Although targeted therapy has made successful inroads in the treatment of non–small-cell lung cancer, similar success has yet to be experienced in small-cell lung cancer (SCLC).
A number of attempts at treating SCLC with targeted therapies have failed, but now there is a glimmer of hope, with positive results from a phase 2 clinical trial with sunitinib (Sutent, Pfizer).
Sunitinib, a vascular endothelial growth factor tyrosine kinase inhibitor, is currently approved for use in the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumors.
The new results with sunitinib in SCLC were published onlineMarch 2 in the Journal of Clinical Oncology. The results support further study of this approach, say the researchers, who suggest that a next step would be another phase 2 trial, this time with overall survival as an endpoint.
However, in an acompanying editorial, Natasha Leighl, MD, of the Princess Margaret Cancer Center, Toronto, Canada, cautions that there has been quite a list of failures in SCLC. She notes that previous clinical trial experience suggests that even after a positive phase 2 trial, the chances of a successful phase 3 trial are only 28%.
"Will sunitibib be the next advance in the treatment of SCLC or just another blind alley? There is only one way to find out," she writes in the editorial.
Patients With Extensive-Stage SCLC
The Cancer and Leukemia Group B (CALGB) 30504 (ALLIANCE) study enrolled 144 patients with extensive stage (ES) SCLC, which is characterized by extrathoracic metastatic disease, malignant pleural effusion, contralateral supraclavicular adenopathy, or contralateral hilar adenopathy.
All patients were first treated with cisplatin or carboplatin and etoposide on days 1 through 3 every 3 weeks for four to six cycles. Patients achieving a complete response (CR) or a partial response (PR) then went on to receive prophylactic cranial irradiation (PCI), the standard of care in SCLC.
Patients who achieved a CR, a PR, or stable disease (SD) were randomly assigned in a double-blinded manner to maintenance sunitinib (a loading dose of 150 mg on day 1, then 37.5 mg daily) or placebo. Maintenance therapy was initiated anytime between week 3 and week 8 after day 1 of the last chemotherapy cycle.
Patients who experienced disease progression while receiving placebo were allowed to receive open-label sunitinib.
CALGB 30504 was initiated in 2007 and closed in 2011. Of 144 patients enrolled, 138 received induction chemotherapy; 95 of these patients experienced at least SD; 10 did not receive maintenance therapy. Of the remaining 85 patients, 41 were randomly assigned to placebo, and 44 were randomly assigned to maintenance sunitinib. Median follow-up was 17.2 months. Forty-three percent of patients responding to chemotherapy received PCI.
Efficacy and Safety of Maintenance Sunitinib
The results show that PFS was significantly longer for patients receiving maintenance sunitinib: 3.7 months vs 2.1 months for those receiving placebo (P = .022). With a hazard ratio of 1.62 (placebo vs sunitinib), patients receiving maintenance sunitinib had a 62% lower risk for progression (95% confidence interval: 1.02 - 2.60).
Median OS was also longer for patients receiving maintenance sunitinib (9.0 months vs 6.9 months for placebo); however, OS did not achieve significance (P = 0.16); 1-year OS was 63% for patients receiving sunitinib and 44% for those receiving placebo.
Single-agent maintenance sunitinib showed activity in SCLC, the researchers note. Three (7%) patients in the sunitinib arm converted to a CR after initiating maintenance sunitinib. Disease control rate (CR+PR+SD) was higher for patients receiving sunitinib (50% vs 37% for placebo) during maintenance treatment.
Of the 41 patients receiving maintenance placebo, 44% crossed over to sunitinib following progression; of 13 evaluable patients from the crossover arm, 10 (77%) achieved SD.
Adverse events of grade 3 or greater were more frequent in patients receiving sunitinib maintenance: 54% vs 32% for those receiving placebo. Adverse events of 5% or greater frequency occurring with sunitinib were fatigue (19%), decreased neutrophil count (14%), decreased leukocytes (7%), and decreased platelets (7%). Grade 4 events with maintenance sunitinib included GI hemorrhage (one patient), thrombocytopenia (one patient), and pancreatitis, hypocalcemia, and elevated lipase (one patient). Twenty-one of 43 patients receiving maintenance sunitinib had dose modifications.
