Samer Tabchi

Immune-mediated respiratory adverse events of checkpoint inhibitors.

Purpose of review Immune checkpoint inhibitors have demonstrated remarkable efficacy with durable responses in the treatment of various malignancies. This new class of therapeutic agents is associated with a toxicity profile that differs from conventional cytotoxic therapy. The present review is focused on one of these toxicities affecting the respiratory system. Recent findings Many types of immune-related adverse events (irAEs) have been identified since the emergence of checkpoint inhibitors including colitis, nephritis, myasthenia gravis-like syndromes, acute interstitial nephritis, pneumonitis, and endocrinopathies. Although pneumonitis is relatively less frequent than other irAEs, this toxicity is by no means inconsequential as it has led to treatment-related deaths during the initial testing phases. Summary Immune-mediated pneumonitis is a potentially serious but relatively infrequent adverse event associated with the use of immune checkpoint inhibitors. IrAEs can be challenging for oncologists who are still unfamiliar with the early presenting symptoms and subsequent management of these toxicities, especially in the context of a rapidly expanding science. A high index of suspicion for pneumonitis must be maintained in patients receiving checkpoint inhibitors and who present new onset respiratory symptoms because this type of toxicity can be severe and potentially fatal.

Severe agranulocytosis in a patient with metastatic non-small-cell lung cancer treated with nivolumab.

Immune checkpoint inhibitors are novel agents in the process of revolutionising cancer care. These agents have become a very appealing therapeutic alternative since they are much better tolerated than cytotoxic therapy, due to their relatively favorable toxicity profile. However, adverse events associated with these agents usually involve the immune system and can have serious implications jeopardising survival. Herein we report the first case of immune-mediated agranulocytosis due to Nivolumab therapy. The patient suffered from Staphylococcus infection during her agranulocytosis which only responded to high dose corticosteroid therapy.

Anti-EGFR Therapy for Metastatic Colorectal Cancer in the Era of Extended RAS Gene Mutational Analysis

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In the past 2 decades, advances in cancer therapeutics allowed for a remarkable improvement in terms of survival for patients with metastatic CRC. The advent of targeted therapy, coupled with more efficient chemotherapy regimens, was the pillar achievement that contributed to the success of CRC therapy. Cetuximab and panitumumab, monoclonal antibodies targeting the epidermal growth factor receptor pathway, are the focus of this review since their mechanism of action and efficiency are closely related to the mutational status of a predictive biomarker, the Kristen rat Sarcoma viral oncogene (KRAS). More recently, another biomarker, the neuroblastoma rat sarcoma viral oncogene (NRAS), was found to be as valuable for the refinement of this targeted therapy. The arguments for the use of extended analysis of the RAS gene are thoroughly reviewed because they directly affect the choice of targeted agents and potentially the choice of backbone chemotherapy.

Antiangiogenesis for Advanced Non-Small-Cell Lung Cancer in the Era of Immunotherapy and Personalized Medicine

Over the past decade, patients with advanced non-small-cell lung cancer (NSCLC) have witnessed substantial advances in regards to therapeutic alternatives. Among newly developed agents, angiogenesis inhibitors were extensively tested in different settings and have produced some favorable outcomes despite several shortcomings. Bevacizumab is the most examined agent in this context and has demonstrated significant survival benefits when combined with standard chemotherapy in eligible patients. Preliminary results on the addition of bevacizumab to erlotinib in patients with EGFR-mutated NSCLC seem promising. Other antiangiogenic agents were also tested, but ramucirumab and nintedanib are the only agents with a positive impact on survival. More recently, immune checkpoint inhibitors (ICIs) have had considerable success due to their prolonged durations of response, yet response rates are still deemed suboptimal, and various combination therapies are being tested in an effort to improve efficacy. Preclinical evidence suggests an immunosuppressive effect of pro-angiogenic factors, which sets up a plausible rationale for combining ICIs and antiangiogenic agents. Herein, we review the landmark data supporting the success of angiogenesis inhibitors, and we discuss the potential for combination with immunotherapy and targeted agents.

