Among patients with triple negative breast cancer (TNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer, preoperative radiation therapy (RT) with Keytruda (pembrolizumab) demonstrated safety, high pathologic complete response rates and notable three-year event-free survival (EFS), according to study findings published in Journal of Clinical Oncology.
These findings suggest PD-L1 expression and tumor infiltrating lymphocytes may prove as predictive biomarkers for preoperative anti-PD1/RT response. In addition, TIL reduction after adding RT to ant-PD1 highlights the importance of treatment sequencing.
Glossary
Tumor-infiltrating lymphocytes (TILs): Cell that helps destroy tumor cells
Event-free survival: Time lived without recurrence of cancer or death.
pCR: No cancer cells left after treatment
TNF-a and IFN-y: Serum proinflammatory markers that detect inflammation.
Immune checkpoint inhibitor (ICI): Allows immune system to attack cancer cells
Metastatic: Spreading
Ki-67: Protein that indicates rapid division
KEYNOTE-522 chemotherapy: Preoperative therapy with four cycles of Keytruda plus taxol and paraplatin
“The exceptional results with preoperative RT/IT provide preliminary data for novel treatment approaches that may afford de-escalation of chemotherapy in select patients with TNBC,” study authors wrote.
After a median follow-up of 32 months, 41% of patients experienced severe or worse side effects. The pathologic complete response rate was 59.2% for patients with TNBC, 33.3% for HR+/HER2- and 54.5% for the entire group of patients. Additionally, 77.8% of TNBC and 41.6% of HR+/HER2- patients showed a near pathologic complete response. After three years, the event-free survival was 80% and all patients’ PD-L1 expression increased after anti-PD1 and anti-PD1/RT, compared with baseline. Adding RT to anti-PD1 decreased tumor infiltrating lymphocytes significantly and baseline TILs correlated with PD-L1 expression and TNF-a.
Notably, PD-L1 expression at baseline and after anti-PD1 were closely associated with TILs, and both expressions correlated with the circulating levels of TNF-a and IFN-y.
“Our findings of reduced TILs after RT enforced the notion that RT should be administered before or concurrently with ICI [immune checkpoint inhibitor], not afterward,” study authors wrote.
Out of 66 patients, nine had severe side effects probably or related to Keytruda and/or preoperative radio therapy, 44% underwent immediate reconstruction, and three had life-threatening side effects, although not attributed to Keytruda or radiotherapy. In addition, 42.4% of patients had immediate reconstruction and did not experience reconstruction failure.
Most patients received an anthracycline and taxanes-containing regimen, 35% of TNBC received KEYNOTE-522 chemotherapy, 51 received mastectomy and 49% received breast-conserving surgery.
Criteria that excluded patients from the trial included those with HER2+, T4d, metastatic (spreading) disease and factors precluding immunotherapy receipt. All patients met at least two of the following criteria: moderate to poor differentiation of cancer cells, Ki-67 (protein that indicates rapid division) greater than 20% and estrogen receptors less than 75% by IHC.
Patients received two cycles of 200 milligrams of Keytruda through the veins once every three weeks. Radiation therapy was given within the first three days of the second Keytruda cycle.
Regarding cancer types, 54 had TNBC and 12 had HR+/HER2- breast cancer.
“In summary, to our knowledge, this first phase I/IIb study demonstrated the safety of combined preoperative RT with pembrolizumab in patients with breast cancer receiving NAC. Efficacy was high despite the decline in TILs after RT and withholding pembrolizumab during NAC,” study authors concluded. “This novel combination resulted in potent immunogenic responses, paving the way for future opportunities for this window regimen.”
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