston and Marburg virus are not. Taking advantage of previous studies of cathepsin B inhibitor-resistant viruses (Wong et al., J. Virol. 84:163-175, 2010), we found that virus-specific differences in the requirement for cathepsin B are correlated with sequence polymorphisms at residues 47 in GP1 and 584 in GP2. We applied these findings to the analysis of additional ebolavirus isolates and correctly predicted that the newly identified ebolavirus species Bundibugyo, containing D47 and I584, is cathepsin B dependent and that ebolavirus Zaire-1995, the single known isolate of ebolavirus Zaire that lacks D47, is not. We also obtained evidence for virus-specific differences in the role of cathepsin L, including cooperation with cathepsin B. These studies strongly suggest that the use of endosomal cysteine proteases as host factors for entry is a general property of members of the family Filoviridae.