Management of stage III non–small cell lung cancer

Optimal management of patients with locally advanced non-small cell lung cancer remains challenging in the context of this heterogeneous disease. Despite aggressive therapeutic approaches, survival benefits are still unsatisfactory for what might be viewed as a localized malignancy. A combined modality approach offers patients superior outcomes, especially because technological advances and refined surgical procedures now provide better results with fewer complications. Nevertheless, several features of therapy remain controversial and lack formal prospective data. Traditional cytotoxic chemoradiation therapy may have reached a plateau and future perspectives opting to integrate molecularly targeted agents and immunotherapy might be the way to improve outcomes in this disease subset.

Adding checkpoint inhibitors to tyrosine kinase inhibitors targeting EGFR/ALK in non-small cell lung cancer: a new therapeutic strategy

SummaryAfter the massive approval of checkpoint inhibitors in the treatment of numerous malignancies and settings, checkpoint inhibitors-based combination therapies are emerging as a new therapeutic modality. Nivolumab and pembrolizumab (anti-PD1 agents) were recently approved as second-line treatment in NSCLC after progression on platinum-doublets. In parallel, targeting EGFR/ALK in NSCLC using tyrosine kinase inhibitors (TKI) demonstrated remarkable outcomes and was approved as standard treatment, in patients with EGFR mutation or ALK rearrangement. Combining TKI targeting EGFR/ALK with checkpoint inhibitors seems a promising therapeutic option and is being evaluated in different trials. We aimed in this paper to elucidate the rationale behind this combination, to report the premilinary results of ongoing trials evaluating this association and finally, to discuss briefly the possible future indication of this treatment modality.

Factors influencing treatment selection and survival in advanced lung cancer.

PURPOSE Despite numerous breakthrough therapies, inoperable lung cancer still places a heavy burden on patients who might not be candidates for chemotherapy. To identify potential candidates for the newly emerging immunotherapy-based treatment paradigms, we explored the clinical and biologic factors affecting treatment decisions. METHODS We retrospectively reviewed the records of patients diagnosed at our university-affiliated cancer centre between 1 January 2011 and 31 December 2013. Patient demographics, systemic treatment, and survival were examined. RESULTS During the 3-year study period, 683 patients fitting the inclusion criteria were identified. First-line therapy was administered in 49.5% of patients; only 22.4% received further lines of therapy. The main reasons for withholding therapy were poor performance status [ps (43.2%)], rapidly deteriorating ps (31.9%), patient refusal of therapy (20.9%), and associated comorbidities (4%). Older age, the presence of brain metastasis at diagnosis, and non-small-cell histology were also associated with therapeutic restraint. Oncology referrals were infrequent in patients who did not receive therapy (32.2%). Older patients and those with a poor ps experienced superior survival when treatment was administered (hazard ratio: 0.25; 95% confidence interval: 0.16 to 0.38; and hazard ratio: 0.44; 95% confidence interval: 0.23 to 0.87 respectively; p < 0.001). CONCLUSIONS Advanced lung cancer still poses a therapeutic challenge, with a high proportion of patients being deemed unfit for therapy. This issue cannot be resolved until appropriate measures are taken to ensure the inclusion of older patients and those with a relatively poor ps in large clinical trials. Immunotherapy might be interesting in this setting, given that it appears to be more tolerable. Another consequential undertaking would be the deployment of strategies to reduce wait times during the diagnostic process for patients with a high index of suspicion for lung cancer.

