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Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - June 2014 VOL 4, NO 2 - From the Literature
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ALK- Positive Non–Small-Cell Lung Cancer Responds to Ceritinib Treatment

Background: Non–small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib. Despite initial responses to crizotinib, resistance ultimately occurs. In preclinical studies, ceritinib, a novel, oral aden-
osine triphosphate–competitive inhibitor of the ALK tyrosine kinase, has shown greater antitumor potency than crizotinib.

Methods: This phase 1 clinical trial consisted of 2 dose-finding phases and included 130 patients. In the dose-escalation phase, 59 patients with tumors harboring ALK mutations were treated with ceritinib at doses of 50 mg to 750 mg once daily in 21-day cycles. In an expansion phase, 71 patients were treated at the maximum tolerated dose of 750 mg daily. Among the 130 patients enrolled, 122 had advanced NSCLC and had previously received cytotoxic chemotherapy. Of the 122 patients with advanced NSCLC, 68% had previously received crizotinib.

Results: Among the 114 patients with NSCLC who received ≥400 mg of ceritinib daily, the overall response rate was 58%, which included 1 (1%) confirmed complete response and 65 (57%) partial responses. The overall response rate was 56% among 80 patients previously receiving crizotinib, and 62% among the 34 crizotinib-naïve patients. Among 114 patients receiving ≥400 mg daily, the median progression-free survival was 7 months, which was similar at 6.9 months in the crizotinib relapse group and was 10.4 months in crizotinib-naïve patients.

The most common adverse events were nausea (82%), diarrhea (75%), vomiting (65%), fatigue (47%), and elevated alanine aminotransferase (ALT; 35%) levels. The most common grade 3 or 4 drug-related adverse events were increased ALT levels (21%), increased aspartate aminotransferase levels (11%), diarrhea (7%), and increased lipid lipase levels (7%), all of which were reversible on discontinuation of treatment. Of 130 patients, 66 (51%) required at least 1 dose reduction. In 8 of the 130 patients (6%), ceritinib was permanently discontinued as a result of an adverse event. Of 81 patients receiving the 750-mg dose, 50 (62%) required at least 1 dose reduction; in 32 patients in the latter group, the reduction occurred in cycle 3 or later. No treatment-related deaths occurred.

In this phase 1 study, ceritinib produced a highly active response rate in patients with advanced ALK-rearranged NSCLC, including patients with previous crizotinib treatment and irrespective of the presence of ALK-resistance mutations. Because ceritinib induced substantial and durable responses in a majority of cases, this new agent may be an alternative treatment for patients with ALK-rearranged NSCLC who no longer respond to crizotinib.

Source: Shaw AT, Kim D-W, Mehra R, et al. Ceritinib in ALK-rearranged non–small-cell lung cancer. N Engl J Med. 2014;370: 1189-1197.

Commentary by Robert J. Ignofo
It was astonishing to this reviewer when a phase 1 study of a new ALK inhibitor, ceritinib, was published in one of the highest impact factor journals in the United States, the New England Journal of Medicine. However, it was the impressive results reported in the group of patients with highly resistant disease, many of whom had received previous treatment with standard crizotinib therapy, that led to the publication of this study. A surprisingly high response rate and improvement in progression-free survival (PFS) rates were observed in the dose-finding and the expansion phase of the study. Ceritinib was equally effective—approximately 60% response rate and median PFS of 7 to 10 months—in patients with resistant and nonresistant ALK-positive NSCLC. These outcomes are substantially better than that seen in patients who had relapsed after crizotinib therapy and then received other agents—approximately 10% response rate. The toxicity profile of ceritinib is similar to that of other epidermal growth factor receptor inhibitors and includes diarrhea, nausea, vomiting, and fatigue, which were dose-limiting, with doses of >600 mg daily. Ceritinib is a definite advance in the treatment of ALK-positive NSCLC and should be studied further to determine if it can be moved into second-line therapy, and even first-line therapy.

