Jason Broderick

Sprycel (dasatinib), an oral medication that helps reduce the production of damaged white blood cells in the body, has been approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The approval is based on results with Sprycel demonstrated in 97 pediatric patients with CP-CML enrolled across two studies, an open-label, nonrandomized, single-arm phase 2 trial and an open-label, nonrandomized, dose-ranging phase 1 trial. Fifty-one patients (all from the single-arm trial) were newly diagnosed, and the remaining 46 (29 from the single-arm study and 17 from the dose-ranging trial) were intolerant or resistant to prior Gleevec (imatinib).

At a median follow-up of 4.5 years, more than half of the responding patients in the treatment-naïve cohort had not progressed at the time of the data cutoff, so the median duration of complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and major molecular response (MMR) could not be estimated. The same was true at the median follow-up time of 5.2 years for the previously treated cohort.

The range of duration of response (DOR) for the newly diagnosed patients was 2.5+ to 66.5+ months for CCyR, 1.4 to 66.5+ months for MCyR, 5.4+ to 72.5+ months for patients who achieved MMR by month 24, and 0.03+ to 72.5+ months for patients who achieved MMR at any time. The ‘+’ denotes a censored observation. Among the Gleevec-intolerant cohort, the DOR ranges were 2.4 to 86.9+ months for CCyR, 2.4 to 86.9+ months for MCyR, and 2.6+ to 73.6+ months for MMR.

“Options for pediatric patients with chronic myeloid leukemia are limited, and it is challenging to conduct clinical trials investigating potential new treatments in this small patient population,” Lia Gore, M.D., University of Colorado School of Medicine and Children’s Hospital Colorado, said in a statement. “Dasatinib is an important new option to help address the unmet needs of children with Philadelphia chromosome-positive CML in chronic phase.”

The 3-, 6-, 12- and 24-month CCyR rates among newly diagnosed patients were 43.1 percent, 66.7 percent, 96.1 percent and 96.1 percent, respectively. In the previously treated group, the corresponding rates were 45.7 percent, 71.7 percent, 78.3 percent and 82.6 percent, respectively.

The 3-, 6-, 12- and 24-month MCyR rates among treatment-naive patients were 60.8 percent, 90.2 percent, 98.0 percent and 98.0 percent, respectively. The corresponding rates in the Gleevec-intolerant group were 60.9 percent, 82.6 percent, 89.1 percent and 89.1 percent, respectively.

The 3-, 6-, 12- and 24-month MMR rates among newly diagnosed patients were 7.8 percent, 31.4 percent, 56.9 percent and 74.5 percent, respectively. The corresponding rates in the previously treated group were 15.2 percent, 26.1 percent, 39.1 percent and 52.2 percent, respectively.

Across both patient groups, 14.4 percent experienced treatment-related serious adverse events (AEs). AEs occurring in 15 percent or more of patients included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity and abdominal pain.

“While chronic myeloid leukemia is rare in children, accounting for less than three percent of all pediatric leukemias, it is often more aggressive in younger patients than in adults and until recently, there have been few available treatment options,” Vickie Buenger, President, Coalition Against Childhood Cancer, said in a statement. “The FDA’s decision to approve the expanded use of Sprycel in children with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase may bring new hope to these patients and their families.”

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Sprycel (dasatinib), an oral medication that helps reduce the production of damaged white blood cells, has been approved by the Food and Drug Administration for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.
 

Sprycel Approved for CML Subset

The FDA has granted an accelerated approval to Tecentriq (atezolizumab) as a frontline treatment for patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin chemotherapy. The approval was announced by Genentech, the immunotherapy drug’s manufacturer.

“It is encouraging to see continued progress in the treatment of advanced bladder cancer, which until last year had not seen any major advancements in more than 30 years,” said Andrea Maddox Smith, chief executive officer, Bladder Cancer Advocacy Network. “We are excited that Tecentriq is now a treatment option for people with advanced bladder cancer who are unable to receive a cisplatin-based chemotherapy as an initial treatment.”

The approval is based on data from the single-arm phase II IMvigor210 trial. In a study cohort of 119 cisplatin-ineligible, treatment-naive patients, the objective response rate with Tecentriq was 23.5 percent, including a complete response rate of 6.7 percent.

Tecentriq was previously approved for people with locally advanced or mUC who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of receiving chemotherapy before surgery or after surgery.

“We are pleased that Tecentriq will now be available to more people with advanced bladder cancer, including those who are unable to receive initial treatment with cisplatin chemotherapy,” said Sandra Horning, MD, chief medical officer and head of Global Product Development at Genentech.

“Tecentriq was the first cancer immunotherapy approved by the FDA for people with advanced bladder cancer and has become a standard of care in those whose disease has progressed after receiving other medicines, either before or after surgery, or after their disease has spread.”

The IMvigor210 cohort enrolled 123 patients with cisplatin-ineligible locally advanced or mUC at 47 locations in North America and Europe between June 9, 2014, and March 30, 2015. Patients received 1200 mg of intravenous Tecentriq every three weeks until progression. The primary endpoint was objective response rate, with secondary outcomes measures including progression-free survival and overall survival.

