Craig H. Reynolds

PointBreak: A Randomized Phase III Study of Pemetrexed Plus Carboplatin and Bevacizumab Followed by Maintenance Pemetrexed and Bevacizumab Versus Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer

PURPOSE PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). RESULTS Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. CONCLUSION OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability.

Randomized Phase III Trial of Gemcitabine-Based Chemotherapy With In Situ RRM1 and ERCC1 Protein Levels for Response Prediction in Non–Small-Cell Lung Cancer

PURPOSE We evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy. PATIENTS AND METHODS A randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology. RESULTS One hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = -0.41; P = .001 for RRM1; r = -0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels. CONCLUSION Single-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.

Pemetrexed in Relapsed Small-Cell Lung Cancer and the Impact of Shortened Vitamin Supplementation Lead-In Time: Results of a Phase II Trial

Introduction: We undertook a phase II trial to assess the efficacy and safety of single-agent pemetrexed (P) in relapsed small-cell lung cancer (SCLC) patients. Methods: Patients had limited- or extensive-stage SCLC, performance status 0 to 2, and one prior chemotherapy regimen. Initial P dose was 500 mg/m2 every 21 days. Planned sample sizes were 36 sensitive (S) patients in a two-stage sequential fashion with early stopping rule, and 25 refractory (R) patients in a single-stage design without stopping rule. Patients received folic acid and Vitamin B12 prior to P, and B12 could be given up until P treatment. Primary outcome measure was response rate. Results: Enrollment occurred from July 2004 to March 2006. The stopping rule was invoked when <3 of 14 S patients responded. The protocol was amended to evaluate P 900 mg/m2 in cohorts of 40 S and 40 R patients. Overall, 121 patients were enrolled, with 116 patients treated. S (n = 53) and R (n = 63) patients were analyzed separately at both dose levels. Across the 4 treatment groups (S500, S900, R500, R900), 1 patient (2.63%) in the S900 group had a partial response. Overall, 18 patients (16%) had stable disease. Eighty-seven patients (75%) had progressive disease. Responses were not evaluable in 10 patients (8.6%). Overall response rate was 0.9%. Across treatment groups, disease control rates (partial response + stable disease) were 20%, 15.8%, 21.7%, and 12.5%, respectively. Median time to progression ranged from 1.2 to 1.5 months, median survival times ranged from 2.5 to 6.1 months, and 1-year survival rates ranged from 5.6 to 25.8%. Common grade 3/4 hematologic toxicities (at 500 and 900 mg/m2) were neutropenia (16%; 9%) and leukopenia (11%; 8%), and nonhematologic toxicities were dyspnea (11%; 10%) and fatigue (16%; 9%). Retrospective analysis of cycle 1 events by timing of B12 administration showed no trend toward more frequent serious toxicities when B12 was given <7 days prior to P. Conclusions: Single-agent P 500 mg/m2 shows minimal activity in relapsed SCLC patients. P can be given at 900 mg/m2 without significant increase in serious toxicities, but does not seem to increase efficacy. B12 given <7 days before P does not seem to be associated with increased serious toxicities.

Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment

ABSTRACT Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk‐to‐benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs.

A Phase III Randomized Trial of Gemcitabine–Oxaliplatin versus Carboplatin–Paclitaxel as First-Line Therapy in Patients with Advanced Non-small Cell Lung Cancer