Rituximab Active in Nodular Lymphocyte–Predominant Hodgkin Lymphoma

Background: Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) is a rare type of Hodgkin lymphoma that represents approximately 5% of all cases. Unlike classic Hodgkin lymphoma, the malignant cells of NLPHL universally express CD20. Rituximab, an anti-CD20 monoclonal antibody, has therefore been evaluated as a treatment option for this patient population. Previous preliminary results of a phase 2 clinical trial using single-agent rituximab in patients with NLPHL showed that the overall response rate was 100%, but the estimated median freedom from progression was less than 1 year. These are the mature results of the phase 2 trial of rituximab induction, with and without maintenance rituximab, in patients with NLPHL.

Methods: In this new study, researchers modified the study protocol of rituximab induction with and without maintenance rituximab in patients with NLPHL to evaluate patient response rate at 2 years.

The study included 39 patients with previously treated or with newly diagnosed NLPHL. The initial protocol included 23 patients (ie, rituximab group) who received rituximab 375 mg/m2 administered once weekly for 4 weeks. The protocol was amended after this patient cohort had enrolled to include 16 patients (ie, rituximab plus maintenance group) who received maintenance dosing with rituximab 375 mg/m2 administered in 4 once-weekly doses at 6-month intervals for 2 years. For patients with previously untreated disease, the median age at treatment was 38 years, and the median time from diagnosis to treatment induction was 4 months. The median time from original diagnosis of NLPHL to study entry in patients experiencing relapse was 12.7 years, and the median age at treatment was 44 years. The primary end point was progression-free survival (PFS), and the secondary end points were complete response and overall response rate.

Results: After 4 weekly treatments, the overall response rate was 100%, with 67% of patients achieving complete response and 33% achieving partial response. No difference in the overall response rate was observed in previously treated patients versus treatment-naïve patients.
At a median follow-up of 9.8 years in the rituximab group, the PFS was 3 years. At the median follow-up of 5 years in the rituximab plus maintenance group, the PFS was 5.6 years. The median overall survival was not reached in either group. The estimated 5-year PFS and overall survival rates for patients in the rituximab group compared with patients in the rituximab plus maintenance group were 39.1% and 95.7% versus 58.9% and 85.7%, respectively.

Treatment-related adverse events were minimal in both groups, and no grade 3 or 4 toxicities were observed. A total of 23 patients experienced relapse, and 9 of these patients had evidence of transformation to aggressive B-cell lymphoma.

The researchers concluded that rituximab is well-tolerated and is an active single agent in patients with NLPHL who had received no previous treatment and in patients with relapsed disease. Although the responses are not durable in the majority of the patients, a substantial minority experience remission lasting more than 5 years.

Because single-agent rituximab is not curative for NLPHL, it should be primarily considered in patients in the relapsed setting. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of repeated biopsy and longer-term follow-up.

Source: Advani RH, Horning SJ, Hoppe RT, et al. Mature results of a phase II study of rituximab therapy for nodular lymphocyte–predominant Hodgkin lymphoma. J Clin Oncol. 2014;32:912-918.

Commentary by Robert J. Ignofo
NLPHL is an indolent form of Hodgkin lymphoma, with an 8-year survival rate of 94% in patients with stage III disease and 41% in patients with stage IV disease. Before the advent of rituximab, most patients were treated with the standard chemotherapy regimen of mechlorethamine, vincristine, procarbazine, and prednisone, or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Today, the guidelines from the National Comprehensive Cancer Network (NCCN) recommend rituximab as first-line therapy. Relapse occurs in approximately 25% of patients, who often respond again to rituximab. The NCCN recommends that rituximab may be added to standard ABVD; cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, and prednisone. The current study was developed to assess whether maintenance rituximab will improve outcomes in patients with newly diagnosed or relapsed NLPHL, and this strategy can prevent the transformation to aggressive non-Hodgkin lymphoma.