Among the 123 patients, 119 received at least one dose of Tecentriq. Responses occurred regardless of PD-L1 status and across poor prognostic factor subgroups. The median duration of response was not reached. There was an association between tumor mutation load and response. The median progression-free survival was 2.7 months and overall survival was 15.9 months.

The most common grade 3/4 adverse events included fatigue (8 percent), urinary tract infection (5 percent), anemia (7 percent), diarrhea (5 percent), increase in the level of creatinine in the blood (5percent), increase of the liver enzyme alanine transaminase (4 percent), hyponatremia (15percent), decreased appetite (3 percent), and back/neck pain (3 percent).

Adverse events led to 5 patients discontinuing treatment. Five patients died, due to sepsis, cardiac arrest, myocardial infarction, respiratory failure, and respiratory distress. An additional patient had inflammation of the brain due to the herpes simplex virus and disease progression at the time of death.

The accelerated approvals of Tecentriq are contingent on results from an ongoing confirmatory phase III study, IMvigor 211 (NCT02302807), which is comparing Tecentriq with chemotherapy in patients with locally advanced or metastatic urothelial bladder cancer in the frontline setting and after progression on at least one prior platinum-containing regimen.

The FDA has granted an accelerated approval to Tecentriq as a frontline treatment for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy.

Tecentriq Approved as First-Line Treatment for Some Patients With Bladder Cancer

The PALOMA-3 trial examining an Ibrance (palbociclib) regimen in HR-positive/HER2-negative breast cancer was halted after an independent panel determined it met the primary endpoint of improving progression-free survival (PFS). The results were announced by Pfizer, the company developing Ibrance, which noted that these are the first randomized phase 3 data reported for the CDK 4/6 inhibitor.

“We’re gratified to be able to stop the trial early and are engaging in discussions with health authorities regarding a regulatory path forward,” Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology, said in a statement.

The multicenter PALOMA-3 study randomized 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment in a 2:1 ratio to fulvestrant plus either placebo or Ibrance. Faslodex was administered at 500 mg (IM) on days 1 and 15 of cycle 1, and then on day 1 of each cycle thereafter, and patients received oral Ibrance at 125 mg/day continuously for the first 3 weeks of each cycle, followed by 1 week off. Treatment cycles were 28 days for both arms.

Beyond the primary PFS endpoint, secondary endpoints for the trial included overall survival, objective response, and duration of response. The adverse events reported for the Ibrance/fulvestrant combination were commensurate with those observed with previous single-agent use of the drugs. Pfizer intends to submit the full results from the study for presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting in June.

While not approved for the use explored in PALOMA-3, Ibrance has received an accelerated approval as a frontline treatment for postmenopausal women with ER-positive, HER2-negative metastatic breast cancer, based on findings from the phase 2 PALOMA-1 trial.

In the open-label phase 2 study, treatment with Ibrance plus letrozole reduced the risk of disease progression by 51 percent compared with letrozole alone. The median PFS with Ibrance was 20.2 versus 10.2 months for letrozole alone.

PALOMA-1 trial randomized 165 postmenopausal patients with ER-positive, HER2-negative advanced breast cancer in a 1:1 ratio in two parts: Part 1 contained 66 patients and Part 2 had 99 patients. Continuous daily letrozole was administered at 2.5 mg with or without Ibrance at 125 mg daily for 3 weeks followed by 1 week of rest until progression. The primary endpoint was PFS by investigator assessment.

The rate of grade 3/4 neutropenia was significantly higher in the Ibrance arm compared with letrozole alone (54 percent versus 1 percent). Additionally, the rate of grade 3/4 leucopenia (19 percent versus 0 percent) and fatigue (4 percent versus 1 percent) were higher with Ibrance. No cases of febrile neutropenia or neutropenia-related infections were reported in the study.

Altogether, 13 percent of patients discontinued treatment as a result of side effects in the Ibrance arm compared with 2 percent for letrozole. The most frequently reported serious adverse events with the combination were pulmonary embolism (4 percent) and diarrhea (2 percent).

At the time of approval, PALOMA-1 coauthor Dennis Slamon heralded the decision. “With the FDA approval, this study represents a potential practice-changing result. I believe palbociclib will now become a standard treatment approach for postmenopausal women with ER+/HER2- metastatic breast cancer,” Slamon, a professor of medicine and director of the Revlon/UCLA Women’s Cancer Research Program, said in a statement.

The confirmatory phase 3 trial for Ibrance's accelerated approval is PALOMA-2. This study is comparing the combination of Ibrance and letrozole with letrozole alone as a frontline treatment for postmenopausal women with ER-positive, HER2-negative advanced breast cancer (NCT01740427).

As Pfizer awaits the PALOMA-2 data, Rothenberg noted that the company is pleased with what the PALOMA-3 outcomes have shown. “The results of this trial are especially important because they help us understand the potential of Ibrance to improve outcomes in patients with this difficult to treat cancer.”

