The United Kingdom’s National Institute for Health and Care Excellence has recommended isatuximab-irfc in combination with pomalidomide and dexamethasone as a treatment option for select patients with relapsed/refractory multiple myeloma.
The United Kingdom’s National Institute for Health and Care Excellence (NICE) has recommended isatuximab-irfc (Sarclisa) in combination with pomalidomide and dexamethasone as a treatment option for select patients with relapsed/refractory multiple myeloma.1
The recommendation is specifically for patients who previously received lenalidomide (Revlimid) and a proteasome inhibitor, and whose disease progressed on their last treatment, only if they have received 3 previous line of therapy and the conditions in the managed access agreement for the monoclonal antibody plus pomalidomide/dexamethasone are followed.
“Isatuximab plus pomalidomide and dexamethasone could be cost effective after 3 previous lines of treatment when the company’s commercial offer as part of a managed access agreement is used,” NICE stated in the final appraisal document. “Therefore, isatuximab plus pomalidomide and dexamethasone is recommended for use in the Cancer Drugs Fund.”
Sanofi had proposed that the combination be used only for patients who had already received 3 prior lines of therapy. The committee noted that although effective options for third-line treatment are needed, the clinical and cost-effectiveness data for the combination at this time are not adequate for decision making.
In the fourth-line treatment setting, patients are typically given pomalidomide and dexamethasone or daratumumab (Darzalex) monotherapy in the Cancer Drugs Fund. Clinical data indicate that the isatuximab combination delays disease progression and prolongs survival compared with pomalidomide/dexamethasone alone. However, because the trial has not been completed, the longer-term benefit of this approach remains unknown, according to NICE.
Moreover, because of limitations to the clinical evidence that is available, the cost effectiveness estimates for the triplet following 3 prior lines of therapy remain uncertain, the committee added. The proposed list price for isatuximab in the company submission is £506.94 for a 100-mg vial of the drug or £2534.70 for a 500-mg vial.
Estimates appear to be higher than what NICE considers to be a suitable use for National Health Service (NHS) resources. As such, at this time, the isatuximab combination is not recommended for routine use in the NHS.
However, additional data from the ongoing ICARIA-MM trial (NCT02990338) and from clinical practice in the NHS could potentially address some of the uncertainties raised by the committee, according to NICE.
In the pivotal phase 3 ICARIA-MM trial, investigators compared isatuximab plus pomalidomide and dexamethasone with pomalidomide and dexamethasone alone. Patients with relapsed/refractory multiple myeloma who received at least 2 previous lines of therapy, including lenalidomide and a proteasome inhibitor, were included. The primary end point of the trial was progression-free survival (PFS).
Results from the trial showed that the addition of isatuximab to pomalidomide/dexamethasone resulted in a greater than 40% reduction in the risk of disease progression or death versus pomalidomide/dexamethasone in this patient population. Moreover, the objective response rate observed with the triplet was 60.4% versus 35.3% with the doublet (P <.0001).2
At a median follow-up of 11.6 months, the median PFS per independent review was 11.53 months with the triplet versus 6.47 months with the doublet (hazard ratio [HR], 0.596; 95% CI, 0.44-0.81; P =.001). At the time of the analysis, overall survival (OS) data were not yet mature; however, a trend toward improved survival was observed in the experimental arm (HR, 0.687; 95% CI, 0.461-1.023). The median OS had not yet been reached in either treatment arm, and the OS rates at 1 year for the triplet and doublet regimens was 72% versus 63%, respectively.
The PFS findings per investigator assessment proved to be comparable to those seen via independent review. The median PFS in the investigational and control arms was 11.14 months and 6.54 months, respectively (HR, 0.602; 95% CI, 0.444-0.816; P =.0009).
Because Sanofi positioned the isatuximab combination as a treatment option for use after 3 prior lines, the company provided efficacy data from a post-hoc subgroup of patients from ICARIA-MM who had received 3 previous lines of therapy.
At the interim data cutoff of October 2018, the median follow-up was 11.6 months in the trial for patients who had received 3 prior lines of therapy. With regard to PFS, the interim subgroup analysis was based on only approximately 50% of participants experiencing events. Results showed that the triplet resulted in a median PFS of 13.3 months versus 7.8 months with pomalidomide/dexamethasone (HR, 0.598; 95% CI, 0.348-1.03; P = .0611).
With regard to time to death, the interim subgroup analysis was based on 11 deaths in the investigational arm (n = 52) and 23 deaths in the control arm (n = 58). Results showed that the median OS had not yet been reached in the triplet arm versus the doublet arm. The HR for OS with the isatuximab combination versus pomalidomide/dexamethasone was 0.494 (95% CI, 0.23-1.02; P =.0502).
“The committee acknowledged the immaturity of the data in this ongoing trial,” according to NICE. “It concluded that isatuximab plus pomalidomide and dexamethasone was likely to extend PFS and OS compared with pomalidomide plus dexamethasone after 3 previous lines of treatment, but noted that median follow-up was short, the subgroup was small, and the data were immature.”
To demonstrate potential OS benefit beyond the follow-up period in ICARIA-MM, Sanofi identified a study that pooled OS data from 2 single-arm trials, GEN501 and SIRUS, of daratumumab. The median follow-up of the pooled data was 36.3 months, whereas the median follow-up for ICARIA-MM was 11.6 months. The evidence review group noted that “it was reasonable to assume that treatments of the same class might follow a similar statistical model.”
The group determined that using the Weibull distribution would not allow them to extrapolate the OS data for the isatuximab triplet; instead, they expressed that they preferred the exponential to the Weibull distribution to estimate OS. The group also performed an analysis using the lognormal distribution, which they deemed to be plausible based on current evidence. The committee agreed that lognormal distribution was appropriate to estimate PFS.
Although the company performed an alternative survival analysis using other trial outcomes such as minimal residual disease, depth of response to treatment, and PFS data, it was not determined to be robust.
Because the evidence base was immature, the committee did not recommend the triplet for routine use in the NHS. However, the committee did determine that the triplet met criteria to be used as treatment in multiple myeloma within the Cancer Drugs Fund.