EVEROLIMUS APPROVED FOR ALL GI LOW GRADE NETs

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has newly endorsed two hematologic cancer drugs and one drug for neuroendocrine tumors (NETs). All three drugs now move onto review and possible approval from the European Commission.

CHMP adopted a positive opinion for everolimus (Afinitor,Novartis) for the treatment of unresectable or metastatic, well-differentiated (grade 1 or 2), nonfunctional NETs of gastrointestinal (GI) or lung origin in adults with progressive disease.

There is an unmet need in this setting because there are currently few or no treatment options in Europe for these patients.

Everolimus was approved earlier this year by the US Food and Drug Administration (FDA) for the same use.

The recommendation of everolimus in Europe is based on efficacy and safety data from the pivotal phase 3 RADIANT-4 study, in which everolimus reduced the risk for progression in patients with progressive, well-differentiated, nonfunctional, locally advanced or metastatic NETs of GI or lung origin by 52%, compared with placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35 - 0.67; P < .00001).

Median progression-free survival was 7.1 months longer with everolimus than with placebo (11.0 vs 3.9 months).

The most common treatment-related grade 3/4 adverse events (≥5%) for everolimus and placebo, respectively, were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%), and infections (7.0% vs 0.0%).

The most common treatment-related adverse events of any grade (incidence ≥10%) were stomatitis (63%), diarrhea (31%), fatigue (31%), infections (29%), rash (27%) and peripheral edema (26%).

Recommendations in Hematologic Cancers

CHMP also recommended broadening the existing marketing authorization for ibrutinib (Imbruvica, Janssen/Pharmacyclics) for the first-line treatment of adults with chronic lymphocytic leukemia (CLL).

Ibrutinib is already approved for the treatment of adults with relapsed or refractory mantle cell lymphoma, for the treatment of adults with CLL who have received at least one previous therapy, or for the first-line treatment of patients with a 17p deletion or TP53 mutation who are unsuitable for chemoimmunotherapy. It is also indicated for use in patients with Waldenström's macroglobulinemia.

The new recommendation is based on data from the phase 3 randomized open-label RESONATE-2 trial, which compared ibrutinib with chlorambucil in treatment-naïve patients.

The rate of progression-free survival at 18 months was better with ibrutinib than with chlorambucil (90% vs 52%).

Overall survival was significantly prolonged with ibrutinib (HR, 0.16; CI, 0.05 - 0.56; P = .001). In fact, at 24 months, overall survival was 98% with ibrutinib and 85% with chlorambucil.

The safety of ibrutinib was consistent with previously reported studies.

The most common adverse events (≥20%) of any grade in the RESONATE-2 trial for ibrutinib were diarrhea (42%), fatigue (30%), cough (22%), and nausea (22%).

Ibrutinib was approved by the FDA in March for the first-line treatment of CLL.

Finally, CHMP recommended extending the authorized indication of obinutuzumab (Gazyvaro, Roche) to patients with follicular lymphoma who were previously treated with chemotherapy. Obinutuzumab is to be used in combination with bendamustine.

Obinutuzumab was first approved in Europe in 2014 for use in combination with chlorambucil in patients with previously untreated CLL.

Both follicular lymphoma and CLL affect B-lymphocytes.

The new recommendation is based on the results from a phase 3 trial that compared obinutuzumab in combination with bendamustine (and followed by obinutuzumab as a maintenance treatment) with bendamustine alone in 321 patients with follicular lymphoma who did not respond to or whose disease progressed with chemotherapy.

Median progression-free survival was longer in patients treated with obinutuzumab plus bendamustine than in those treated with bendamustine alone (29 vs 14 months).

The most common adverse effects reported with the combination of obinutuzumab plus bendamustine were consistent with the known safety profiles of the individual medicines.

Obinutuzumab was approved by the FDA for follicular lymphoma earlier this year.