The PALOMA-3 trial examining an Ibrance (palbociclib) regimen in HR-positive/HER2-negative breast cancer was halted after an independent panel determined it met the primary endpoint of improving progression-free survival.

Ibrance Delays Progression of Breast Cancer in Phase 3 Trial

Kyprolis (carfilzomib) doubled progression-free survival (PFS) versus Velcade (bortezomib) in patients with relapsed multiple myeloma in the phase 3 ENDEAVOR trial. The results were announced by the developer of Kyprolis, Amgen, and its subsidiary Onyx Pharmaceuticals, Inc.

The head-to-head ENDEAVOR study randomized 929 patients with relapsed multiple myeloma to low-dose dexamethasone plus Kyprolis or Velcade. At a planned interim analysis, the trial met its primary endpoint with a significant improvement in PFS with Kyprolis: 18.7 versus 9.4 months.

Enrolled patients were required to have received between one and three previous treatment regimens. The international trial was conducted at 235 locations.

Treatment with Kyprolis reduced the risk of disease progression by 47 percent versus Velcade. Results were also superior with Kyprolis for the secondary outcome measures of overall response rate (ORR) and lower incidence of neuropathy. Data for overall survival (OS) have not yet matured.

Adverse event (AE)—induced treatment discontinuations and on-study deaths were similar between the two treatment groups. The rates for cardiac and renal failure were higher in the Kyprolis arm versus the Velcade arm. These rates were comparable to those reported in the pivotal phase 3 ASPIRE study, which examined Kyprolis, Revlimid (lenalidomide) and low-dose dexamethasone versus Revlimid, and low-dose dexamethasone alone in 792 patients with relapsed multiple myeloma.

The frequency of dyspnea and hypertension in the Kyprolis versus the Velcade arm in ENDEAVOR increased compared with the incidents reported in ASPIRE. 

Amgen intends to submit full data for ENDEAVOR for presentation at the 2015 ASCO Annual Meeting this summer.

The Food and Drug Administration (FDA) granted an accelerated approval to Kyprolis in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including Velcade and an immunomodulatory agent. This indication was based on data from a single-arm clinical trial that enrolled 266 patients with relapsed multiple myeloma who received at least two prior therapies. In this study, the ORR with Kyprolis was 22.9 percent. As a condition of the approval, Onyx was required to submit a full analysis from the ASPIRE trial.

Earlier this year, a supplemental New Drug Application was submitted to the FDA for the full regulatory approval of Kyprolis as a treatment for patients with relapsed multiple myeloma based on the results from ASPIRE. Early results from the study were announced in August 2014. Keith Stewart, from the Mayo Clinic in Scottsdale, Ariz., presented full data from the trial at the 2014 annual meeting of the American Society for Hematology held in December.

ASPIRE found that the combination of Kyprolis, Revlimid and low-dose dexamethasone reduced the risk of progression by 31 percent compared with Revlimid and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The median PFS with Kyprolis was 26.3 months compared with 17.6 months without the proteasome inhibitor.

At the 24-month interim analysis, 73.3 percent of patients in the Kyprolis arm were alive versus 65 percent with the two-drug regimen. The median overall survival was not yet reached with a trend favoring the carfilzomib arm.

The ORR was 87.4 percent versus 66.9 percent and the median duration of response was 28.6 months compared with 21.2 months with and without Kyprolis, respectively. Of patients who responded, the complete response rate was 17.7 percent with Kyprolis versus 5.1 percent without and the very good partial response rate was 70.4 percent with Kyprolis versus 40.7 percent in the control arm.

Treatment discontinuation due to an adverse event occurred in 15.2 percent of patients treated with Kyprolis compared with 17.4 percent with the two-drug regimen.

The most common severe hematologic adverse events with Kyprolis compared with the control arm were neutropenia, anemia and thrombocytopenia. The most common severe nonhematologic side effect was pneumonia.

For the three-drug regimen versus the two-drug regimen, respectively, all-grade acute renal failure occurred in 8.4 percent of patients versus 7.2 percent, cardiac failure was seen in 6.4 percent of patients versus 4.1 percent, and ischemic heart disease was experienced by 5.9 percent of patients compared with 4.6 percent.

ENDEAVOR is the first of two phase 3 trials comparing Kyprolis head-to-head with Velcade in multiple myeloma. Results are still anticipated for the CLARION study, in which the two drugs, in combination with melphalan and prednisone, are being compared in the frontline setting (

Kyprolis doubled progression-free survival versus Velcade in patients with relapsed multiple myeloma in the phase 3 ENDEAVOR trial. 

Author | Jason Broderick

Sprycel Approved for CML Subset

Tecentriq Approved as First-Line Treatment for Some Patients With Bladder Cancer

Ibrance Delays Progression of Breast Cancer in Phase 3 Trial

Kyprolis Doubles Progression-Free Survival Over Velcade in Multiple Myeloma Trial