NICE Rejects Pembrolizumab Plus Chemotherapy for Select Metastatic TNBC

Breast Cancer

The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) has issued draft guidance recommending against pembrolizumab (Keytruda) plus chemotherapy as a treatment for patients with metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 with a combined positive score (CPS) of 10 or more and who have not received chemotherapy for metastatic disease.^1,2

It was concluded that although pembrolizumab plus chemotherapy is more effective than paclitaxel or nab-paclitaxel (Abraxane), the long-term benefit of this approach is still unclear. Moreover, no trial data have directly compared the pembrolizumab combination with that of atezolizumab (Tecentriq) plus chemotherapy, which is already recommended by NICE. Therefore, the agency determined that cost-effectiveness estimates for pembrolizumab in combination with chemotherapy are higher than what it considers to be an acceptable use of National Health Service resources.

“I know that today’s announcement will be disappointing for people with this type of breast cancer, as well as for their families and carers,” Helen Knight, program director in the NICE Centre for Health Technology Evaluation, said in a statement. She acknowledged that certain patients who are not eligible to receive the atezolizumab combination may be eligible to receive the pembrolizumab combination.

“We are committed to working with the company to try to resolve the issues identified by the committee,” Knight added. “In the meantime, I would encourage anyone with an interest in this topic to give us their feedback on this draft guidance.”

In October 2021, the European Commission approved pembrolizumab plus chemotherapy for this population based on data from the phase 3 KEYNOTE-355 trial (NCT02819518).³ Study participants were randomized 2:1 to receive chemotherapy alone (n = 281) or pembrolizumab at 200 mg every 3 weeks plus nab-paclitaxel at 100 mg/m2 on days 1, 8, and 15 every 28 days; paclitaxel at 90 mg/m2 on days 1, 8, and 15 every 28 days; or gemcitabine at 1000 mg/m2 and carboplatin under the curve 2 on days 1 and 8 every 21 days (n = 566).

The primary end points were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1–positive tumors, both the CPS of 10 or higher and 1 or higher subsets, and in the intention-to-treat (ITT) population.⁴

After a median follow-up of 44.1 months, the median OS in the subset of patients with a CPS of 10 or higher was 23.0 months (95% CI, 19.0-26.3) in the pembrolizumab arm vs 16.1 months (95% CI, 12.6-18.8) with chemotherapy alone (HR, 0.73; 95% CI, 0.55-0.95; 1-sided P = .0093).

The median PFS for this population was 9.7 months (95% CI, 7.6-11.3) with pembrolizumab compared with 5.6 months (95% CI, 5.3-7.5) with chemotherapy alone (HR, 0.66; 95% CI, 0.50-0.88). The addition of pembrolizumab also resulted in an objective response rate of 52.7% (95% CI, 45.9%-59.5%) in this subset vs 40.8% (95% CI, 31.2%-50.9%) with chemotherapy alone.

The committee reviewed clinical evidence from KEYNOTE-355 and agreed that excluding data pertaining to gemcitabine/carboplatin is appropriate for decision making because this regimen would not be expected to be used in the United Kingdom. After reviewing evidence from the trial, the committee concluded that the pembrolizumab combination is more effective than paclitaxel or nab-paclitaxel; however, the long-term benefit of this approach is uncertain.

Because there is no head-to-head evidence comparing the use of pembrolizumab plus chemotherapy with that of atezolizumab plus chemotherapy, Merck Sharp and Dohme performed a network meta-analysis to allow for indirect comparisons between the 2 approaches. To do this, they considered KEYNOTE-355 and IMpassion130 (NCT02425891). The latter trial evaluated atezolizumab plus nab-paclitaxel vs placebo plus nab-paclitaxel in patients with TNBC who did not previously receive treatment for metastatic disease.

