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American Society of Clinical Oncology 2017
This year’s annual meeting of the American Society of Clinical Oncology (ASCO) hosted approximately 38,000 oncology professionals from June 1–5 in Chicago. We review below key sessions on prostate cancer, non–small-cell lung cancer, and hepatocellular carcinoma.
LATITUDE: A Phase 3, Double-Blind, Randomized Trial of Androgen Deprivation Therapy With Abiraterone Acetate Plus Prednisone or Placebo In Newly Diagnosed High-Risk Metastatic Hormone-Naïve Prostate Cancer Patients
Mortality risk was reduced in the phase 3 LATITUDE trial among men with high-risk, newly diagnosed metastatic prostate cancer when abiraterone acetate (Zytiga, Janssen Biotech) and prednisone were added to androgen deprivation therapy (ADT). While docetaxel plus ADT has been the standard of care for patients with metastatic prostate cancer and high metastatic burden since 2015, abiraterone is much easier to tolerate than docetaxel, Dr. Fizazi said. He noted that patients with newly diagnosed, metastatic, hormone-naïve prostate cancer have a poor prognosis, especially in the presence of high-risk characteristics. Among men with newly diagnosed prostate cancer, about 3% in the United States and up to about 60% in the Asia–Pacific region have metastatic disease.
LATITUDE included men with two or more high-risk features (Gleason score of 8 or higher, three or more bone lesions, and measurable visceral disease) and randomized them to ADT plus 1,000 mg abiraterone acetate once daily plus prednisone 5 mg once daily (n = 597) or ADT plus placebo (n = 602). The trial, conducted at 235 sites in 34 countries in Europe, Asia–Pacific, Latin America, and Canada, had overall survival (OS) and radiographic progression-free survival (PFS) as its primary efficacy endpoints.
Dr. Fizazi reported that OS was 66% in the group receiving abiraterone and 49% in the placebo group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.51–0.76; P < 0.0001). Radiographic PFS was 33.0 months in the abiraterone group and 14.8 months in the placebo group (HR, 0.47; 95% CI, 0.39–0.55; P < 0.0001). Improvements in the secondary endpoints (time to prostate-specific antigen progression, pain progression, next symptomatic skeletal event, chemotherapy, or subsequent prostate cancer therapy) for the abiraterone group were all highly significant.
Grade 3–4 hypertension, hypokalemia, aspartate transaminase increases, alanine transaminase increases, and cardiac disorders were reported more often in the abiraterone group than in the placebo group. These adverse events, Dr. Fizazi noted, were consistent with those reported in prior studies among patients in this population.
“The benefit from early use of abiraterone we saw in this study is at least comparable to the benefit from docetaxel chemotherapy, which was observed in prior clinical trials, but abiraterone is much easier to tolerate, with many patients reporting no side effects at all,” Dr. Fizazi concluded.
ASCO discussant Sumanta Kumar Pal, MD, said: “This is good news because using abiraterone could help many people live longer with fairly few additional side effects.”
Dacomitinib Versus Gefitinib for the First-Line Treatment of Advanced EGFR-Mutation–Positive Non–Small-Cell Lung Cancer: A Randomized, Open-Label Phase 3 Trial
Dacomitinib (Pfizer), an investigational second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), may offer a new option for the management of advanced EGFR-mutated non–small-cell lung cancer (NSCLC). The ARCHER 1050 trial results showed longer progression-free survival (PFS) and duration of response (DOR) for dacomitinib than for gefitinib (Iressa, AstraZeneca), the standard first-generation EGFR TKI. Dr. Mok noted at an ASCO press conference that dacomitinib is characterized by irreversible inhibition of EGFR (also known as human epidermal growth factor receptor 1 or HER1), HER2, and HER4.
The primary endpoint in the open-label phase 3 ARCHER 1050 trial was PFS by blinded independent review. The trial compared oral dacomitinib 45 mg once daily (n = 227) and oral gefitinib 250 mg once daily (n = 225) as first-line treatment for advanced NSCLC with EGFR-activating mutations.