The results of this study show that although rituximab does not cure NLPHL, induction plus maintenance ri-tuximab improves disease-free survival by almost 3 years versus rituximab induction alone. Unfortunately, 9 of 23 patients progressed to an aggressive non-Hodgkin lymphoma, 6 of whom received rituximab maintenance. Of note, the median overall survival had not been reached; even for progressing patients, the median overall survival was 52 months, reflecting an indolent disease. Rituximab is an acceptable therapy for treating patients with newly diagnosed or relapsed NLPHL. Further follow-up is needed to determine if maintenance therapy with rituximab with improve overall survival in this group of patients.

Dovitinib Active, but Not Superior to Sorafenib, in Patients with Metastatic Renal Cancer

Therapies targeting vascular endothelial growth factor (VEGF) and mTOR signaling pathways are standard first-line and second-line treatment options for patients with metastatic renal cell carcinoma. However, an unmet medical need exists for patients who had previously received VEGF-targeted and mTOR inhibitor therapies. Fibroblast growth factor pathway activation may be a mechanism of escape from VEGF-targeted therapies. Dovitinib (TKI258) is an oral tyrosine kinase inhibitor that inhibits VEGF, fibroblast growth factor receptors, and platelet-derived growth factor receptors. Therefore, researchers sought to compare dovitinib versus sorafenib as third-line targeted therapies in this patient population.

Methods: The Global Oncologic Learnings for Dovitinib trial was a multicenter, open-label, randomized, phase 3 trial that included 570 patients with metastatic renal cell carcinoma with clear cell or a component of clear cell histology, and who had received 1 previous VEGF-targeted therapy (eg, sunitinib or bevacizumab) and 1 previous mTOR inhibitor (eg, everolimus or temsirolimus). Patients were randomly assigned in a 1:1 ratio to receive dovitinib 500 mg orally according to a 5-days-on and 2-days-off schedule (N = 284), or to sorafenib 400 mg twice daily (N = 286). Randomization was stratified by risk group and by region. Patient characteristics were well-balanced between both groups. The primary end point was progression-free survival (PFS) on masked central review. Efficacy was assessed in all patients who were randomly assigned, and safety was assessed in patients who received at least 1 dose of the study drug.

Results: The findings showed no difference in PFS between the 2 treatment groups. The median follow-up was 11.3 months. The median PFS times were 3.7 months in the dovitinib group and 3.6 months in the sorafenib group (hazard ratio [HR], 0.86; P = .063). No subgroup had a clinically significant PFS benefit with dovitinib versus sorafenib treatment in analysis by patient demographics and disease characteristics. The median PFS times according to favorable-, intermediate-, and poor-risk Memorial Sloan Kettering Cancer Center status were 5.5 months versus 3.7 months, 3.7 months versus 3.7 months, and 3.6 months versus 2.1 months, respectively. Partial response was noted in 4% of the patients in each group. In the dovitinib and sorafenib groups, the median overall survival times were 11.1 months and 11 months, respectively (HR, 0.96).

Common grade 3 and 4 adverse events included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), and anemia (5%) in the dovitinib group; and hypertension (17%), fatigue (8%), dyspnea (7%), palmar-plantar erythrodysesthesia (6%), and anemia (6%) in the sorafenib group. The most common serious adverse event in the dovitinib and sorafenib groups was dyspnea (6% and 5%, respectively). Adverse events led to dose change or interruption in 51% of the patients receiving dovitinib and in 49% of the patients receiving sorafenib.

Although dovitinib showed activity in this setting, the researchers concluded that dovitinib and sorafenib had similar efficacies when used as third-line targeted treatments for metastatic renal cell carcinoma. The 11-month median overall survival highlights the need for study and identification of novel agents in this setting.

Source: Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:286-296.

Commentary by Robert J. Ignofo
Dovitinib is not inferior to sorafenib for the treatment of advanced metastatic renal cancer. In comparative studies of a new drug that demonstrate noninferiority, one may look at other outcomes, particularly adverse effects, to determine if the new drug will be a useful treatment. In this study, dovitinib was generally associated with more adverse effects than sorafenib. It produced more diarrhea, nausea, vomiting, and leukopenia, whereas sorafenib caused more hand-foot syndrome. Therefore, dovitinib offers an active alternative drug for treating metastatic renal-cell carcinoma and may be substituted for sorafenib in patients who find some of its adverse effects intolerable.