The results of the analysis are considered confidential, so they were not publicly shared. The point estimates favored the pembrolizumab combination but had wide credible intervals that crossed 1, and as such, were not considered to be of statistical significance. It was agreed that the meta-analysis had limitations due to heterogeneity between trials. The committee concluded that although the analysis was suitable for decision making because there no other available data are available, the results should be interpreted with caution. Overall, the committee felt that the results regarding the relative efficacy of the 2 combinations remained unclear.

“Taking into account all confidential discounts, the committee noted that the company’s base-case ICER compared with taxanes was above £30,000 per QALY gained and compared with atezolizumab combination was above £20,000 per QALY gained. If all the suggested adjustments were incorporated, the ICERs would be much higher,” they wrote in the document. “The committee concluded that the cost-effectiveness estimates for pembrolizumab combination compared with taxanes and atezolizumab combination were higher than what NICE considers a cost-effective use of NHS resources. Therefore, the committee did not recommend pembrolizumab combination for use in the NHS.”

In July 2021, the FDA granted regular approval to pembrolizumab plus chemotherapy for patients with unresectable or metastatic TNBC whose tumors express PD-L1 with a CPS of 10 or more. The agency simultaneously approved pembrolizumab for patients with high-risk, early-stage TNBC to be used in combination with chemotherapy as neoadjuvant treatment and then continued as a single-agent adjuvant treatment following surgery.⁵

The regulatory decisions were based on data from the phase 3 KEYNOTE-522 trial (NCT03036488), which showed that when the immunotherapy was combined with carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide prior to surgery, it significantly prolonged event-free survival vs the same neoadjuvant chemotherapy regimens alone in previously untreated patients with stage II or stage III disease.⁶

In the trial, patients were randomized 2:1 to receive pembrolizumab at 200 mg every 3 weeks (n = 784) or placebo (n = 390). All participants received 4 cycles of carboplatin plus paclitaxel, which was followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. Following surgery, adjuvant pembrolizumab was continued for 9 cycles or until patients experienced disease recurrence or unacceptable toxicity.

At a median of 39.0 months, the pembrolizumab regimen resulted in a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; P = .00031). The regimen also reduced the risk of death by 28% vs chemotherapy alone in this population (HR, 0.72; 95% CI, 0.31-1.02; P = .03214), although these data did not cross the boundary for statistical significance.

In August 2021, Genentech voluntarily withdrew an accelerated approval indication for atezolizumab in combination with nab-paclitaxel for patients with metastatic TNBC with tumors expressing PD-L1 after the agent did not reach its primary PFS end point in a confirmatory trial.⁷

References

1. NICE draft guidance does not recommend pembrolizumab plus chemotherapy for triple negative breast cancer. News release. NICE; March 8, 2022. Accessed March 9, 2022. https://bit.ly/3MCplwx
2. NICE. Final appraisal document – Pembrolizumab plus chemotherapy for untreated, triple-negative, locally recurrent unresectable or metastatic breast cancer. March 8, 2022. Accessed March 9, 2022. https://bit.ly/3MCplfQ
3. European Commission approves Merck’s KEYTRUDA (pembrolizumab) plus chemotherapy as treatment for certain patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC). News release. Merck; October 22, 2021. Accessed March 9, 2022. https://bit.ly/3C1U2FH
4. Cortés J, Cescom DW, Rugo HS, et al. KEYNOTE-355: final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Ann Oncol. 2021;32(suppl 5):S1289-S1290. doi:10.1016/annonc.2021.08.2089
5. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. News release. FDA; July 27, 2021. Accessed March 9, 2022. https://bit.ly/3okq9f0
6. KEYTRUDA (pembrolizumab) plus chemotherapy before surgery and continued as a single agent after surgery showed statistically significant event-free survival (EFS) result versus neoadjuvant chemotherapy alone in high-risk early-stage TNBC. News release. Merck; July 15, 2021. Accessed July 27, 2021. https://bit.ly/3B6YQto
7. Genentech provides update on Tecentriq US indication for PD-L1-positive, metastatic triple-negative breast cancer. News release. Genentech; August 27, 2021. Accessed March 9, 2022. https://bit.ly/3L4uHA0