NICE Rejects Nivolumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has issued guidelines recommending against nivolumab (Opdivo) for use in patients with recurrent or metastatic head and neck squamous cell carcinoma who experienced disease progression during or after platinum-based chemotherapy.¹

The committee reviewed additional evidence collected as part of the Cancer Drugs Fund managed access agreement for the PD-1 inhibitor in this indication, and it showed that patient who receive the agent are likely to live up to 9 months longer than those who receive docetaxel, methotrexate, or cetuximab (Eribitux).

However, whether nivolumab extends survival for more than 3 months in patients who are fit enough to receive docetaxel or those with a low PD-L1 score remains unclear, according to agency. As such, the question of whether the agent meets the agency’s criteria to be considered as a life-extending treatment remains unknown.

Moreover, the committee stated that the cost-effectiveness estimates for nivolumab in this patient population also are highly uncertain. “But they are likely to be at the higher end of what NICE considers as acceptable use of National Health Service (NHS) resources, and could exceed the maximum,” the agency stated in the document. “So nivolumab is not recommended.”

The clinical evidence evaluated came from the open-label, phase 3 CheckMate-141 trial (NCT02105636), which evaluated nivolumab versus investigator’s choice of therapy. Those in the control arm were given 1 of 3 potential weekly therapies: docetaxel (47%), methotrexate (41%), or cetuximab (12%).

Notably, in the original appraisal, the committee stated that excluding paclitaxel from the trial and including cetuximab, a drug that was not used in clinical practice at that time, introduced uncertainty about the relevance of the trial to clinical practice within the United Kingdom. They also permitted the assumption that docetaxel and paclitaxel could be considered to be equivalent, although they did not feel that docetaxel was equivalent to methotrexate.

“For this guidance review, the clinical expert acknowledged that the trial took place in several countries where standard care differs from NHS clinical practice,” according to the appraisal document. “He suggested that the investigator-choice arm of the trial was an appropriate comparison even though cetuximab is not standard care in NHS clinical practice and methotrexate is only offered to people with poor performance status and may be less effective.”

Results from the trial demonstrated that patients in the intention-to-treat (ITT) population who received nivolumab had a median overall survival (OS) of 7.7 months versus 5.1 months with investigator’s choice of treatment (HR, 0.69; 95% confidence interval [CI], 0.55-0.86).

Because patients who received investigator’s choice of treatment were able to switch over to nivolumab, the committee stated that it was unclear how such a switch impacted OS; they noted that this could potentially bias the results against the PD-1 inhibitor.

Moreover, although a numerical survival benefit was observed with nivolumab over docetaxel, the benefit was not determined to be statistically significant. As such, they stated that “there was uncertainty associated with the results from the docetaxel subgroup because of the small number of people in the subgroup analysis, and because the effect of treatment switching was unknown.” Despite this, it was agreed that the analysis was relevant and reached the decision that the effectiveness of nivolumab versus docetaxel alone remained unclear.

The committee also examined the effectiveness of nivolumab based on PD-L1 expression. In the subgroup of patients with a PD-L1 score of 1% and above, the median OS improved by 3.6 months (HR, 0.54; 95% CI, 0.39-0.76) with nivolumab. In the subset of those with a PD-L1 score of less than 1%, the median OS improved by 1 month with the PD-1 inhibitor (HR, 0.74; 95% CI, 0.50-1.10).

The committee concluded “that there was evidence that nivolumab is clinically beneficial for tumors with a PD-L1 core of 1% and above but the benefit for those with a low PD-L1 score was less certain,” according to the document.

Systemic Anti-Cancer Therapy (SACT) data were also reviewed by the committee; these findings had been collected from a total of 506 patients who were treated with nivolumab through the Cancer Drugs Fund between October 2017-October 2019. The information proved to be in line with what was reported in clinical trials, according to a clinical expert.

Specifically, the OS rate at 1 year was comparable in the ITT population who received nivolumab and the SACT data, at 33.4% and 34%, respectively. The median OS in the trial and in the SACT data was 7.7 months and 6.5 months, respectively, but the 95% Cis were noted to overlap.

Additionally, the time to treatment discontinuation in the SACT data proved to be longer than what was observed in the trial, at 3.0 months (95% CI, 2.7-3.3). Data from the trial remain confidential and cannot yet be shared with the public. The median follow-up in the trial was 48.2 months versus 6.2 months with the SACT data.

The list price for nivolumab is £439 per 40-mg vial, £1,097 per 100-mg vial, and £2,633 per 240-mg vial. The committee noted that because of all of the areas of uncertainty with nivolumab in this indication, an acceptable incremental cost-effectiveness ratio (ICER) is toward the lower end of the range that is normally considered to be a cost-effective use of NHS resources.

“The committee noted the high level of uncertainty for the docetaxel subgroup specifically regarding the clinical effectiveness, appropriate extrapolation methods, and the end-of-life criteria,” according to the document.

The committee’s base-case assumptions also differed from the company’s base-case assumptions, which included a lifetime treatment benefit with the PD-1 inhibitor, treatment-dependent utilities, and a 2-year stopping rule.

According to the company, the base-case ICER was £37,257 per QALY gained in the ITT population. Moreover, the ICER increased to £46,540 per QALY gained when the time-to-death disutility decrements and the stopping rule were removed. When the treatment-independent utility values were also applied, the ICER increased to £54,700 per QALY gained. When the stopping rule and the time-to-death disutility decrements were removed and the time-to-treatment discontinuation was extrapolated with the same distribution in 2 arms, the ICER was £41,888 per QALY gained. Lastly, the ICER was £49,233 per QALY gained when the treatment-independent utility values were also applied.

The committee noted that the ICER was £41,695 per QALY gained in the docetaxel subgroup; this proved to be £4,442 per QALY gained higher than what was observed in the ITT population. The committee concluded that due to uncertainty over how adjusted extrapolation methods for OS, PFS, and time to discontinuation would impact cost effectiveness, as well as the ICER, it could not recommend the agent for routine use in the NHS.

Reference

Appraisal consultation document: nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy. National Institute for Health and Care Excellence. Issued January 2021. Accessed January 8, 2021. https://bit.ly/2MKWeN8.