Evidence That Sunitinib Has Activity in SCLC
Corresponding author Neal E. Ready, MD, PhD, associate professor of medicine at the Duke University Medical Center, Durham, North Carolina, told Medscape Medical News: "This study provides evidence that the sunitinib — a vascular endothelial growth factor receptor [VEGFR] inhibitor — has activity in SCLC."
He indicated that three patients achieved a CR with maintenance sunitinib, indicating that sunitinib may have "hit" a driver mutation in this subset of patients. "Trying to understand the driver mutations requires tissue for correlative studies. We have requested tissue samples of these patients," Dr Ready told Medscape Medical News. Next-generation sequencing of these tissue samples, if available, will hopefully provide clues to driver mutations in SCLC, he noted.
Dr Ready indicated that the ALLIANCE investigators undertook a secondary analysis that showed that patients who received PCI benefited most with maintenance sunitinib. This analysis is being prepared for publication, he told Medscape Medical News.
He also pointed out that maintenance sunitinib was less toxic than sunitinib in the relapsed setting. Sunitinib-related grade 3/4 toxicities occurred in 46% of patients receiving maintenance sunitinib, but such toxicities occurred in 90% of patients receiving placebo who crossed over to sunitinib on disease progression, Dr Ready indicated. "In the relapsed setting, these agents may not be tolerated, and chemotherapy has less activity in the relapsed setting," he said.
Challenges in Advancing Treatment Options in SCLC
Dr Leighl notes in the editorial that there have been a number of failed clinical trials of antiangiogenic agents in SCLC, including SALUTE (bevacizumab in ES SCLC), the French Intergroup IFCT-0802 (bevacizumab in ES SCLC), a phase 2 SWOG (aflibercept in limited and ES SCLC), and an NCIC Clinical Trials Group (vandetinib in limited and ES SCLC).
These studies, which used inhibitors of the VEGF/VEGFR, showed either excessive toxicities or lack of clinical benefit. Most were done in the setting of relapsed SCLC.
"Targeted agents have less activity in the second-line and third-line relapsed setting of SCLC. While SCLC is sensitive to initial treatment, relapsed SCLC has acquired multidrug resistance," Dr Ready told Medscape Medical News.
Given that half the patients required sunitinib dose reduction in CALGB 30504, Dr Leighl discussed the possibility of dose reduction to 25 mg daily, which may be better tolerated and has shown activity when used as maintenance after irinotecan/carboplatin in ES SCLC. However she did caution that lowering the dose of antiangiogenic agents (eg, cediranib) to improve tolerability has failed in other lung cancer trials
Although Dr Ready indicated that lowering the maintenance dose of sunitinib to 25 mg daily was a possibility, he was optimistic that an alternate strategy may provide clinical benefits with less toxicity — starting maintenance therapy at a priming dose of 25 mg and increasing it to the 37.5 mg therapeutic dose in patients who show no toxicity — an approach that is the standard of care in thyroid cancer.
"The CALGB 30504 study also showed that a potential paradigm for treating patients may be chemotherapy followed by PCI and maintenance sunitinib," he said.
Why Is SCLC Treatment So Challenging?
When asked why advancing treatments in SCLC has proved so challenging, Dr Leighl told Medscape Medical News: "I think our understanding of isolated drivers of SCLC remains limited. Thus, I think a greater understanding of the pathobiology and functional drivers of SCLC is critical for us to better target therapy."
There are ongoing studies of checkpoint inhibitors in SCLC, including drugs such as ipilumumab targeted with chemotherapy (in phase 3 trial with first-line etoposide/platinum chemotherapy) and PD-1 checkpoint inhibitors, she added.
She also indicated that a better understanding of the biology of SCLC and greater investment from drug manufacturers would advance treatment options in SCLC.
In her own practice, Dr Leighl treats patients with ES SCLC with etoposide/platinum and considers thoracic radiation; if the patient has a response or has stable disease and is well after initial therapy, she considers prophylactic cranial irradiation.
"If there are trials available, these are an excellent opportunity for patients," Dr Leighl told Medscape Medical News.
Several CALGB investigators report ties to industry. Dr Leighl reports no relevant financial relationships.
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