Justine V. Cohen

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.

BACKGROUND Immunotherapy targeting the PD-1 axis has activity in several tumour types. We aimed to establish the activity and safety of the PD-1 inhibitor pembrolizumab in patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC). METHODS In this non-randomised, open-label, phase 2 trial, we enrolled patients aged 18 years or older with melanoma or NSCLC with untreated brain metastases from the Yale Cancer Center. Patients had at least one untreated or progressive brain metastasis between 5 and 20 mm in diameter without associated neurological symptoms or the need for corticosteroids. Patients with NSCLC had tumour tissue positive for PD-L1 expression; this was not required for patients with melanoma. Patients were given 10 mg/kg pembrolizumab every 2 weeks until progression. The primary endpoint was brain metastasis response assessed in all treated patients. The trial is ongoing and here we present an early analysis. The study is registered with ClinicalTrials.gov, number NCT02085070. FINDINGS Between March 31, 2014, and May 31, 2015, we screened 52 patients with untreated or progressive brain metastases (18 with melanoma, 34 with NSCLC), and enrolled 36 (18 with melanoma, 18 with NSCLC). A brain metastasis response was achieved in four (22%; 95% CI 7-48) of 18 patients with melanoma and six (33%; 14-59) of 18 patients with NSCLC. Responses were durable, with all but one patient with NSCLC who responded showing an ongoing response at the time of data analysis on June 30, 2015. Treatment-related serious and grade 3-4 adverse events were grade 3 elevated aminotransferases (n=1 [6%]) in the melanoma cohort, and grade 3 colitis (n=1 [6%]), grade 3 pneumonitis (n=1 [6%]), grade 3 fatigue (n=1 [6%]), grade 4 hyperkalemia (n=1 [6%]), and grade 2 acute kidney injury (n=1 [6%]) in the NSCLC cohort. Clinically significant neurological adverse events included transient grade 3 cognitive dysfunction and grade 1-2 seizures (n=3 [17%]) in the melanoma cohort. INTERPRETATION Pembrolizumab shows activity in brain metastases in patients with melanoma or NSCLC with an acceptable safety profile, which suggests that there might be a role for systemic immunotherapy in patients with untreated or progressive brain metastases. FUNDING Merck and the Yale Cancer Center.

Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment

This case report documents pseudoprogression in brain metastases treated with antibodies to PD-1. Use of immune checkpoint inhibitors in melanoma and other malignancies is increasing, making it important to recognize and treat effects unique to brain metastases. The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential. Cancer Immunol Res; 4(3); 179–82. ©2015 AACR.

Possible Interaction of Anti–PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases

Patients undergoing stereotactic radiosurgery for brain metastases may show unexpected effects in the lesions after treatment with antibodies to PD-1. Assessments of clinical and radiologic changes need accurate interpretation in this growing patient population. Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the brain. The interaction of these systemic therapies with other modalities of treatment for brain metastases, namely, SRS, has not been fully characterized. We report two patients with metastatic malignancies to the brain who received SRS followed by immunotherapy with monoclonal antibodies (mAb) to programmed death 1 (PD-1). Both patients appeared to have early clinical and radiologic progression of their treated lesions, which was highly suspicious for tumor progression. Both patients underwent surgical resection of their lesions and the material was submitted for histopathologic examination. Pathologic examination in both cases showed predominantly radiation-induced changes characterized by reactive astrocytosis and vascular wall infiltration by T lymphocytes. The accelerated response to SRS in these two patients was temporally related to the initiation of immunotherapy. We propose a possible biologic interaction between SRS and the PD-1 mAbs. Additionally, awareness of this potential occurrence is critical for accurate interpretation and proper management of clinical and radiologic findings in these patients. Cancer Immunol Res; 4(6); 481–7. ©2016 AACR.

PD-L1 Studies Across Tumor Types, its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors

Purpose: With recent approval of inhibitors of PD-1 in melanoma, non–small cell lung cancer (NSCLC) and renal cell carcinoma, extensive efforts are under way to develop biomarkers predictive of response. PD-L1 expression has been most widely studied, and is more predictive in NSCLC than renal cell carcinoma or melanoma. We therefore studied differences in expression patterns across tumor types. Experimental Design: We used tissue microarrays with tumors from NSCLC, renal cell carcinoma, or melanoma and a panel of cell lines to study differences between tumor types. Predictive studies were conducted on samples from 65 melanoma patients treated with PD-1 inhibitors alone or with CTLA-4 inhibitors, characterized for outcome. PD-L1 expression was studied by quantitative immunofluorescence using two well-validated antibodies. Results: PD-L1 expression was higher in NSCLC specimens than renal cell carcinoma, and lowest in melanoma (P = 0.001), and this finding was confirmed in a panel of cell lines. In melanoma tumors, PD-L1 was expressed either on tumor cells or immune-infiltrating cells. The association between PD-L1 expression in immune-infiltrating cells and progression-free or overall-survival in melanoma patients treated with ipilimumab and nivolumab was stronger than PD-L1 expression in tumor cells, and remained significant on multivariable analysis. Conclusions: PD-L1 expression in melanoma tumor cells is lower than NSCLC or renal cell carcinoma cells. The higher response rate in melanoma patients treated with PD-1 inhibitors is likely related to PD-L1 in tumor-associated inflammatory cells. Further studies are warranted to validate the predictive role of inflammatory cell PD-L1 expression in melanoma and determine its biological significance. Clin Cancer Res; 23(15); 4270–9. ©2017 AACR.

