The UK’s National Institute for Health and Clinical Excellence has published draft guidelines recommending against the use of pembrolizumab plus chemotherapy as a treatment for patients with metastatic triple-negative breast cancer whose tumors express PD-L1 with a combined positive score of 10 or greater and who have not received chemotherapy for metastatic disease.
The UK’s National Institute for Health and Clinical Excellence (NICE) has published draft guidelines advising against pembrolizumab (Keytruda) plus chemotherapy as a treatment for patients with metastatic triple-negative breast cancer (TNBC) whose tumors expressing PD-L1 with a combined positive result (CPS) of 10 or greater 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. Additionally, no trial data has directly compared the combination of pembrolizumab with that of atezolizumab (Tecentriq) plus chemotherapy, already recommended by NICE. Therefore, the agency has determined that the cost-effectiveness estimates of pembrolizumab in combination with chemotherapy are above what it considers an acceptable use of National Health Service resources.
“I know today’s announcement will be disappointing for people with this type of breast cancer, as well as their families and caregivers,” said Helen Knight, program director at the NICE Center for Health Technology. Assessment, in a press release. She acknowledged that some 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 encourage anyone interested in this topic to provide us with feedback on these draft guidelines.”
In October 2021, the The European Commission has 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 200 mg every 3 weeks plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 every 28 days; paclitaxel 90 mg/m2 on days 1, 8 and 15 every 28 days; or gemcitabine 1000 mg/m2 and carboplatin below the curve 2 on days 1 and 8 every 21 days (n=566).
The primary endpoints were progression-free survival (PFS) and overall survival (OS) in participants with PD-L1 positive tumors, both CPS of 10 or more and 1 or more subsets, and with the intention to treat (ITT).4
After a median follow-up of 44.1 months, the median OS in the subgroup of patients with a CPS of 10 or greater was 23.0 months (95% CI, 19.0-26.3) in the arm pembrolizumab versus 16.1 months (95% CI, 12.6-18.8) with chemotherapy alone (HR, 0.73; 95% CI, 0.55-0.95; one-sided P = 0.0093).
The median PFS for this population was 9.7 months (95% CI, 7.6-11.3) with pembrolizumab versus 5.6 months (95% CI, 5.3-7.5) with chemotherapy alone (HR, 0.66; 95% CI, 0.50-0.88). Adding pembrolizumab also resulted in an objective response rate of 52.7% (95% CI, 45.9% to 59.5%) in this subgroup versus 40.8% (95% CI, 31.2% to 50.9%) with chemotherapy alone.
The committee reviewed the clinical evidence for KEYNOTE-355 and agreed that the exclusion of data for gemcitabine/carboplatin is appropriate for decision-making as this regimen is not expected to be used in the UK. After reviewing the trial evidence, the committee concluded that pembrolizumab is more effective than paclitaxel or nab-paclitaxel; however, the long-term benefits of this approach are uncertain.
Since there is no direct evidence comparing the use of pembrolizumab plus chemotherapy versus atezolizumab plus chemotherapy, Merck Sharp and Dohme performed a network meta-analysis to allow indirect comparisons between the 2 approaches. To do this, they considered KEYNOTE-355 and IMpassion130 (NCT02425891). This latest trial evaluated atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel in patients with TNBC who had not received treatment for metastatic disease before.
The results of the analysis are considered confidential, so they have not been shared publicly. The point estimates were in favor of the pembrolizumab combination, but had wide credible ranges that exceeded 1, and as such were not considered statistically significant. It was agreed that the meta-analysis had limitations due to heterogeneity between trials. The committee concluded that although the analysis was appropriate for decision-making as there are no other data available, the results should be interpreted with caution. Overall, the committee considered that the results concerning the relative efficacy of the 2 combinations remained unclear.
