Patients with high-risk, early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer treated with neoadjuvant (presurgical) Keytruda (pembrolizumab) plus chemotherapy followed by adjuvant (postsurgical) Keytruda plus endocrine therapy experienced a statistically significant increase in pathologic complete response (pCR, when there is no detectable disease in biopsied or surgically removed tissue following treatment) when compared with patients treated with neoadjuvant placebo plus chemotherapy followed by adjuvant Keytruda and endocrine therapy, according to data from the phase 3 KEYNOTE-756 trial presented at the 2023 ESMO Congress.
At a data cutoff date of May 25, 2023 and a median follow-up of 33.2 months, 24.3% of the 635 patients who received Keytruda had achieved a pCR versus 15.6% of the 643 patients who received placebo.
“Although we may say that this subtype, in general, has a better prognosis than other breast cancer subtypes, we all know that there is a high-risk subpopulation for whom we also reserve chemotherapy,” Fatima Cardoso, director of the breast unit at Champalimaud Clinical Center in Lisbon, Portugal, said in a presentation of the data.
In the phase 2 I-SPY2 trial, Keytruda plus neoadjuvant chemotherapy improved estimated pCR rates vs. neoadjuvant chemotherapy alone, at 30% vs. 13%, in patients with hormone receptor-positive, HER2-negative breast cancer.
“Immune checkpoint inhibition may enhance endogenous anticancer immunity when combined with chemotherapy,” Cardoso explained in the presentation.
KEYNOTE-756 included those with locally confirmed invasive ductal breast carcinoma. Patients needed to have T1c to T2 disease and one to two positive lymph nodes or T3 to T4 disease with zero to two positive lymph nodes. Eligible patients were also required to be treatment-naïve and have centrally confirmed, ER-positive, HER2-negative, grade 3 disease.
A total of 1,278 patients were randomly assigned evenly to receive either 200 milligrams of Keytruda or placebo every three weeks for four cycles plus 12 weeks of Taxol (paclitaxel) at 80 milligrams/m2 followed by four cycles of 200 milligrams of Keytruda or placebo plus either Adriamycin (doxorubicin) at 60 milligrams /m2 every three weeks or Ellence (epirubicin) at 100 milligrams/m2 every three weeks and Cytoxan (cyclophosphamide) at 600 milligrams/m2 every two weeks or every three weeks.
Following surgery, patients received either 200 milligrams of Keytruda or placebo every three weeks for six months, endocrine therapy for up to 10 years and radiotherapy if indicated.
Of the 635 patients in the intention-to-treat population who received Keytruda, 99.8% started paclitaxel, 94.2% started Adriamycin plus Cytoxan or Ellence plus Cytoxan, 96.7% had documented surgery and 75.3% began adjuvant treatment. Fourteen patients (2.2%) discontinued neoadjuvant treatment because of progressive disease (PD). The safety evaluable Keytruda population included 634 patients.
Of the 643 patients in the intention-to-treat population who received placebo, 99.7% started paclitaxel, 95.2% started Adriamycin plus Cytoxan or Ellence plus Cytoxan, 98.1% had documented surgery, and 81.5% began adjuvant treatment. Thirteen patients (2.0%) discontinued neoadjuvant treatment because of PD. The safety-evaluable placebo population included 642 patients.
“All subgroups derive a benefit from Keytruda,” Cardoso noted in the presentation. Particularly, 55.9% of patients with ER-low disease who received Keytruda (34 patients) achieved a pCR versus 30.2% of those who had ER-low disease and received placebo (43 patients).”
“This is a piece of data that is very important for those of us who believe these tumors behave more like triple-negative (disease) than ER-positive (disease),” Cardoso emphasized.
In the neoadjuvant phase of the trial, 98.4% and 98.6% of patients in the Keytruda and placebo arms, respectively, experienced any-grade treatment-related side effects. In the Keytruda arm, grade 3 to 5 and serious side effects occurred in 52.5% and 18.5% of patients compared with 46.4% and 10.3% of patients in the placebo arm.
Treatment-related side effects led to discontinuation of any drug in 19.1% and 10.1% of patients in the Keytruda and placebo arms, respectively. In the Keytruda arm, one patient died from acute myocardial infarction (heart attack).
The most common treatment-related side effects in the Keytruda and placebo arms, respectively, were alopecia (64% vs. 60.9%), nausea (48.3% vs. 50.0%), anemia (32.3% vs. 25.5%), fatigue (30% vs. 28.0%), diarrhea (27.1% vs. 20.2%), increased alanine transaminase (24.9% vs. 22.9%), neutropenia (23.0% vs. 24.6%), increased aspartate aminotransferase (21.6% vs. 16.7%), decreased neutrophil counts (21.6% vs. 23.8%), asthenia (21.1% vs. 18.1%), vomiting (20.0% vs. 16.8%) and peripheral neuropathy (17.5% vs. 20.2%).
In the neoadjuvant phase of the trial, 32.8% and 7% of patients in the Keytruda and placebo arms, respectively, experienced any-grade immune-mediated side effects. Grade 3 to 5 and serious immune-mediated side effects occurred in 7.1% and 6.2% of patients in the Keytruda arm compared with 1.2% and 1.7% of those in the placebo arm. Immune-mediated side effects led to discontinuation of any drug in 7.7% and 1.6% of patients in the Keytruda and placebo arms, respectively. No immune-mediated side effects resulted in death in either arm.
The most common immune-mediated side effects in the Keytruda and placebo arms, respectively, were hypothyroidism (17.5% vs. 1.7%), hyperthyroidism (9% vs. 0.5%), pneumonitis (2.8% vs 1.4%), adrenal insufficiency (2.5% vs. 0%), severe skin reactions (2.2% vs. 0.5%), hypophysitis (1.9% vs. 0.2%), thyroiditis (1.7% vs. 0.3%), hepatitis (1.3% vs. 0.5%), colitis (0.9% vs. 0.8%) and vasculitis (0.8% vs. 0.6%).
“There was a consistent benefit (with Keytruda,) independent of the definition of pCR,” Cardoso concluded. “Safety was also consistent with what we already know, (and there were) no new safety signals.”
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