Pembrolizumab: another option for triple-negative breast cancer


Based on the KEYNOTE-3551 and KEYNOTE-5222 trials, the indication for pembrolizumab has been extended to patients with early-stage triple-negative breast cancers (TNBC) in combination with chemotherapy as neoadjuvant treatment and continued as monotherapy as adjuvant treatment after surgery, and in combination with chemotherapy in locally recurrent unresectable or metastatic TNBC where programmed death ligand 1 (PD-L1) is expressed.3

Pembrolizumab is an anti-programmed death 1 (PD-1) antibody with efficacy in a range of solid tumors.To explore the importance of this indication in the Australian context, the limbic spoke with Doctor Sally Baron-Hay, Medical Oncologist at GenesisCare North Shore.

“These two trials have paved the way for pembrolizumab as an option in these aggressive tumours. KEYNOTE-355 looked at first-line treatment in the advanced setting in patients with unresectable disease.1 KEYNOTE-522 looked at treatment in the adjuvant and neoadjuvant setting, which has proven to be a good place to put a checkpoint inhibitor.2 In combination with chemotherapy, the tumour microenvironment becomes more permissive to monoclonal antibody treatment,”2 explained Dr Baron-Hay.

Pembrolizumab first-line in the advanced setting in unresectable TNBC

“KEYNOTE-355 is the pembrolizumab equivalent of the IMpassion-130 trial with atezolizumab,”4 noted Dr Baron-Hay. “While KEYNOTE-355 started a bit later than the IMpassion-130 trial, the investigators changed the primary endpoint (progression-free survival; PFS) to be assessed in patients whose tumours expressed PD-L1 with a combined positive score (CPS) of 10 or more.1 We saw a significant benefit for PFS and OS in this trial, which was similar to what was observed in IMpassion130.1,4 Importantly, these benefits were seen across multiple chemotherapy backbones, including a taxane or gemcitabine plus carboplatin regimens.”1

KEYNOTE-355 was a phase III, randomised, double-blind, international trial in 566 patients with previously untreated, locally recurrent inoperable or metastatic TNBC assigned to pembrolizumab-chemotherapy and 281 assigned to placebo-chemotherapy.1 The median follow-up was 44.1 months and in the patients with PD-L1 CPS ≥10, the median OS was 23.0 months in the pembrolizumab-chemotherapy arm versus 16.1 months in the placebo-chemotherapy arm (hazard ratio; HR 0.73; 95% confidence interval; CI: 0.55 to 0.95; p=0.0185).1

“In the first-line setting, it is important to get as much disease reduction as possible, because patients with a heavy disease burden tend to do worse. The KEYNOTE-355 trial demonstrates that pembrolizumab can move into the standard of care role in patients with PD-L1 positive disease,” suggested Dr Baron-Hay. She continued, “Perhaps one controversial area that remains is consistency of PD-L1 testing. There are multiple assays we can choose from. I opt for a primary block.”

The KEYNOTE-522 is the other phase III, randomised, double-blind trial, this time in patients with previously untreated stage II or stage III TNBC who were candidates for definitive surgery.2

“In KEYNOTE-522, patients underwent an intensive chemotherapy regimen with a taxane plus carboplatin followed by doxorubicin or epirubicin plus cyclophosphamide.2 I think the investigators would have been looking at giving pembrolizumab the best opportunity to work well in this setting, and it paid off. The challenge with optimising the chemotherapy is to not kill T-cells but break the tumour down enough for the monoclonal antibody to gain access to the tumour epitopes,” noted Dr Baron-Hay.

The primary endpoints of KEYNOTE-522 were a pathological complete response at the time of definitive surgery and event-free survival in the intent-to-treat population. In the 784 patients in the pembrolizumab-chemotherapy arm, 64.8% had a pathological complete response (95% CI 59.9 to 69.5) and 51.2% (95% CI 44.1 to 58.3) in the 390 patients on placebo-chemotherapy. After a median follow-up of 15.5 months, the patients in the pembrolizumab-chemotherapy arm 7.4% had disease progression that precluded surgery versus 11.8% in the placebo-chemotherapy arm.2 Unlike the IMpassion-130 trial, in KEYNOTE-522, the pathological complete response benefit was consistent across patient subgroups, including PD-L1 expression.2

“For me, KEYNOTE-522 shows how pembrolizumab not only has utility in tumour reduction in the breast, but also in priming the host immune system to help protect against breast cancer as well,” explained Dr Baron-Hay.

When it comes to implementing pembrolizumab in Australian clinical settings, Dr Baron-Hay acknowledged that local experience needs to grow. “We have not had a lot of exposure to pembrolizumab in breast cancer in Australia before, but we do have experience in other tumours. Endocrine replacement therapy may be required in some patients, and in my experience most patients are happy to do so knowing that it is in exchange for cure of their breast cancer,” said Dr Baron Hay.

“Now we can give pembrolizumab in the neoadjuvant and adjuvant settings, we’re thinking about where we can go next. But right now, it is an exciting time for this group who have had to rely solely on cytotoxic chemotherapy to take on their tumour,” concluded Dr Baron-Hay.

Disclosure

This article was sponsored by MSD Australia. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Keytruda product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

  1. Cortes J, et al. N Engl J Med 2022;387:217-226.
  2. Schmid P, et al. N Engl Med 2020;382:810-821.
  3. KEYTRUDA Product Information.
  4. Schmid P, et al. N Engl Med 2018;379(22):2108-2121.

 

 

 

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