After standard chemotherapy, maintenance therapy with sunitinib delayed relapse by approximately 1.5 months compared with placebo for patients with extensive-stage small cell lung cancer (SCLC), according to new findings from a phase II trial.

Dr. Neil Ready, MD, PhD, of the Duke Cancer Institute in Durham, North Carolina, presented results from the randomized, phase II Cancer and Leukemia Group B (CALGB) 30504 trial (Ready N et al., 2013) at the 2013 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.

Sunitinib is an oral, multitargeted receptor tyrosine kinase (RTK) inhibitor that shows potent and selective activity against vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), stem cell factor receptor (KIT), and other molecular targets implicated in tumor growth and angiogenesis. Sunitinib is currently approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor. Although sunitinib and other RTK inhibitors have been studied extensively in non-small cell lung cancer (NSCLC) (Gridelli C et al.), few studies have examined sunitinib in SCLC.

CALGB 30504 Study Design

The CALGB 30504 trial began in 2007 as a phase I trial of concurrent therapy with sunitinib and standard chemotherapy in untreated extensive-stage SCLC. The concurrent regimen was not feasible, however, due to the risk of grade 5 neutropenia (Ready N et al., 2010). In 2008, the CALGB 30504 protocol was amended to a randomized phase II trial designed to evaluate maintenance sunitinib following chemotherapy. In the current analysis, 85 patients received 4-6 cycles of standard-dose chemotherapy with cisplatin/etoposide or carboplatin/etoposide every 21 days. Patients were randomly assigned to maintenance therapy with sunitinib 37.5 mg/day (n = 44) or placebo (n = 41) until disease progression. Crossover to sunitinib maintenance was permitted in the placebo arm at disease progression.

The median patient age was 60 years (range, 39-77 years). The majority of patients (76.5%) completed 6 cycles of chemotherapy; 26% received cisplatin and 74% received carboplatin. Among patients with a complete or partial response (n = 78), 34 patients (44%) received prophylactic cranial irradiation 4 to 6 weeks after completing chemotherapy.

Patients completed a median of two cycles of maintenance therapy (range, one to 17 cycles). In the sunitinib arm, 68% of patients completed 1 to 4 cycles, while 23% completed 5 to 8 cycles. Four patients (9%) completed 9 or more cycles of sunitinib maintenance. The crossover rate was high, with 40% of patients in the placebo group initiating sunitinib following disease progression.

Improved Progression-Free Survival

The CALGB 30504 trial met its primary endpoint of improved progression-free survival after chemotherapy with maintenance sunitinib. The median progression-free survival was 3.77 months in the sunitinib maintenance group, compared with 2.30 months in the placebo group (HR, 1.53; P = 0.037).

Despite the high crossover rate, maintenance sunitinib showed a trend toward improved overall survival compared with placebo. The median overall survival was 8.95 months in the sunitinib group and 6.89 months in the placebo arm (HR, 1.17; P = 0.27).

Evidence of Single-Agent Activity

An analysis of tumor size before and after crossover to sunitinib in six patients with disease progression in the placebo group also demonstrated the single-agent antitumor activity of sunitinib. In the 6 to 12 weeks prior to crossover, the tumors were exhibiting rapid growth. Following crossover to sunitinib, tumor growth slowed in each case, and some tumors decreased in size.

In another case, the pattern of tumor response during chemotherapy and maintenance provided additional support for single-agent activity with sunitinib. The patient showed a partial response to chemotherapy, which plateaued between cycles 4 and 6, but converted to a complete response during sunitinib maintenance. The complete response was maintained without progression for 15 cycles (45 weeks) of maintenance therapy.

Safety Findings

Maintenance sunitinib appeared safe and feasible at this dose. During maintenance, 46.5% of patients in the sunitinib group reported at least 1 grade 3/4 adverse event, compared with 19.5% of patients in the placebo group. The most common grade 3/4 adverse events during sunitinib maintenance were fatigue (19%), neutropenia (14%), leukopenia (7%), thrombocytopenia (7%), and hyponatremia (5%). Grade 4 events included gastrointestinal hemorrhage (n = 1) and pancreatitis (n = 1).

Next Steps

A biomarker analysis of blood samples is being planned, with the goal of identifying prognostic and predictive markers that may guide the selection of patients for maintenance therapy. A randomized phase III trial is being proposed to test the hypothesis that maintenance sunitinib after standard chemotherapy improves survival in patients with extensive-stage SCLC.

Dr. Ready explained the rationale for additional studies of maintenance sunitinib. “We felt that the [phase II] results were consistent with the hypothesis that there could be a 2-month or more improvement in overall survival with maintenance sunitinib in this setting. We feel that it is reasonable to consider a phase III trial to test that hypothesis,” Dr. Ready said.

Source: The oncologist

Current and Future Options for Targeting Activated Kinases in Acute and Chronic Leukemias

Contributors: Anna Azvolinsky, PhD, Anne Jacobson, MPH, CCMEP, CMPP

Tyrosine kinase oncogenes such as BCR-ABL and FLT3 are commonly mutated and activated in acute and chronic myeloid leukemias. The development of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myelogenous leukemia (CML) and provided new treatment options for patients with chronic myeloproliferative neoplasms and acute leukemias. In a special session at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on the role of targeted therapy in acute and chronic leukemias, experts discussed the current clinical issues and future opportunities associated with the targeted inhibition of aberrant signaling pathways that drive the development and progression of these malignancies.

Chronic Myelogenous Leukemia

Resistance to BCR-ABL-targeted therapy in patients with CML arises through an array of potential mechanisms, ranging from non-specific multidrug resistance to inherent BCR-ABL genetic alterations. Michael J. Mauro, MDof the Knight Cancer Institute, Oregon Health & Science University, in Portland, Oregon, discussed targeted approaches to managing treatment resistance in patients with CML.