Dr. Mok reported that median PFS was 14.7 months in the dacomitinib arm and 9.2 months in the gefitinib arm (hazard ratio, 0.59; 95% confidence interval, 0.47–0.74; P < 0.0001). PFS rate curves separated quickly at about six months between the two treatment arms, and at 24 months were 30.6% for dacomitinib and 9.6% for gefitinib. While objective responses were observed for a similar proportion of patients (74.9% for dacomitinib versus 71.6% for gefitinib), median DOR was 14.8 months for dacomitinib and 8.3 months for gefitinib (P < 0.0001). Overall survival data, he noted, are not yet mature.
The incidence of adverse events was greater for dacomitinib compared with gefitinib. Dose reduction rates were 66.1% for dacomitinib and 8.0% for gefitinib, with reductions occurring sooner and lasting longer with dacomitinib. With dacomitinib, the most common severe (grade 3) events were acne in 14% of patients and diarrhea in 8% of patients. Liver enzyme abnormalities, the most common severe (grade 3) side effect of gefitinib, were reported in 8% of patients. Dr. Mok commented that dacomitinib shares the issue of increased side effects of the skin and gastrointestinal tract seen with afatinib (Gilotrif, Boehringer Ingelheim), a second-generation agent already approved by the Food and Drug Administration. “In spite of this, the activity seen in this study should allow for consideration of this effective therapy in this patient population,” he said. Dr. Mok concluded that dacomitinib is a more potent EGFR inhibitor.
ASCO expert discussant John Heymach, MD, PhD, commented further: “It’s been nearly 15 years since EGFR-targeted therapies were introduced, helping extend survival for thousands of patients in the time since. The second generation of these therapies is more effective, but can also cause greater side effects, so patients and their doctors will need to weigh the risks and benefits.”
Phase 3 Trial of Lenvatinib Versus Sorafenib In First-Line Treatment of Patients With Unresectable Hepatocellular Carcinoma
In the results of the REFLECT study, lenvatinib (Lenvima, Eisai, Inc.) demonstrated noninferiority for overall survival (OS) versus sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) for patients with advanced unresectable hepatocellular carcinoma (uHCC). Beyond that primary endpoint, lenvatinib was superior to sorafenib in progression-free survival (PFS), time to progression (TTP), and overall response rate (ORR), said Dr. Cheng, the REFLECT lead author, in an oral presentation.
While global phase 3 trials of sunitinib, brivanib (investigational, Bristol-Myers Squibb), linifanib (investigational, Abbott Laboratories), and erlotinib (Tarceva, OSI Pharmaceuticals) plus sorafenib have failed to meet primary endpoints of noninferiority or superiority over the past 10 years in HCC, sorafenib has been the only first-line systemic drug to extend OS. Lenvatinib, an oral multikinase inhibitor, targets vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1, 2, 3, and 4, platelet-derived growth factor-alpha, and RET and KIT oncogene mutations. Lenvatinib is currently approved for use in thyroid cancer and renal cell carcinoma in the United States. It has shown promising clinical activity in prior phase 2 research among advanced HCC patients.
REFLECT investigators enrolled 954 uHCC patients (mean age, 61 years; 85% male), randomizing them 1:1 to lenvatinib dosed according to body weight (60 kg or greater, 12 mg per day; less than 60 kg, 8 mg per day) or sorafenib 400 mg (twice daily). All patients had one or more measurable target lesions, Barcelona Clinic liver cancer stage B or C, Child–Pugh class A liver disease, Eastern Cooperative Oncology Group performance status of 1 or less, and no prior systemic therapy. OS was the primary endpoint.
Although results were not adjusted for duration of treatment, Dr. Cheng reported that median duration of treatment was 5.7 months in the lenvatinib group and 3.7 months in the sorafenib group, with 87.6% and 83.0% of the planned starting doses being delivered in the lenvatinib and sorafenib groups, respectively.