Comparing Chemotherapy and EGFR Kinase Inhibitors for Patients with Advanced NSCLC and Wild-Type EGFR

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the preferred treatment option for patients with advanced non–small-cell lung cancer (NSCLC) who have tested positive for EGFR mutations, because of better outcomes than conventional chemotherapy. However, it is unclear if EGFR TKIs are as efficacious as chemotherapy in patients without EGFR mutations (known as EGFR wild-type), which account for the majority of patients with advanced NSCLC.

Methods: This systematic review and meta-analysis of randomized controlled trials was conducted to determine the association between the first-generation EGFR TKI treatments (erlotinib and gefitinib) versus chemotherapy and survival in patients with advanced NSCLC harboring wild-type EGFR. Using PubMed, EMBASE, the Cochrane Database, and meeting abstracts of the American Society of Clinical Oncology and the European Society for Medical Oncology, researchers identified 11 randomized controlled trials, with 1605 patients with wild-type EGFR (811 patients in the TKI group, and 794 patients in the chemotherapy group). In all, 4 trials were performed in the first-line setting, 4 in second-line, and 3 in second-line or later settings. All 11 trials used TKIs in their standard dosing and schedule (erlotinib 150 mg daily, gefitinib 250 mg daily). The primary end point was progression-free survival (PFS), and the secondary end points were objective response rate and overall survival.

Results: In this pooled analysis, chemotherapy was associated with longer PFS compared with EGFR TKI in patients with wild-type tumors (hazard ratio [HR], 1.41; 95% confidence interval [CI], 1.1-1.81). In a subgroup analysis of 4 trials using more sensitive platforms, conventional chemotherapy demonstrated a longer PFS compared with TKI (HR, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy improvement in PFS was also significant in 6 second-line or later trials (HR, 1.34; 95% CI, 1.09-1.65). The higher objective response rate (including complete and partial responses) of chemotherapy also supported the longer PFS in patients with wild-type EGFR tumors compared with TKI therapy (16.8% vs 7.2%, respectively). However, the overall survival did not differ between the groups.

The researchers acknowledged that the apparent discrepancy between the PFS/objective response rate and overall survival can be explained by the large crossover rates of the included trials. Therefore, they note, the findings suggest that in patients with wild-type EGFR tumors, conventional chemotherapy could be the preferred treatment option over EGFR TKI. The investigators cautioned that this recommendation cannot be conclusive, because overall comparisons were based on randomization. Toxicity outcomes were also not assessed.

Source: Lee J-K, Hahn S, Kim D-W, et al. Epidermal growth factor tyrosine kinase inhibitors vs conventional chemotherapy in non–small cell lung cancer harboring wild-type epidermal growth factor receptor: a meta-analysis. JAMA. 2014;311:1430-1437.

Commentary by Robert J. Ignofo
EGFR mutations are a predictive marker for EGFR TKIs in patients with NSCLC. First-generation EGFR TKIs are considered a first-line therapy in patients with EGFR-mutated NSCLC. However, the majority of patients with NSCLC have no EGFR mutations (ie, wild-type disease). Thus, this large meta-analysis was undertaken to determine if first-generation EGFR TKIs have a therapeutic role compared with conventional chemotherapy. The bottom line is that conventional doublet chemotherapy in EGFR wild-type NSCLC produces a significantly higher response rate and a longer progression-free disease than EGFR TKIs. However, there was no difference in overall survival. Of note, in this study toxicities were not assessed. This study had limitations as a result of a possible unbalanced randomization of patients with EGFR wild-type disease. In addition, the impact of treatment crossover could not be assessed, because overall outcomes were reported only for the combined wild-type and mutated groups. This commentator believes that performing a large randomized trial of first-generation EGFR TKIs in patients with EGFR wild-type NSCLC would not be fruitful and would be a very expensive endeavor. It is suggested that investigators wait until more effective TKIs for patients with EGFR wild-type NSCLC become available.

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Last modified: April 27, 2020