Unmet needs in squamous cell carcinoma of the lung: potential role for immunotherapy

Squamous cell carcinoma of the lung accounts for 20–30% of non-small cell lung cancers (NSCLC). Despite the differences in disease characteristics between squamous and non-squamous NSCLC, both have historically been treated similarly in the clinic. Recently approved drugs have revealed differences in activity and safety profiles across histologic subtypes and have applicability in treating non-squamous, but not typically squamous, NSCLC. Exploration of immune checkpoints—co-inhibitory molecules used to regulate immune responses—has resulted in novel immunotherapies designed to interrupt signaling through the cytotoxic T lymphocyte-associated antigen-4 or programmed cell death protein-1 pathways on lymphocytes. Modulation of these pathways can lead to restored antitumor immune responses, and preliminary evidence shows that agents targeting these pathways have activity in lung cancer, including squamous NSCLC

Maintenance Therapy in Advanced Non-small Cell Lung Cancer: Current Status and Future Implications

Maintenance therapy for patients with advanced non-small cell lung cancer has been an area of intense investigation. Maintenance therapy has been divided into two broad categories: continuation maintenance when the chemotherapy or targeted agent was part of a defined number of cycles of combination therapy and in the absence of disease progression is continued as a single agent or switch maintenance when a third agent is initiated after four cycles of platinum-based double-agent chemotherapy in the absence of disease progression. Two monoclonal antibodies, cetuximab and bevacizumab, are used as continuation maintenance, but the incremental benefit of the maintenance therapy with these agents is undetermined. Phase III trials have not revealed an overall survival benefit for continuation maintenance chemotherapy, and this approach should be considered investigational. Phase III trials have demonstrated an improvement in overall survival with switch maintenance therapy with pemetrexed compared with placebo in patients with nonsquamous histology and erlotinib compared with placebo. Phase III trials have not revealed an improvement in quality of life with maintenance therapy. In the trials of maintenance therapy, 30 to 40% of patients enrolled in the observation or placebo arm did not receive second-line therapy, and among the patients who did receive second-line therapy, there was significant heterogeneity in the therapy. The development of maintenance therapy has raised issues about the role of treatment-free intervals in routine clinical care, trial design issues such as the optimal endpoint, the ethics of a placebo arm, and the implications of maintenance therapy for first-line trials

Treatment Paradigms for Advanced Stage Non-small Cell Lung Cancer in the Era of Multiple Lines of Therapy

Abstract:: The duration of first-line and the timing of second-line therapy for advanced non-small cell lung cancer has been an area of recent investigation. Five trials have been performed that have investigated shorter (3–4 cycles) versus longer duration of platinum-based therapy; four trials revealed an equivalent overall survival with the shorter duration of therapy, and one trial revealed superior survival with the longer duration of therapy. The toxicity and quality of life data has either been equivalent or favored the shorter duration of therapy. Two trials have investigated the timing of a second-line therapy after completion of four cycles of platinum-based therapy versus the standard treatment paradigm of initiating second-line therapy upon disease progression. Both of these trials have revealed a statistically significant improvement in the progression-free survival, and a trend towards improved survival for the earlier use of second-line therapy. Only 50 to 60% of patients on the standard treatment arm initiated second-line therapy, and the promising results observed are most likely related to the fact that a higher percentage of patients received second-line therapy on the experimental arm. Several trials have investigated maintenance chemotherapy, and these trials have not revealed a survival benefit probably due to the fact that many patients experience disease progression or unacceptable toxicity during the initial or maintenance therapy. The addition of a targeted agent (bevacizumab or cetuximab) to the initial chemotherapy and the continuation of the targeted agent after completion of the chemotherapy have yielded superior overall survival in comparison to chemotherapy alone. The incremental benefit of the maintenance therapy with the targeted agent is unknown