“Taking into account all confidential discounts, the committee noted that the company’s baseline ICER against taxanes was greater than £30,000 per QALY gained and against the atezolizumab combination was greater than £20,000 per QALY gained. If all of the suggested adjustments were incorporated, the ICERs would be significantly higher,” they wrote in the paper. “The committee concluded that the cost-effectiveness estimates of the pembrolizumab combination compared to the “Taxanes plus atezolizumab were above what NICE considers to be a cost-effective use of NHS resources. Therefore, the committee did not recommend the combination of pembrolizumab for use in the NHS.”
In July 2021, the FDA granted approval of pembrolizumab plus chemotherapy for patients with unresectable or metastatic TNBC whose tumors express PD-L1 with a CPS of 10 or greater. The agency simultaneously approved pembrolizumab for patients with high-risk, early-stage TNBC to be used in combination with chemotherapy as a neoadjuvant therapy and then continued as adjuvant therapy as monotherapy after surgery.5
Regulatory decisions were based on data from the KEYNOTE-522 Phase 3 trial (NCT03036488), which showed that when immunotherapy was combined with carboplatin and paclitaxel, followed by doxorubicin or epirubicin and cyclophosphamide before surgery, this significantly prolonged event-free survival. vs the same neoadjuvant chemotherapy regimens alone in previously untreated patients with stage II or III disease.6
In the trial, patients were randomized 2:1 to receive pembrolizumab 200 mg every 3 weeks (n=784) or placebo (n=390). All participants received 4 cycles of carboplatin plus paclitaxel, followed by 4 cycles of doxorubicin or epirubicin plus cyclophosphamide. After surgery, adjuvant pembrolizumab was continued for 9 cycles or until patients experienced disease recurrence or unacceptable toxicity.
At a median of 39.0 months, treatment with pembrolizumab resulted in a 37% reduction in the risk of disease progression that prevented definitive surgery, local/distant recurrence, second primary cancer, or death at all. whatever the cause (RR, 0.63; 95% CI, 0.48-0.82; P = .00031). The diet also reduced the risk of death by 28% compared to chemotherapy alone in this population (RR, 0.72; 95% CI, 0.31-1.02; P = 0.03214), although these data did not cross the limit of 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 PD-L1-expressing tumors after the agent failed to reach its primary endpoint of PFS in a confirmatory trial.7
- NICE’s draft guidelines do not recommend pembrolizumab plus chemotherapy for triple-negative breast cancer. Press release. PLEASANT; March 8, 2022. Accessed March 9, 2022. https://bit.ly/3MCplwx
- PLEASANT. Final evaluation 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
- The European Commission approves Merck’s KEYTRUDA (pembrolizumab) plus chemotherapy as a treatment for certain patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC). Press release. Merck; October 22, 2021. Accessed March 9, 2022. https://bit.ly/3C1U2FH
- Cortés J, Cescom DW, Rugo HS, et al. KEYNOTE-355: Final Results of a Phase III Randomized Double-Blind Study of Pembrolizumab + First-Line Chemotherapy Versus Placebo + Chemotherapy for Metastatic TNBC. Anne Oncol. 2021;32(supplement 5):S1289-S1290. doi:10.1016/announce.2021.08.2089
- FDA approves pembrolizumab for high-risk, early-stage triple-negative breast cancer. Press release. FDA; July 27, 2021. Accessed March 9, 2022. https://bit.ly/3okq9f0
- KEYTRUDA (pembrolizumab) plus chemotherapy before surgery and continued as a single agent after surgery showed statistically significant event-free survival (EFS) outcome compared to neoadjuvant chemotherapy alone in high-risk TNBC at a early stage. Press release. Merck; July 15, 2021. Accessed July 27, 2021. https://bit.ly/3B6YQto
- Genentech provides an update on the U.S. indication of Tecentriq for PD-L1 positive metastatic triple negative breast cancer. Press release. Genentech; August 27, 2021. Accessed March 9, 2022. https://bit.ly/3L4uHA0