Purpose: This phase III study compared the efficacy and tolerability of gemcitabine and oxaliplatin (GEMOX) with paclitaxel and carboplatin (PCb) in chemotherapy-naive patients with stage IIIB/IV non-small cell lung cancer. Patients and Methods: Patients aged 18 years or older were randomized to PCb (paclitaxel 225 mg/m2 followed by carboplatin area under the curve = 6 on day 1 every 3 weeks) or GEMOX (gemcitabine 1,000 mg/m2 on days 1 and 8 followed by oxaliplatin 130 mg/m2 on day 1 every 3 weeks) for up to six cycles. The primary end point was progression-free survival (PFS), with tumor response rate, overall survival (OS), and quality of life as secondary end points. Results: The study was terminated after 383 patients had been randomized (371 received treatment) as the incidence of adverse events had exceeded the protocol-specified safety threshold (≥20% in either arm). No formal statistical comparisons were conducted. Median PFS was 4.44 months and 4.67 months in the GEMOX and PCb groups, respectively. Objective response rates (complete or partial) were 15.2% and 22.4% in the GEMOX and PCb arms, respectively. Median OS was 9.90 months (GEMOX) and 9.24 months (PCb); post hoc analyses showed median OS in patients aged 70 years or older to be similar to those younger than 70 years. PFS was similar in both groups of patients with adenocarcinoma histology, although OS favored the GEMOX group. Quality of life was improved from baseline in both groups. Toxicity profiles were comparable between the groups. Conclusion: PFS, OS, and objective response rates with GEMOX were similar to PCb. Nevertheless, toxicities limit the adoption of this regimen for routine use in advanced non-small cell lung cancer.

An open‐label pilot study of pentostatin, mitoxantrone, and rituximab in patients with previously untreated, Stage III or IV, low‐grade non‐Hodgkin lymphoma

In a previous study, the authors demonstrated that the combination of pentostatin (P) and rituximab (R) was well tolerated and was active in patients with low‐grade non‐Hodgkin lymphoma (NHL). In the current study, mitoxantrone (M) was added to P + R to evaluate the toxicity and efficacy of this three‐drug combination (PMR).

Clinicopathologic Features of Advanced Squamous NSCLC

Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.

Quality of Life Analyses from the Randomized, Open-Label, Phase III PointBreak Study of Pemetrexed-Carboplatin-Bevacizumab followed by Maintenance Pemetrexed-Bevacizumab Versus Paclitaxel-Carboplatin-Bevacizumab followed by Maintenance Bevacizumab in Patients with Stage IIIB or IV Nonsquamous Non–Small-Cell Lung Cancer

Introduction: Treatment impact on quality of life (QoL) informs treatment management decisions in advanced nonsquamous non–small-cell lung cancer (NS NSCLC). QoL outcomes from the phase III PointBreak trial are reported. Methods: Chemonaive patients (n = 939) with stage IIIB/IV nonsquamous non–small-cell lung cancer and Eastern Cooperative Oncology Group performance status 0 to 1 were randomized (1:1) to pemetrexed-carboplatin-bevacizumab (pemetrexed arm) or paclitaxel-carboplatin-bevacizumab (paclitaxel arm). Patients without progressive disease received maintenance pemetrexed-bevacizumab (pemetrexed arm) or bevacizumab (paclitaxel arm). QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-General (FACT-G), FACT-Lung (FACT-L), and FACT/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) instruments. Subscale scores, total scores, and trial outcome indices were analyzed using linear mixed-effects models. Post hoc analyses examined the association between baseline FACT scores and overall survival (OS). Results: Mean score differences in change from baseline significantly favored the pemetrexed arm for the neurotoxicity subscale score, FACT-Ntx total scores, and FACT-Ntx trial outcome index. They occurred at cycle 2 (p < 0.001) and persisted through induction cycles 2 to 4 and six maintenance cycles. Investigator-assessed, qualitative, drug-related differences in grade 2 (1.6% versus 10.6%) and grade 3 (0.0% versus 4.1%) sensory neuropathy and grade 3/4 fatigue (10.9% versus 5.0%, p = 0.0012) were observed between the pemetrexed and paclitaxel arms. Baseline FACT-G, FACT-L, and FACT-Ntx scores were significant prognostic factors for OS (p < 0.001). Conclusions: Randomized patients reported similar changes in QoL, except for less change from baseline in neurotoxicity on the pemetrexed arm; investigators reported greater neurotoxicity on the paclitaxel arm and greater fatigue on the pemetrexed arm. Higher baseline FACT scores were favorable prognostic factors for OS.

Current and Emergent Therapy Options for Advanced Squamous-Cell Lung Cancer

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC.

Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies

&NA; Patients with non–small‐cell lung cancer, including squamous‐cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non–small‐cell lung cancer, with a focus on SqCLC.