MEK inhibition in non-small cell lung cancer

KRAS mutations are the most common mutations in non-small cell lung cancer (NSCLC) with adenocarcinoma histology. KRAS mutations result in the activation of the RAF-MEK-ERK pathway, and agents that target RAF-MEK-ERK pathways have been investigated in KRAS mutant NSCLC. The two agents furthest in development are selumetinib and trametinib. Trametinib has greater binding for the MEK1/2 allosteric site, and generally has superior pharmacokinetics. A randomized phase II trial of docetaxel with and without selumetinib revealed that the combination resulted numerically superior overall survival, and a statistically significant improvement in progression-free survival and objective response rate. However, a concerning rate of hospital admission, grade 3 or 4 neutropenia, and febrile neutropenia was observed with the combination. Trials have investigated MEK inhibitors as single agents, and in combination with erlotinib or chemotherapy. The data do not support the further development of single agent MEK inhibitors or in combination with erlotinib. The activity of MEK inhibitors appears to be similar in patients with KRAS mutant and wild-type NSCLC suggesting KRAS mutation status is not a reliable biomarker for efficacy. It is possible that mutations of genes in addition to KRAS mutations impact the activity of MEK inhibitors, or specific subsets of KRAS mutations may be resistant or susceptible to MEK inhibition. Other potential explanations are gene amplifications, alternative RNA splicing of genes resulting in activation of their protein products, and deregulation of noncoding RNAs and consequent altered protein expression

Annual Review of Advances in Lung Cancer Clinical Research: A Report for the Year 2009

The use of positron emission tomography compared with conventional staging increases the detection of extrathoracic metastases and reduces the number futile thoracotomies in patients being evaluated for surgical resection. Long-term follow-up of one of the two adjuvant chemotherapy trials revealed a continued overall survival (OS) benefit to adjuvant chemotherapy. In locally advanced non-small cell lung cancer, a phase III trial of chemoradiotherapy alone and with surgical resection revealed no statistically significant difference in OS between the treatment arms. In advanced stage non-small cell lung cancer, a phase III trial compared gefitinib with carboplatin and paclitaxel in a clinically enriched patient population for epidermal growth factor receptor (EGFR) tyrosine kinase (TK) mutations; among patients with an EGFR TK mutation, patients in gefitinib arm compared with carboplatin and paclitaxel arm experienced a statistically significant superior response rate and progression-free survival, and among patients without EGFR TK mutation patients in the gefitinib arm compared with carboplatin and paclitaxel experienced a statistically significant inferior response rate and progression-free survival. A phase III trial of platinum-based therapy with and without cetuximab in the first-line setting revealed improved OS in the cetuximab arm. A phase III trial of maintenance pemetrexed compared with placebo in patients who had not progressed after initial platinum-based therapy revealed an improvement in OS of patients in the pemetrexed arm with nonsquamous histology. In limited-stage small cell lung cancer, a phase III trial compared standard and high-dose prophylactic cranial irradiation and revealed no significant difference in the rate of brain metastases between the two treatment arms

Annual Review of Advances in Non-small Cell Lung Cancer Research: A Report for the Year 2010

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Third-generation chemotherapy agents in the treatment of advanced non-small cell lung cancer: A meta-analysis [2]

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The Feasibility of Adjuvant Carboplatin and Docetaxel in Patients with Curatively Resected Non-small Cell Lung Cancer

Adjuvant cisplatin-based chemotherapy improves overall survival; however, chemotherapy compliance has been difficult. Carboplatin (C) is better tolerated than cisplatin, and carboplatin-based adjuvant therapy may have better chemotherapy compliance.The primary end point of this multicenter phase II trial was the feasibility of delivering carboplatin and docetaxel (C/D). An “adequate exposure” was defined as receiving four cycles of C/D within 12 weeks of initiating adjuvant therapy. A sample size of 72 patients provided 88% power to detect a true adequate exposure of rate of at least 80%. Patients with resected non-small cell lung cancer, a good functional status, and preserved organ function were eligible. Adjuvant therapy was initiated between 2 and 8 weeks after surgery, and consisted of four cycles C (area under the curve = 6), and D 75 mg/m every 3 weeks.Seventy-two patients were treated, and the patient demographics were: median age 65 years (range 47–84), gender male/female 67%/33%, stage I (40%), II (36%) IIIA (22%) and IIIB (1%), and the two most common histologies were: adenocarinoma (44%), and squamous cell carcinoma (42%). Fifty-seven patients (79%) received four cycles within 12 weeks, and 15 (21%) of patients did not complete four cycles for the following reasons: adverse events ( = 5), patient refusal ( = 5), disease progression during active therapy ( = 3), and intercurrent illness ( = 2). No treatment related deaths were observed and the primary toxicities were hematologic (grade 4 neutropenia 42% and febrile neutropenia 11% of patients). Twenty-six patients (36%) received growth colony stimulating factor (G-CSF) supportive therapy during their treatment, and G-CSF supportive therapy was used in 21.6% of all cycles.C/D has an acceptable toxicity profile with the use of G-CSF supportive therapy and the majority of patients completed four cycles of therapy within 12 weeks

Beliefs among Physicians in the Diagnostic and Therapeutic Approach to Non-small Cell Lung Cancer

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