Median OS was similar for the two groups: 13.6 months in the lenvatinib group (95% confidence interval [CI], 12.1–14.9) and 12.3 months in the sorafenib group (95% CI, 10.4–13.9) (overall hazard ratio [HR], 0.92; overall 95% CI, 0.79–1.06). The noninferiority standard had been set at an HR of less than 1.08.
These results were “well below the noninferiority margin. Therefore, lenvatinib met its primary endpoint of noninferiority to sorafenib,” Dr. Cheng said. OS trends favored lenvatinib across all subgroups with the exception of neutral findings in the Western population (non-Asia–Pacific) and those with macrovascular invasion or extrahepatic spread.
PFS by modified RECIST criteria, a secondary endpoint, also favored lenvatinib at 7.4 months versus 3.7 months for sorafenib (HR, 0.66; P < 0.00001). PFS was extended with lenvatinib in all subgroups. TTP estimates favored lenvatinib similarly at 8.9 months versus 3.7 months for sorafenib (HR, 0.63; P < 0.00001).
Among additional secondary endpoints, the ORR (complete plus partial responses) for lenvatinib was 24.1% versus 9.2% for sorafenib (odds ratio, 3.13; 95% CI, 2.15–4.56; P < 0.00001). Progressive disease rates were 14.9% for lenvatinib and 30.9% for sorafenib, and disease control rates (complete plus partial response plus stable disease) were 75.5% for lenvatinib and 60.5% for sorafenib.
Dr. Cheng noted that higher levels of baseline alpha-fetoprotein (AFP) are associated with poor outcomes in HCC patients. A REFLECT analysis stratified according to AFP levels of less than 200 ng/mL or 200 ng/mL or greater confirmed that higher levels of AFP were associated with less favorable outcomes. In the patients with higher baseline AFP, median OS was 10.4 months for lenvatinib compared with 8.2 months for sorafenib (HR, 0.78).
Dose modification, reduction, or interruption rates for treatment-emergent adverse events were similar for lenvatinib and sorafenib. Serious adverse event rates, however, were higher for lenvatinib (18% versus 10%). Grade 3–4 hypertension was reported at a rate of 23% in the lenvatinib group and at 14% in the sorafenib group. Grade 3–4 skin problems (such as palmar–plantar erythrodysesthesia) were more common in the sorafenib group (3% for lenvatinib versus 11% for sorafenib).
Assessment of health-related quality of life (QOL) as measured through the most recent European Organization for Research and Treatment of Cancer QOL (EORTC QLQ-C30) and the HCC-specific QLQ-HCC18 questionnaires declined similarly (reflecting worsened quality of life) after treatment in both groups. The QLQ-C30 measures for role functioning and for pain and diarrhea, plus a measure of nutrition and body image, both worsened significantly sooner (P < 0.05) in the sorafenib group than in the lenvatinib group.
Tanios Behaii-Saab, MD, of the Mayo Clinic in Phoenix, Arizona, commented on the study results at an ASCO “Highlight of the Day” session: “It’s clear that lenvatinib may become another first-line option for patients with advanced HCC.” He cautioned, however, that lenvatinib is not yet approved for liver cancer and that the measures showing superiority for lenvatinib PFS and ORR were secondary endpoints, limiting the strength of superiority conclusions from the REFLECT data.
Phase 3, Multicenter, Open-Label, Randomized, Controlled Trial of Selective Internal Radiation Therapy Versus Sorafenib in Locally Advanced Hepatocellular Carcinoma: The SIRveNIB Study
The investigator-initiated, open-label, phase 3 SIRveNIB study compared selective internal radiation therapy (SIRT) versus sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals, Inc.) in patients with locally advanced hepatocellular carcinoma (HCC). SIRT with SIR-Spheres yttrium-90 (Y-90) resin microspheres (Sirtex Medical, Inc.) is approved for the treatment of colorectal hepatic metastases and entails a one-time delivery of the microspheres to the liver via the hepatic artery. Sorafenib, an approved oral molecular targeted therapy that requires continuous oral dosing at 400 mg twice daily, was administered in this trial for a median of 13.8 weeks.