Concurrent driver mutations/rearrangements in non-small-cell lung cancer

Purpose of review The concept of mutually exclusive oncogenic driver alterations has prevailed over the past decade, but recent reports have stressed the possible occurrence of dual-positive non-small-cell lung cancer (NSCLC) and even triple-positive disease for these oncogenes. This entity presents novel prognostic and therapeutic challenges. The present review highlights the available data in an effort to clarify the clinical and pathological significance of coexisting mutations as well as the subsequent therapeutic consequences. Recent findings Patients with a known driver oncogene can be successfully treated with the appropriate tyrosine kinase inhibitor, which will provide them with significant responses and lesser toxicities compared with cytotoxic therapy. Unfortunately, most patients will eventually progress. Although some resistance mechanisms have been identified, others remain to be determined but the emergence of secondary oncogenes could be part of the answer. Summary Approximately 20–25% of NSCLC harbor treatable driver mutations/rearrangements; epidermal growth factor receptor mutation, anaplastic lymphoma kinase and ROS-1 gene rearrangements are the main alterations for which a Food and Drug Administration-approved tyrosine kinase inhibitor can be used. Because of recent technological advances, high sensitivity assays with a broad range of genomic targets have become more easily accessible in clinical practice, which has led to an increased detection of coexisting driver alterations in patients with advanced NSCLC. The prognostic/predictive and therapeutic implications of this novel entity are still unsettled for the time being. Randomized trials specifically designed to address this subset of patients will soon be necessary to help determine the optimal therapeutic agent to administer.

Checkpoint inhibitors in gastrointestinal cancers: Expectations and reality

Immune checkpoint inhibitors represent revolutionary anti-cancer agents, being rapidly approved in different malignancies and settings. Gastrointestinal (GI) cancers represent a wide variety of tumors with specific characteristics and different responses to various therapeutic alternatives; while some are chemo-sensitive others are chemo-resistant and only respond to more aggressive cytotoxic regimens, targeted therapies or a combination of both. Preliminary results of immune checkpoint inhibitors in some GI cancers are promising, namely in hepatocellular carcinoma, anal cancers and microsatellite instability high colorectal cancers. An impressive instead of a impressive number of immune checkpoint inhibitors are being evaluated in different indications in GI cancers as single agents or in combination with other agents. We reported in this paper ongoing and published trials evaluating immune checkpoint inhibitors in hepatocellular carcinoma and biliary tract cancers, esophageal, gastric, pancreatic, colorectal and anal cancers and we discussed the future perspectives of these agents in GI cancers.

Successful treatment of Evans syndrome with Tacrolimus

The patient presented to our center in October 2008 with severe thrombocytopenia along with hemolytic anemia and was then diagnosed with Evans Syndrome. All necessary blood tests to rule out co-existing infection or systemic disease were thoroughly investigated. During her hospitalization, she had an acute hemorrhagic stroke and was transferred to the intensive care unit where plasma exchange was performed; several sessions of plasma exchange followed and hemolysis ceased as a result. However, thrombocytopenia persisted. Subsequently, the patient was started on oral Cyclosporine (Cyclosporine Therapeutic index: 300–400 nanograms/mL) with a combination of Cyclophosphamide, Vincristine and anti-D immune globulin. Unfortunately, this combined therapy failed to increase and maintain an adequate platelet count and the patient was referred for matched sibling hematopoietic cell transplantation in June 2010. After an initial increase in platelet counts, without ever reaching a threshold of 100 000/mm, the platelet levels began to fluctuate in August 2010 and started dropping again in October of the same year to a nadir of 5 000/mm. Since then, the patient was re-challenged with multiple lines of therapy such as follows: Glucorticoids, Rituximab, Mycophenolate Mofetil, Eltrombopag and finally Cyclosporine. However, none of these agents showed a significant or durable response, making the patient mostly transfusiondependent since then. In January 2014, the patient was no longer prescribed Cyclosporine and prednisone. Instead, she was given Tacrolimus at an initial dose of 3 mg every twenty-four hours in two divided doses. The aim was to target whole‐blood trough levels of 10–20ng/ml. Within 4 weeks, her platelets had reached 30 000/mm after Tacrolimus dosing was increased to 5 mg per day (5000/mm when Tacrolimus was started). In March, her platelet levels reached 60,000/mm and kept Invest New Drugs (2015) 33:254–256 DOI 10.1007/s10637-014-0155-9