Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0–2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3–4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477.
1060 Background: Although hyperglycemia is recognized as a common adverse event (AE) on alpelisib (ALP), this AE has been little studied outside clinical trials. We report the frequency of ALP-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. Methods: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with ALP+fulvestrant (FUL) between August 2019 and December 2021. Five primary characteristics (diabetes, prediabetes, body mass index (BMI), age, Asian ancestry) were evaluated as independent risk factors for ALP-associated hyperglycemia using ordinal logistic regression that considered 3 glycemic levels: normoglycemia, grade 2, and grade 3-4 hyperglycemia. Overall risk of error from multiple hypothesis testing was kept below 5% using the False Discovery Rate method. Results: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years, 13.0% with Asian ancestry. One third (33.7%) of patients had pre-existing diabetes, another 9.8% had pre-diabetes only. One third (32.6%) were obese, another third (31.5%) were overweight. Hypertension and hyperlipidemia were present in 53.3% and 41.3%, respectively. On ALP+FUL, 59 (64.1%) current subjects developed hyperglycemia of grade 1-4, a rate no different than the 181/284 (63.7%) reported in the ALP+FUL arm of the SOLAR-1 trial. Among our subjects, risk of grade 2-4 hyperglycemia was independently increased by 4 of 5 hypothesized risk factors, specifically pre-existing diabetes (Odds Ratio 3.75, 95% Confidence Interval: 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), each unit of BMI above 20 (1.17, 1.07-1.28), but not by additional year of age (1.01, 0.97-1.05). Exploratory analysis detected no association with pre-existing hypertension or hyperlipidemia. Conclusions: These findings suggest that Asian ancestry merits further study as a predisposing factor for ALP-associated hyperglycemia. Our study of this AE also demonstrates that pre-existing hyperglycemia and greater BMI are independent risk factors; diabetes and pre-diabetes confer similar degrees of risk; risk from BMI begins after BMI 20 and rises incrementally; and age is not a contributing factor.
Background Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. Patients and Methods We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. Results The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects’ risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). Conclusion While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.
e13071 Background: Pembrolizumab (pembro) in combination with chemotherapy (chemo) has recently become standard of care in patients with programmed death-ligand 1 (PD-L1) positive metastatic triple negative breast cancer (mTNBC). Optimal chemo partner with pembro remains debatable. The current phase I study evaluated the safety and efficacy of doxorubicin (dox) + pembro in anthracycline-naïve mTNBC patients (NCT02648477). Methods: Patients with mTNBC, no prior anthracycline, and ≤2 lines of prior chemo for metastatic disease were enrolled. Patients received pembro 200mg IV and 50-60 mg/m2 dox IV every 3 weeks x6, followed by pembro maintenance until progression or unacceptable toxicity. The primary objectives were safety and objective response rate (ORR per RECIST 1.1). For the safety lead-in, we employed a 3-at-risk rolling design. Results: Ten patients were accrued between March 2016 and November 2019. The trial stopped early due to poor accrual. The first 3 patients received dox at 50mg/m2 without dose limiting toxicities and dose was escalated to 60mg/m2 for the remaining patients. Median age was 62 years (range 41-87). Grade ≥ 3 AEs were: 4 neutropenia, 2 dyspnea, 2 fatigue, 1 oral mucositis, 1 hyponatremia, 1 acidosis, 1 alkalosis, 1 hypotension and 1 respiratory failure. One patient (age 87) received 1 dose of therapy, developed neutropenia and respiratory failure which led to death, and was not eligible for response assessment. 1 patient did not have RECIST measurable disease. Two patients had dose delay (1 G3 neutropenia and 1 G2 upper airway infection). 1 patient had dose reduction due to G3 fatigue. Immune toxicity was consistent with known pembro toxicity. Of 9 evaluable patients, responses were : 1 CR, 3 PR, 2 UPR, 2 SD and 1 PD, which translated to a best ORR of 67% (95% CI, 13.7%, 78.8%). CBR at 6 mo was 56% (95% CI 21.2%, 86.3%). Median follow-up time was 34.6 mo (range 14.5 - 45.4 mo). Median PFS was 5.2 mo (95% CI 4.7, NA); and median OS was 15.6 mo (95% CI 13.3, NA). Eight patients had PD-L1 (22C3) testing: 4 positive and 4 negative. No association between the PD-L1 status and response was observed. Conclusions: The combination of pembro+dox was well tolerated and had modest activity in anthracycline-naïve patients with mTNBC. The finding needs to be further confirmed with future study. Clinical trial information: NCT02648477.
This study investigated the safety and antitumor activity of aromatase inhibitors (AI) with immune checkpoint inhibitor (ICI) pembrolizumab in patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (MBC) in a phase II study with a safety lead-in (NCT 02648477). Patients received pembrolizumab plus AI up to 2 years or until confirmed progression or unacceptable toxicity. Key eligibility criteria were HR+ HER2− MBC; RECIST v1.1 measurable disease; adequate organ function; and ECOG 0-1. Primary endpoints were safety and overall response rate. A 3-at-risk design was used for the safety lead-in with a targeted accrual of 20 patients. Grade 2 adverse events (AEs) included 35% fatigue, 20% rash, and 10% hot flashes. Grade 3 immune-related AEs (irAEs) related to pembrolizumab included 5% elevated AST/ALT, 5% rash, and 5% lymphopenia. Two (10%) patients had partial responses, three (15%) had stable disease, and 15 (75%) had progression of disease. Median progression-free survival was 1.8 months (95% CI 1.6, 2.6), median overall survival was 17.2 months (95% CI 9.4, NA), and median follow-up time was 40.1 months (range 31.3–46.8 months). The combination was well tolerated, but clinical activity was comparable to AI alone.
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