NICE Rejects Treatments for Head and Neck Cancer and AML

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has issued guidelines recommending against pembrolizumab (Keytruda) for use in treatment-naïve patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) whose tumors express PD-L1 with a combined positive score (CPS) of ≥1.¹ The agency also recommended against gilteritinib (Xospata) for patients with relapsed/refractory acute myeloid leukemia (AML) who harbor a FLT3 mutation.²

Pembrolizumab in HNSCC

With regard to pembrolizumab as monotherapy and in combination with platinum-based chemotherapy and 5-fluorouracil (5-FU), the committee recommended that the agency request further clarification and analyses from Merck, the developer of the PD-1 inhibitor. The company should provide the following information, according to NICE:

• A full comparison of baseline patient characteristics for 2 subgroups: those whose cancer started inside or outside of the oral cavity;
• Overall survival (OS) data for the 2 subgroups and a formal statistical analysis to adjust for imbalances in baseline patient characteristics in the subgroups;
• OS extrapolation curves, after adjusting for imbalances in baseline patient characteristics for the 2 subgroups;
• An alternative utility value for progressive disease, based on published literature;
• Examination of techniques to provide full incremental analyses for the 2 subgroups Execute alternative analyses using data from the phase III KEYNOTE-048 trial to compare pembrolizumab with platinum chemotherapy and 5-FU. This information should be made available to NICE for the next appraisal meeting, according to the appraisal consultation document.

Data from the protocol-specified final analysis of the KEYNOTE-048 trial showed that the combination of pembrolizumab and chemotherapy resulted in a significant improvement in OS compared with the standard EXTREME regimen, comprised of cetuximab (Erbitux) plus either carboplatin or cisplatin and 5-FU in patients with a CPS of ≥20 (HR, 0.60; 95% CI, 0.45-0.82; P =.0004) and those with a CPS of ≥1 (HR, 0.65; 95% CI, 0.53-0.80; P <.0001).³

Single-agent pembrolizumab was not found to significantly improve OS versus EXTREME in the overall study population (HR, 0.83; 95% CI, 0.70-0.99; P =.0199) at final analysis. However, there was a larger OS improvement in those with a CPS of ≥20 (HR, 0.58; 95% CI, 0.44-0.78) and in patients with a CPS of ≥1 (HR, 0.74; 95% CI, 0.61-0.90).

In the appraisal consultation document, the agency explained that while evidence from clinical trials has demonstrated that those with metastatic or unresectable recurrent HNSCC that is PD-L1—positive with a CPS of ≥1 have been shown to have a longer survival with pembrolizumab compared with cetuximab plus platinum-based chemotherapy and 5-FU, uncertainty surrounding such evidence exists.

“The comparator drugs in the trial do not reflect what happens in the National Health Service in England (NHS) in England. In the comparator arm of the trial all people were given cetuximab with platinum chemotherapy and 5-FU, regardless of whether the cancer started inside or outside the oral cavity,” the agency stated in the document. “This is not established clinical practice in the NHS in England.”

The agency added that clinical evidence had not been provided for patients whose cancer originated outside the oral cavity. Additionally, data pertaining to the clinical and cost effectiveness of the treatment in the 2 patient subgroups were deemed incomplete. As such, the agency declared that they were unable to recommend the use of pembrolizumab in this patient population at this time.

In June 2019, the FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent HNSCC as monotherapy whose tumors express PD-L1 (CPS ≥1) or in combination with platinum and FU for this patient population, irrespective of PD-L1 expression, based on earlier findings from the KEYNOTE-048 trial.

Gilteritinib in AML

With regard to gilteritinib, the agency noted that although they do not recommend the FLT3 inhibitor for those with relapsed/refractory FLT3-mutated AML, the recommendation is not intended to affect treatment started before the guidance was issued.

In November 2018, the FDA granted approval to gilteritinib for use in adults with relapsed/refractory AML who harbor a FLT3 mutation detectable by an FDA-approved test. The regulatory decision was based on data from the interim analysis of the ADMIRAL trial, which looked at 138 patients. At a median follow-up of 4.6 months, the rate of complete remission (CR) or CR with partial hematologic recovery (CRh) was 21% (n = 29; 95% CI, 14.5-28.8).⁴

Updated data published in the New England Journal of Medicine showed that gilteritinib led to a median event-free survival of 2.8 months versus just 0.7 months with chemotherapy (HR, 0.79; 95% CI, 0.58-1.09), which was not determined to be statistically significant. Additionally, CR with either full or partial CRh was 34.0% with gilteritinib versus 15.3% with chemotherapy (risk difference, 18.6 percentage points; 95% CI, 9.8-27.4). CR rates with gilteritinib and chemotherapy were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8-18.4).⁵

Although clinical evidence has demonstrated that patients who receive gilteritinib have longer survival versus those who receive salvage chemotherapy, uncertainty remains with regard to long-term survival, especially after patients undergo stem cell transplant. As such, data pertaining to the cost-effectiveness of the agent unclear.

“The most likely cost-effectiveness results show that gilteritinib is above the level normally considered a cost-effective use of NHS resources,” the agency states in its appraisal consultation document. “Therefore, gilteritinib is not recommended for routine use in the NHS.”

References

1. Appraisal consultation document: Pembrolizumab for untreated metastatic or unresectable recurrent squamous cell head and neck cancer. National Institute for Health and Care Excellence. bit.ly/2u13hIc. Issued January 2020. Accessed January 15, 2020.
2. Appraisal consultation document: Gilteritinib for treating relapsed or refractory acute myeloid leukaemia. National Institute for Health and Care Excellence. bit.ly/2FV9PLc. Issued January 2020. Accessed January 15, 2020.
3. Rischin D, Harrington KJ, Greil R, et al. Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol. 2019;37(suppl 15; abstr 6000). doi: 10.1200/JCO.2019.37.15_suppl.6000.
4. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicenter, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061-1075. doi: 10.1016/S1470-2045(17)30416-
5. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019;381(18):1728-1740. doi: 10.1056/NEJMoa1902688.