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MBC Applying New Developments

CE / CME

Applying the Latest Developments in Metastatic Breast Cancer Through Education of Healthcare Professionals, Patients, and Caregivers

Nurses: 1.50 Nursing contact hours

Physicians: maximum of 1.50 AMA PRA Category 1 Credits™

Pharmacists: 1.50 contact hours (0.15 CEUs)

Released: October 19, 2023

Expiration: October 18, 2024

Joyce O'Shaughnessy
Joyce O'Shaughnessy, MD
CME/CE Information

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Phase III KEYNOTE-355 Trial of Pembrolizumab + Chemotherapy as First-line Therapy in Metastatic TNBC 

For patients with TNBC, the first thing we need to know is whether their disease is positive for PD-L1 by IHC using the 22C3 antibody directed against PD-L1.5 This is based on data from the phase III KEYNOTE-335 trial, which evaluated chemotherapy with or without pembrolizumab every 3 weeks. We now know that patients need to have a CPS ≥10 to attain a survival benefit from the combination of chemotherapy plus pembrolizumab vs chemotherapy alone.19

Patients who enrolled on the KEYNOTE-335 trial had to have previously untreated metastatic TNBC (N = 847) and had completed their neoadjuvant or adjuvant chemotherapy ≥6 months before recurrence to be eligible. The coprimary endpoints were PFS and OS in the various PD-L1 CPS score subgroups and in the intention-to-treat population.

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KEYNOTE-355 Final Analysis: OS and PFS (Coprimary Endpoints)

The final efficacy data from KEYNOTE-355 are summarized on this slide.20 Although the trial enrolled all-comers, approximately 40% of patients were PD-L1 positive based on a CPS score ≥10. If we look at median OS on the left, we can see approximately 7-month improvement with the addition of pembrolizumab to chemotherapy in patients with a CPS score of ≥10, with median OS of 16.1 months without pembrolizumab vs 23.0 months with pembrolizumab (1-sided P = .0093). In addition, 14% more patients were alive at 2 years in the pembrolizumab-containing arm.

Among patients with a CPS score ≥1, the data lose statistical significance. There is a 1.6-month difference in median OS in the arms with and without pembrolizumab, which was not statistically significant (17.6 vs 16.0 months; 1-sided P = .0563). 

Thus, this study showed that the CPS for PD-L1 expression on both tumor cells, as well as on infiltrating immune cells, has to be ≥10 for the patient to derive benefit from the addition of pembrolizumab to chemotherapy. This is why it is imperative to know the PD-L1 status in patients with TNBC. This information can be ascertained on a metastatic biopsy, or we can go back to tissue from the primary lesion. 

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KEYNOTE-355 Final Analysis: Safety

The safety profile when adding pembrolizumab to chemotherapy in the first-line setting is quite good overall. Immune-related AEs do occur, but not like we see with pembrolizumab in the adjuvant setting, where there is considerably more in the way of glandular toxicity, such as adrenal insufficiency, diabetes, pituitary inflammation, and hypophysitis.21,22

In the first-line metastatic setting in KEYNOTE-355, we saw that those patients receiving pembrolizumab experienced modestly higher levels of colitis (1.8% vs 1.4%) and pneumonitis (2.5% vs 0%), and the most common events were hypothyroidism (15.8% vs 3.2%) and hyperthyroidism (4.3% vs 1.1%).20 These just occur at lower incidences than in the neoadjuvant and adjuvant curative setting.21,22

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Efficacy of PARP Inhibitors in Subset of Patients With Advanced TNBC and germline BRCA Mutations

PARP inhibitors are a mainstay of treatment in metastatic TNBC, as well as in ET-refractory, metastatic HR-positive/HER2-negative MBC.5

The OlympiAD and EMBRACA studies showed a substantial improvement in median PFS following treatment with a PARP inhibitor (olaparib and talazoparib, respectively) vs single-agent chemotherapy in patients with a germline BRCA mutation.23,24 For OlympiAD and EMBRACA, but not BROCADE, the data are mature enough to show OS outcomes in terms of median OS, as well as in comparison with chemotherapy for olaparib (19.3 vs 17.1 months; hazard ratio: 0.89) and talazoparib (19.3 vs 19.5 months; hazard ratio: 0.848).25,26

In my opinion, the sooner we use PARP inhibitors in the metastatic setting, the more benefit patients may have. As such, in the first-line TNBC setting, if patients are PD-L1 negative but have a germline BRCA mutation, I would offer them treatment with a PARP inhibitor. However, if a patient is PD-L1 positive with CPS of ≥10, then I would hold the PARP inhibitor until after progression on first-line chemotherapy plus pembrolizumab.5

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Your 75-year-old patient with early triple-negative breast cancer (TNBC) received neoadjuvant chemotherapy followed by surgery for localized disease 1 year ago. She now presents with what appears to be metastatic disease progression in the lungs and hip bones leading to a small fracture. Biopsy confirms recurrent metastatic TNBC.

Based on clinical evidence and expert recommendations, which of the following biomarkers can help determine the optimal next line of therapy for this patient?

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