In 2001, the approval of imatinib, the BCR-ABL kinase inhibitor, launched a new area of targeted therapy for CML. Imatinib has been so successful that it has grown to become the targeted therapy all other therapies want to emulate—oncologists often aspire to finding the “imatinib” of other cancer types. As of 2013, five targeted agents are currently available for CML, including two agents, bosutinib and ponatinib, that joined the salvage treatment armamentarium in 2012.

After more than a decade of experience with imatinib in CML, the oncology community has gained critical insight about the development and progression of treatment resistance, with potential implications for other targeted therapies. Importantly, resistance to imatinib is a function both of time and disease volume. Early reduction of disease burden is associated with the reduction or elimination of unstable clones, leading to a reduction in the risk of relapse. Timely cytogenetic and molecular response is a strong predictor of functional cure, which is defined as the absence of meaningful proliferation even after treatment is stopped.

Options for patients who show early resistance to imatinib (e.g., BCR-ABL/ABL >10% at 3 months) include switching to another tyrosine kinase inhibitor based on mutational analysis, evaluating candidacy for stem cell transplant, or referring the patient to a clinical trial. Ongoing trials will evaluate the utility of various approaches to early resistance, including immediate versus delayed switch to an alternate targeted regimen. Treatment selection is further individualized based on a tolerability profile and likelihood of treatment adherence. Among current options, nilotinib, dasatinib, and bosutinib are proven salvage options with promising activity in the front-line setting. Ponatinib also represents a compelling salvage option, particularly for patients with heavily pretreated CML who have stopped responding to all other therapies. A phase III trial comparing ponatinib with imatinib in patients with newly diagnosed chronic-phase CML is currently underway.

Chronic Myeloproliferative Neoplasms

Targeted therapy is rapidly changing the treatment landscape for chronic myeloproliferative neoplasms, including primary myelofıbrosis (MF), essential thrombocytopenia (ET), and polycythemia vera (PV). Following the identification of the JAK2V617F mutation in 2005, the first JAK1/2-targeted therapy was approved just six years later, in 2011. Claire Harrison, DM of the NHS Foundation Trust in the UK, discussed the current standard of care for primary MF, post-ET/PV MF, and other myeloproliferative neoplasms in the era of JAK1/2 inhibitor therapy.

Ruxolitinib was the first oral, selective JAK1/2 inhibitor approved for the treatment of intermediate- and high-risk MF, based on substantial reduction in spleen size and improvements in other constitutional symptoms and quality of life in the phase III COMFORT-1 and COMFORT-2 trials. To date, treatment with ruxolitinib has not resulted in any molecular remissions, although there is hope for the concept of a ‘cure’ with targeted therapy alone. In current practice, allogeneic hematopoietic stem cell transplant is the only curative treatment for patients with MF. Other limitations of current systemic treatment options in MF include concerns about the induction of leukemia as well as the inability to reduce late myeloid transformation.

Building on the success of ruxolitinib, other JAK-targeted inhibitors in development include SAR302503, a selective JAK2 inhibitor; pacritinib, an oral, once-daily, highly selective inhibitor of JAK2 and FMS-like tyrosine kinase 3 (FLT3); and CYT387, an oral JAK1/2 inhibitor. Future clinical trials in this setting may focus on regimens designed to improve the hematologic toxicity profile of current JAK1/2 inhibitor therapy or improve treatment efficacy via the use of novel JAK1/2 inhibitors alone or in combination with other targeted agents, such as histone deacetylase (HDAC), phosphatidylinositol 3 (PI3)-kinase, and smoothened pathway inhibitors.

Acute Leukemia

Advances in the molecular profiling of acute leukemia, particularly the role of activating mutations that result in signaling molecule alterations, may introduce new opportunities for targeted therapy. Neil Shah, MD, PhD of the University of California, San Francisco, discussed the evolving rationale for kinase inhibition in the treatment of acute leukemia.

Acute leukemia is frequently associated with activating mutations in signaling molecules. Kinase inhibitors provide an effective, well-tolerated tool to substantially reduce the burden of disease and, when combined with chemotherapy, improve cure rates in patients with acute myeloid leukemia (AML). The number of possible combination regimens with other targeted agents is growing as novel pathway inhibitors are being developed. Performing detailed molecular analyses of tumor samples is becoming more feasible, and promises to facilitate the personalized selection of rational targeted therapies and combination regimens in the near future.

Several kinase inhibitors are in development for AML, but early stage results lag behind the advances seen in the CML setting. Many of the targeted multikinase inhibitors currently under development in AML may have a role as bridge therapy, providing patients the time to transition to a potentially curative stem cell transplant.

The key obstacle in the development of targeted agents for AML is a lack of a known dominant driver mutation. The most common mutation appears to be a tandem repeats of the activating mutations of the FLT3 receptor tyrosine kinase in about a quarter of patients. Agents such as quizartinib and crenolanib are in clinical trials, but rapid relapse is common. “FLT3 may be a passenger rather than a driver mutation [in AML] and not worth targeting,” saidDr. Shah. Inhibitors of KIT, JAK2, mTOR, and MEK are also under evaluation in AML, but their potential antitumor activity in patients who do not harbor mutated kinases is unknown.

Incorporating next-generation molecular sequencing tools into studies of targeted therapeutics will advance the use of personalized treatment in acute leukemia. Continued participation of patients with AML and other malignancies in clinical trials is strongly encouraged, Dr. Shah said.

Source: The oncologist