Mamta Parikh

New and emerging developments in extensive-stage small cell lung cancer therapeutics.

Purpose of review Extensive-stage small cell lung cancer (ES-SCLC) remains a disease with a dismal prognosis, with median survival of approximately 8–10 months. Despite many attempts to develop effective systemic therapies, very little progress has been made in the last several decades. Platinum-based combination chemotherapy remains the standard of care in the first-line setting and is associated with high response rates albeit short-lived. However, there have been recent advances in the use of radiation therapy, as well as new insights into the biology of SCLC. Recent findings Some of the most appreciable advances in the last decade have involved the use of local radiation therapy. With the use of new laboratory techniques such as genomic sequencing, there remains promise of rationally targeted drug development. Circulating tumor cell research may also provide insights to SCLC biology and further refine treatment. Summary Systemic therapy for SCLC has changed little over the past 30 years with the most significant advances in ES-SCLC relating to radiotherapy rather than systemic therapy. The effectiveness of prophylactic cranial irradiation and thoracic radiotherapy has renewed interest in therapeutics focused on the modulation of DNA damage or repair. Recent developments in genomic sequencing and immunotherapy may translate to new treatment paradigms for SCLC.

Modern Systemic Therapy for Metastatic Renal Cell Carcinoma of the Clear Cell Type

In the last 30 years, there have been many advances in the treatment of metastatic renal cell carcinoma of the clear cell type. Renal cell carcinoma has long been understood to have a component of immune mediation and has been responsive to immune-based therapies; in addition to early cytokine therapy, newer checkpoint inhibition therapies have also demonstrated activity. Molecular characterization of the genome of clear cell renal cell carcinoma enabled identification of the roles of angiogenesis and hypoxic stress. This led to development of small-molecule tyrosine kinase inhibitors and inhibitors of mammalian target of rapamycin that have provided additional benefit to patients. Ongoing strategies of combinations of immune and antiangiogenic therapies may lead to further advancements.

52 – Treatment of Extensive-Stage Small Cell Lung Cancer

This chapter discusses first-line and second-line therapy for patients with extensive-stage small cell lung cancer (ED SCLC). As first-line therapy, a platinum agent plus etoposide or irinotecan remains the standard of care for the treatment of SCLC. However, despite an initially high response rate to frontline platinum-based chemotherapy, ED SCLC will universally relapse, often within 3 to 6 months. Topotecan is approved as a second-line treatment for patients with platinum-sensitive, relapsed disease based on symptom control. Patients who receive no further therapy have a median survival of less than 3 months. Despite progress in the understanding of genomic alterations and signaling pathways in SCLC, clinical experiments with tyrosine kinase inhibitors, other small-molecule inhibitors, other antiangiogenic agents have been disappointing. Recently the evaluation of epigenetic modifies, inhibitors of DNA repair and the cell cycle, immune checkpoint inhibitors and inhibitors of the Notch pathway are showing promising efficacy. No new agents with clinically relevant activity have been identified during the last two decades in ED-SCLC, underscoring the unmet need in this area.

Pembrolizumab Combined With Either Docetaxel or Gemcitabine in Patients With Advanced or Metastatic Platinum-Refractory Urothelial Cancer: Results From a Phase I Study

Introduction: Cytotoxic chemotherapy might prime urothelial cancer (UC) to checkpoint inhibition, prompting a trial of chemotherapy with the programmed death receptor‐1 inhibitor pembrolizumab. Patients and Methods: Patients with advanced, platinum‐refractory UC received pembrolizumab and either docetaxel (arm A) or gemcitabine (arm B). Primary end points were assessments of maximum tolerated dose and dose‐limiting toxicity (DLT). Secondary end points were overall response rate (ORR) and progression‐free survival (PFS). Results: Twelve patients were enrolled in the initial cohorts; 6 in each arm. One DLT was seen in each arm: Grade 3 hypophosphatemia (arm A), Grade 3 diarrhea (arm B). Adverse events of Grade >3 were observed in 7 (54%), the most common being anemia (6; 50%), fatigue (6; 50%), hyponatremia (4; 33%) and neutropenia (3; 25%), with no treatment‐related deaths. There were 5 confirmed responses (1 complete, 4 partial), with an ORR of 42% and disease control rate (DCR) of 58%. Arm A had an ORR of 50% and DCR of 67%, whereas arm B had an ORR of 33% and DCR of 50%. Median PFS was 4.8, 5.7, and 3.7 months for the overall cohort, arm A, and arm B, respectively. Conclusion: Pembrolizumab with either docetaxel or gemcitabine is feasible for treatment of platinum‐refractory advanced UC patients. Preliminary efficacy was observed. Further examination is warranted.

TMPRSS2-ERG Fusions Unexpectedly Identified in Men Initially Diagnosed With Nonprostatic Malignancies

Background TMPRSS2-ERG gene fusions are frequently found in prostate cancer and are pathognomomic for prostatic origin. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Methods Frequency of TMPRSS2-ERG fusions was determined in comprehensive genomic profiles from 64,263 cancer cases submitted to Foundation Medicine to assess genomic alterations suggesting benefit from targeted therapy. Genomic results from an index case of prostate cancer that underwent evolution from adenocarcinoma to pure squamous cell carcinoma are presented. Results TMPRSS2-ERG fusions were identified for 0.86% (250/29030) of male patients and not found for female patients (0/35233). TMPRSS2-ERG fusions were detected in six tumors that were classified as squamous carcinoma, five of which were of unknown primary site. The index case is a patient with a large left retrovesical mass diagnosed as squamous carcinoma by morphologic examination and a history of Gleason 9 prostate cancer with prior prostatectomy and salvage radiation therapy. TMPRSS2-ERG was detected by genomic profiling in the squamous cell tumor, the primary adenocarcinoma of the prostate, and in a metachronous prostatic adenocarcinoma metastasis. Based on these results, the patient received androgen deprivation therapy. A phylogenetic tree demonstrating clonal and histopathologic evolution of prostate cancer in the index patient was constructed. Conclusions In this large CGP dataset, TMPRSS2-ERG fusion was seen in ~30% of prostate cancers regardless of histologic type; the fusion was on occasion detected in advanced cancers not initially carrying a diagnosis of prostate carcinoma. CGP of advanced cancers in men may reveal prostatic origin by detection of the pathognomomic TMPRSS2-ERG fusion gene.