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BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)

Background: Studies of immune checkpoint inhibitors combined with chemotherapy show activity in metastatic breast cancer (MBC). There is no data regarding sequencing of pembrolizumab (pem) in relation to chemotherapy in MBC patients (pts). We investigated the safety of a phased schedule vs concurrent schedule of paclitaxel (pac) and pembrolizumab (pem). Methods: Eligible pts had HR+HER2-negative or triple-negative (TN) MBC, ≥2 lines of hormone therapies and 0-3 prior lines of chemotherapy for MBC. Pts were randomized 1:1 to 2 cycles of pac 80 mg/m2 IV on D1 and D8 followed by pac and pem 200 mg/m2 IV on D1 of a 21-day cycle (Arm A; phased schedule) or pac and pem given together starting D1 of a 21-day cycle (Arm B; concurrent) and continuing until progression or toxicity. Primary objective was to continuously monitor overall grade 3 or 4 treatment-related adverse event (TRAE) rate for each arm and compare to relevant historical controls with Bayesian stopping rules. If the grade 3 or 4 TRAE rate convincingly exceeded 0.35 on either arm, enrollment to that arm would be halted. Secondary objectives were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses assessed PD-L1 and tumor infiltrating lymphocytes (TILs) in the tumor and blood markers immunotyping. Results: Forty female pts were randomized (21 in Arm A and 19 in Arm B). Median age was 40 (range 28-76). Twenty pts were HR+HER2-negative; 20 pts had TNBC; 7 pts had de novo MBC. Median prior lines of chemotherapy was 1 (range 0 - 3); median no. of cycles was 7 (1-27); 7 pts in Arm A did not initiate pembrolizumab due to disease progression. The criteria for stopping enrollment based on Bayesian stopping rules were not met for either arm; 24% of subjects (5 of 21) on Arm A and 32% (6 of 19) on Arm B experienced stopping rule events. At the data cut-off of 2/16/21, with median follow-up of 10.1 months, overall ORR was 30% with 12 partial responses, and ORR in HR+HER2-negative and TNBC were 30% and 30%, respectively. Grade 3-4 TRAE rates were 24% in Arm A and 32% in Arm B. The most common grade 3-4 TRAES were peripheral sensory neuropathy (2 pts [10%] in Arm A; 3 pts [16%] in Arm B), decreased neutrophil count (1 pt [5%] in each Arm), and anemia (1 pt [5%] in each Arm). In the overall group, immune-related adverse events (irAEs) occurred in 28% of pts; 5% of these events were ≥ grade 3 in Arm A (gr 3 AST/ALT increased in 1 pt) and 5% in Arm B (gr 3 lipase increased in 1 pt). The most common irAE was hypothyroidism (6 pts, 15%). Tumor PD-L1 assay and TILs were performed in 39 pts and blood immunotyping on all pts. Seven pts (18%) had PD-L1 positive tumors (PDL-1 H-score ≥ 5, centrally tested) and 19 (48.7%) had significant immune infiltration (TILs score 2-3). Biomarker analysis is currently in progress. Updated data, including ORR, PFS and OS by arm, is expected to be presented. Conclusions: Both the phased and concurrent schedules of pac and pem were found to be safe and feasible. The combination’s safety profile was consistent with the known individual agent’s safety profile. Clinical activity was demonstrated in both metastatic HR+HER2-negative and TNBC pts. Clinical trial information: NCT03018080. Citation Format: Antoinette R. Tan, S. Jean Chai, Myra M. Robinson, Lane B. Hellner, Nagajyothi Gavini, Nanna Sulai, J. David Turner, Jennifer Atlas, David L. Graham, Raghava R. Induru, Kunal C. Kadakia, Geetha D. Vallabhaneni, Arielle L. Heeke, David M. Foureau, Julie G. Fisher. A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-03.

Historically, oncology clinical trials have focused on comparing a new drug’s efficacy to the standard of care. However, as our understanding of molecular pathways in oncology has evolved, so has our ability to predict how patients will respond to a particular drug, and thus comparison with a standard therapy has become less important. Biomarkers and corresponding diagnostic testing are becoming more and more important to drug development but also limit the type of patient who may benefit from the therapy. Newer clinical trial designs have been developed to assess clinically meaningful endpoints in biomarker-enriched populations, and the number of modern, molecularly driven clinical trials are steadily increasing. At the same time, barriers to clinical trial enrollment have also grown. Many barriers contribute to nonenrollment in clinical trials, including patient, physician, institution, protocol, and regulatory barriers. At the protocol level, eligibility criteria have become a large roadblock to clinical trial accrual. Over time, eligibility criteria have become more and more restrictive. To accrue an adequate number of patients to molecularly driven trials, we should consider eligibility criteria carefully and attempt to reduce restrictive criteria. Reducing restrictive eligibility criteria will allow more patients to be eligible for clinical trial participation, will likely increase the speed of drug approvals, and will result in clinical trial results that more accurately reflect treatment of the population in the clinical setting.

Bisphosphonates, synthetic analogues to inorganic pyrophosphates found in the bone matrix, inhibit bone resorption. Bisphosphonates and their related effects on the jaw have been established since 2001. The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is multifactorial and still under investigation. Currently, drugs with mechanisms of action involving remodeling suppression, osteoclast depression, and decreasing angiogenesis are under investigation for causing BRONJ-like symptoms. Further studies are needed to determine the effective length of use of biphosponates and the efficacy of drug holidays to prevent BRONJ.

Six Sigma is a methodology that drives process improvement. It relies heavily on data analysis and statistical tools. Minitab statistical software progresses Six Sigma initiatives through its easy-to-use interface and informative results. This paper discusses a few applications of statistical tools in a variety of Six Sigma projects from the service industry.