Gregory Masters, MD
ASCO named the vastly improved outlook for patients with chronic lymphocytic leukemia (CLL) as its inaugural “Cancer Advance of the Year.” Specifically, the organization is recognizing the approval of four new therapeutic options for CLL over 2013/2014: obinutuzumab, ibrutinib, ofatumumab, and idelalisib.
The announcement was made as part of ASCO’s release today of its annual update on oncology treatment advances: Clinical Cancer Advances 2015: ASCO's Annual Report on Progress Against Cancer
“These new therapies fill an enormous need for thousands of patients living with CLL,” said Gregory Masters, MD, ASCO expert and co-executive editor of the report, in a statement. “For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle.”
The immunotherapies obinutuzumab (Gazyva) and ofatumumab (Arzerra) are approved in the frontline CLL setting, while the small-molecule inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig) are approved for resistant/relapsed CLL.
The first of these four agents approved over 2013/2014 was the anti-CD20 agent obinutuzumab. In November 2013, the FDA approved the drug in combination with chlorambucil as a first-line treatment regimen for patients with CLL based on data from the phase III CLL11 trial. In the study, the obinutuzumab/chlorambucil combination significantly reduced the risk of progression by 84%, when compared with chlorambucil alone.
The approval came with a Boxed Warning, similar to other monoclonal antibodies in this class, regarding hepatitis B reactivation and progressive multifocal leukoencephalopathy, a rare disorder affecting the brain.
In December 2014, the FDA updated the label for obinutuzumab plus chlorambucil to include data from stage 2 of the CLL11 study, which detailed an unprecedented 11.8-month improvement in progression-free survival (PFS) compared with rituximab (Rituxan) plus chlorambucil as a frontline treatment for patients with CLL (26.7 months vs 14.9 months; HR = 0.42; 95% CI, 0.33-0.54; P
The next new option approved for patients with CLL was the BTK inhibitor ibrutinib in February 2014. The FDA approved the agent for patients with CLL who have received at least one previous therapy. The decision was based on data from 48 patients enrolled in the single-arm phase Ib/II PCYC-1102-CA study. At a median 15.6-month follow-up for this group, single-agent ibrutinib produced an overall response rate (ORR) of 58.3% (all partial responses) with a duration of response of up to 24.2 months.
The most common grade 3/4 nonhematological adverse reactions were pneumonia (8%), hypertension (8%), dehydration (6.4%), atrial fibrillation (6.3%), and sinusitis (6%). Additionally, ibrutinib-related grade 3/4 cytopenias were reported in 35% of patients.
In July 2014, the FDA expanded the approval of ibrutinib to include the treatment of patients with CLL who harbor a 17p deletion, based on findings from the phase III RESONATE trial. In RESONATE, ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab.
The anti-CD20 agent ofatumumab, which received a new indication in April 2014, marked the third new CLL treatment option made available over 2013/2014. The indication is for ofatumumab plus chlorambucil for previously untreated patients with CLL who are considered inappropriate for treatment with the chemotherapy fludarabine. The FDA first approved ofatumumab in October 2009 for the treatment of patients with CLL who no longer respond to chemotherapy.
The new approval was based on results from the phase III COMPLEMENT 1 trial, in which ofatumumab and chlorambucil demonstrated a 9.3-month improvement in PFS compared with chlorambucil alone. The ORR with the combination was 82% versus 69% with chlorambucil alone.
Grade 3/4 adverse events occurred in 50% of patients treated with ofatumumab compared with 43% in the chlorambucil monotherapy arm. The most common grade 3/4 toxicity was neutropenia, which occurred in 26% of patients treated with ofatumumab compared with 14% for chlorambucil alone. Grade 3/4 infusion-related adverse events were reported in 10% of patients treated with ofatumumab compared with none for those receiving chlorambucil alone.
And rounding out the impressive 2013/2014 breakthroughs in CLL care was the July 2014 approval of the PI3K-delta inhibitor idelalisib in combination with rituximab for patients with high-risk relapsed or refractory CLL. The approval was based on the phase III Study 116 trial, in which the addition of idelalisib to rituximab improved overall survival by 72% and PFS by 82% versus placebo and rituximab.
The approval for idelalisib included a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation associated with idelalisib. To address concerns with these side effects, idelalisib was also approved along with a Risk Evaluation and Mitigation Strategy (REMS).
In a statement on the naming of these CLL breakthroughs as the Cancer Advance of the Year, ASCO President Peter P. Yu, MD, said, “This has truly been a banner year for CLL and for clinical cancer research as a whole. Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients.”
ASCO’s Annual Report on Progress Against Cancer, now in its 10th year, was published online today in the Journal of Clinical Oncology. The 2015 report was developed by an editorial board of 18 experts representing a wide spectrum of oncology specialties.
Beyond announcing the top advancement in cancer, this year’s report also includes a look back at the last 10 years in oncology and a look forward at projected trends for the next decade, as well as sections on the top research advances from the past year and promising early advances in rare cancers.