Dr. Chow noted that the majority of patients with HCC have locally advanced disease with or without portal vein thrombosis at diagnosis. Those included in the SIRveNIB trial had disease that was not amenable to curative therapies (surgery or transplantation) and had Asian Barcelona Clinic liver cancer stage B and C without extrahepatic metastasis.
“The SIRveNIB rationale was that a definitive phase 3, randomized, controlled trial comparing these two promising therapies in locally advanced HCC would impact on outcomes in a large number of patients and potentially change clinical practice,” Dr. Chow said. The SIRveNIB primary endpoint was overall survival (OS).
SIRveNIB investigators assigned 182 patients to SIRT and 178 to sorafenib. The patients were treated in 27 centers in 11 countries. Mean age overall was approximately 60 years, and about 83% of the patients were men. Fifty-two patients (28.6%) among those randomized to SIRT did not receive the allocated therapy, mostly because of anatomic ineligibility, and 16 patients in the sorafenib group (8.9%) did not receive the allocated therapy.
In the primary intention-to-treat (ITT) analysis, median OS in the SIRT and sorafenib arms was similar at 8.84 months and 10.02 months, respectively (hazard ratio [HR], 1.12; P = 0.360). In the treated population, median OS was 11.27 months for SIRT and 10.41 months for sorafenib (HR, 0.86; P = 0.273). Among secondary endpoints in the ITT population, tumor response rates (TRR) were 16.5% for SIRT and 1.7% for sorafenib (P < 0.001).
For some patients, down-staging of the tumor from “locally advanced” to identical to an “early cancer” after SIRT treatment can be consequential. Tumors once assessed as inoperable become surgery-eligible, and transplantation may also open up as an option. Outcomes for this category of SIRT patients, who are being tested in a subsequent, separate study at 16 centers, are identical to those of patients whose tumors are initially of similar size. “So for this small proportion of patients, this strategy is potentially curative,” Dr. Chow commented. In his surgical center, about 10% of SIRveNIB patients had tumors that were down-staged.
In other ITT secondary endpoints, time to tumor progression (TTP) was 6.08 months for SIRT versus 5.36 months for sorafenib overall (HR, 0.88; P = 0.287) and 6.11 months for SIRT versus 5.39 months for sorafenib for liver progression specifically (HR, 0.87; P = 0.241). Median progression-free survival (PFS) was 5.85 months for SIRT versus 5.06 months for sorafenib overall (HR, 0.89; P = 0.306) and 6.01 months for SIRT versus 5.06 months for sorafenib for liver progression specifically (HR, 0.88; P = 0.259). Advantages for SIRT in the treated population, however, were significant for median TTP overall (P = 0.019), median TTP in the liver (P = 0.013), median PFS overall (P = 0.013), and median PFS in the liver (P = 0.009).
Adverse event rates were significantly lower in the SIRT arm. “For clinicians and patients, this is very important,” Dr. Chow said. Sixty percent of SIRT patients and 84.6% of sorafenib patients had at least one adverse event (P < 0.001). Treatment-related adverse events were reported in 31.5% of SIRT patients and in 74.7% of sorafenib patients (P < 0.0001). Treatment-related grade 3 or higher events occurred in 27.7% of SIRT patients and in 50.6% of sorafenib patients (P < 0.0001). The adverse events occurring significantly more often in the sorafenib arm were diarrhea (P < 0.001), alopecia (P < 0.0001), palmar-plantar erythrodysesthesia (P < 0.0001), rash (P < 0.0001), and hypertension (P < 0.0001).
“Although the study is negative for the superiority primary endpoint … one therapy is clearly less toxic for the patient.” Dr. Chow noted further that SIRT group patients had significantly better TRR, TTP and PFS. “SIRveNIB results can help clinicians and patients make informed treatment choices,” he concluded.