by Sylvie Lapostolle at ASCO
CHICAGO, June 6 (APM) - Adding Genmab and Janssen's Darzalex (daratumumab) to the standard treatment for relapsed or refractory multiple myeloma allowed an unprecedented extension of progression-free survival (PFS) in a Phase III trial presented at the meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
The CASTOR study, whose positive results were announced by the pharmas in March (APMMA 47117), was presented at the plenary session of the conference on Sunday. This session presents four studies whose results are likely to change clinical practice.
Daratumumab is the first anti-CD38 antibody. It has a very specific target which is highly expressed by myeloma cells, and also stimulates the immune system so that it attacks the tumour cells. It was given conditional approval in Europe at the end of May as monotherapy in heavily pretreated multiple myeloma. (APMMA 47957)
In the Phase III CASTOR trial that enrolled 498 patients (who had already received a median of two treatments), the anti-CD38 was evaluated at a dose of 16 mg/kg in addition to the standard treatment, Janssen's Velcade (bortezomib)+dexamethasone, in comparison with this standard treatment. After eight cycles of bortezomib+dexamethasone, daratumumab was administered once a month until progression.
Preliminary studies had shown daratumumab+bortezomib induced deep and lasting responses, with good tolerability, said Dr Antonio Palumbo from Turin University, Italy.
Daratumumab significantly increased PFS, with risk of progression or death reduced by 61%. Median PFS was not reached, compared with 7.2 months in the standard arm, according to the intermediate analysis with 7.4 months' monitoring, he reported.
"This is an unprecedented result in relapsed or refractory multiple myeloma," he emphasised. In other studies, reductions of 25% to 44% at best had been seen, he said at an ASCO press conference.
At 12 months, the PFS rate was 60.7% with the three drugs, double the 26.9% with the standard therapy, he noted in the plenary session.
The difference in time to progression was even greater, as risk of progression was reduced by 70% with the three drugs. The median was not reached, compared with 7.3 months with the standard treatment, and here again, the proportion of progression-free patients at 12 months was more than doubled (65.4% versus 28.8%).
Adding the antibody doubled the complete response rate (19% versus 9%) and also the very good partial response rate (59% versus 29%). The overall response (OR) rate was 83% versus 63%. The proportion of patients without minimal residual disease was five times higher with the antibody (14% versus 3%).
Palumbo noted that the partial responses occurred very rapidly while the complete responses occurred later, sometimes after 12 months' treatment.
Benefit was seen in all subgroups (by age, prognosis, previous treatment), but with a higher reduction in risk of progression or death in patients whose disease was less advanced or who had received fewer treatments, suggesting the drug has maximum effect in early treatment, the investigator said.
PFS in patients who had only had a single previous treatment supported this hypothesis: not reached versus 7.5 months, 77.5% versus 29.4% at one year, and a 69% reduction in risk of progression or death.
Addition of the antibody was well tolerated and did not increase cumulative toxicity. Toxicities were the same as those reported for the antibody alone or for bortezomib+dexamethasone alone.
The most frequent adverse events were thrombocytopaenia (59% versus 44%), peripheral sensory neuropathy (47% versus 38%) - adverse events typical of bortezomib, which were more frequent in the experimental arm owing to longer exposure to this drug -, diarrhoea (32% versus 22%) and anaemia (26% versus 31%). Treatment discontinuation rates owing to tolerability problems were 7% versus 9%.
Injection site reactions were reported by 45% of patients, but only 9% were grade 3 reactions (no grade 4 reactions), and 98% occurred on first administration.
Palumb said the daratumumab+bortezomib+dexamethasone regimen should be considered a new standard of care for patients with relapsed or refractory multiple myeloma.
He said that given the benefit of this regimen on first relapse, it is important to evaluate it rapidly in other stages in first line, as this is probably where it will be most effective.
In May, Genmab and Janssen had announced similar positive results in another Phase III in relapsed or refractory multiple myeloma, but with Celgene's Revlimid (lenalidomide), with risk of progression or death reduced by 63% (APMMA 47909).
Daratumumab was the first antibody approved in multiple myeloma in the U.S. (November 2015), followed closely by AbbVie/Bristol-Myers Squibb's Empliciti (elotuzumab), but the latter was approved slightly before the former in Europe (APMMA 47957).
The EU approval for daratumumab in monotherapy in heavily pre-treated patients is conditional, as it was granted on the basis of a Phase I/II study and one Phase II trial, whereas elotuzumab was approved in relapsed and refractory forms in combination with lenalidomide+dexamethasone on the basis of a Phase III trial.
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