Melanoma central nervous system metastases: current approaches, challenges, and opportunities

Melanoma central nervous system metastases are increasing, and the challenges presented by this patient population remain complex. In December 2015, the Melanoma Research Foundation and the Wistar Institute hosted the First Summit on Melanoma Central Nervous System (CNS) Metastases in Philadelphia, Pennsylvania. Here, we provide a review of the current status of the field of melanoma brain metastasis research; identify key challenges and opportunities for improving the outcomes in patients with melanoma brain metastases; and set a framework to optimize future research in this critical area.

Therapeutic combinations of immune-modulating antibodies in melanoma and beyond.

Immune-modulating antibodies demonstrate activity in increasing numbers of malignancies, and more will be developed in the coming decade. Although active as single agents, optimal outcomes will require combination therapies for many patients. Currently, most combinations are based on either PD-1/PD-L1 antagonists or anti-CTLA-4. The combination of anti-PD-1 with anti-CTLA-4 demonstrates promising activity in metastatic melanoma and metastatic renal cell carcinoma and will be tested in multipe other malignancies. Future combinations will likely involve two or more checkpoint inhibitors, a checkpoint inhibitor in combination with an agonist of costimulation, combinations of costimulatory agents or combinations with antibodies that alter lymphyocyte trafficking. Although opportunities for effective combinations are available, major challeneges include the potential for autoimmune toxicity and the selection of patients.

Evolving Immunotherapy Approaches for Renal Cell Carcinoma

Metastatic renal cell carcinoma (mRCC) continues to be associated with high rates of morbidity and mortality. Renal cell carcinoma (RCC) is typically resistant to cytotoxic chemotherapy, and while targeted therapies have activity and prolong progression-free and overall survival, responses are usually not durable. Modulating the immune system with cytokine therapy, vaccine therapy, cell therapy, and checkpoint inhibitors offers hope of prolonged survival. Standard and emerging immune therapy approaches and combinations of immune therapies and other modalities are reviewed.

Rapidly Fatal Pulmonary Fibrosis in a Patient with Psoriatic Arthritis Treated with Adalimumab

To the Editor: Anti-tumor necrosis factor-α (TNF-α) drugs are used with increasing frequency for disorders involving the skin, joints, and gastrointestinal tract. A wide range of adverse effects have been identified among over one million patients treated with this class of drugs1. These include bacterial infections, mycobacterial infections, fungal infections, cutaneous malignancies, exacerbations of congestive heart failure, and autoimmune diseases1,2,3. In addition, anecdotal reports have linked interstitial lung disease (ILD) and pulmonary fibrosis to etanercept4, infliximab5, or adalimumab6,7. Recently, one study reported no clear pattern of causal relationship of treatment with infliximab and hospitalization for ILD in patients with rheumatoid arthritis (RA)8. Another … Address correspondence to Dr. Cohen; E-mail: justine.cohen{at}uphs.upenn.edu

Intralesional Bleomycin for Warts: Patient Satisfaction and Treatment Outcomes.

Background: The treatment of warts is challenging with regards to both tolerability and efficacy. Objective: Ascertain the efficacy, tolerability, and patient satisfaction of intralesional bleomycin in the treatment of warts. Methods: Retrospective chart review followed by telephone interviews with patients from university-based dermatology referral centers. Results: Seventy-four percent (34/46) of patients had complete resolution (CR) of all warts. Of 34 patients who experienced CR, an average of 1.7 treatments were required. Pain experienced during the procedure and recovery, irrespective of outcome, was rated 5.8 out of 10 (range, 1-10; SD, 2.72; SEM, 0.40). Approximately 70% of patients had pain that lasted less than 2 days after treatment. Seventy-eight percent (36/46) of patients in the study were satisfied with treatment and would recommend it to others. Conclusion: Patients felt bleomycin to be an effective treatment modality for warts, offering high rates of CR in lesions resistant to more traditional therapies.

Paradox of Hope

Do you ever feel like life works like a pendulum? You swing one way for a while...up, up, up...(or down, down, down!) and then, inevitably you find yourself and your life swinging back in equal measure in the opposite direction? No wonder it is so difficult to find a solid place to stand! I often find that when I write about a theme or principle of life-shifting in this blog, that within a short period of time the universe usually compels me to contemplate, read, or re-discover the opposite end of whatever spectrum I happened to be hanging out on. Go figure.