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Optimizing Outcomes in Patients with HER2+ Metastatic Breast Cancer

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Inflammatory cytokines plus the human immunodeficiency virus Tat protein apparently trigger the development of early Kaposi's sarcoma. Activated spindle cells provide a self-perpetuating, autocrine-supported mechanism for further development of hyperplastic lesions. In more advanced stages, a true neoplastic process may develop. [ONCOLOGY 10(Suppl):34-36, 1996]

New Developments: A Look to the Future

Although the 70-Gene MammaPrint (MP) assay was not confirmed to be predictive of distant recurrence (DR) in patients with hormone receptor (HR)–positive, early-stage breast cancer, the assay predicted responses to extended letrozole (Femara) therapy (ELT) and identified subsets of patients with low-risk disease who experienced improved outcomes with ELT. These findings from the phase 3 NSABP B-42 study (NCT00382070) were published in the 

Data showed no statistically significant difference in ELT on DR between tumors classified as MP high risk (MP-HR) or low risk (MP-LR; 

 = .38). A statistically significant 10-year benefit of 3.7% was found for DR in MP-LR tumors, (HR, 0.43; 95% CI, 0.25-0.74, 

.002) but a nonsignificant 2.4% benefit was observed for DR with MP-HR tumors (HR, 0.65; 95% CI, 0.34-1.24; 

Compared with the overall population of the B-42 trial (n = 3903), a significantly improved prognosis for DR was noted among those in the translational MP cohort (n = 1866; 

.036). The study authors noted that the relatively low incidence of DR events—especially among tumors classified as ultralow-risk (MP-UL)—limited the study's power to assess this end point and detect significant differences in outcomes following ELT across subgroups.

There was a significant 10-year ELT benefit for disease-free survival (DFS) and breast cancer-free interval (BCFI) for MP-LR tumors not observed in those with MP-HR disease; the interaction between MP and ELT benefit reached statistical significance for these end points (DFS: interaction 

At 10 years, ELT benefit for DR was not statically significant for MP-UL tumors (HR, 0.53; 95% CI, 0.13-2.15; 

 = .37), although a significant effect occurred in low-non-ultralow risk (MP-LNUL) tumors (HR, 0.42; 95% CI, 0.24-0.77; 

 = .003). This difference was not statistically significant (interaction 

 = .89). At 10 years, the DR rate was 4.0%, the DFS rate was 9.5%, and the BCFI rate was 7.9% among those with MP-LNUL tumors. These benefits in the MP-LNUL subgroup were significant and more pronounced compared with those for patients with MP-UL tumors, where the respective 10-year rates were 3%, 1.8%, and 4.1%.

“Overall, these findings may expand the clinical utility of MP beyond prognostic indication because they provide the first evidence suggesting that MP is predictive of [extended endocrine therapy] benefit,” wrote Priya Rastogi, MD, vice-chair for medical affairs at the National Surgical Breast and Bowel Project and medical oncologist at the Magee-Womens Hospital of the University of Pittsburgh Medical Center, with study coinvestigators in the publication.

 “Future analyses incorporating clinicopathologic characteristics could also further optimize patient selection.”

Included in the prospective-retrospective correlative study were eligible patients with clinical follow-up and available untreated primary tumor tissue. Developers in Irvine, California received tumor blocks, and MP test scores were generated and blinded to clinical outcome. These test results were included in the final clinical data set.

Of patients randomly assigned to letrozole or placebo in the B-42 trial (n = 3966), blocks were available for 2338 patients, with a final translational MP cohort consisting of 1866.

The primary end point of the correlative study assessing the predictive abilities of MP was DR. Secondary end points in this analysis included DFS and BCFI. In the original NSABP-B42 trial, the primary end point was DFS.

The median follow-up time for patients included in the MP cohort was 10.4 years. In total, 706 (37.8%) and 1160 (62.2%) patients were MP-HR or MP-LR, with those in the MP-LR group further disaggregated into MP-UL (n = 252, 13.5%) and low-non-ultralow risk (MP-LNUL, n = 908, 48.7%) subtypes.

There were 102 DR and 457 DFS events observed in the translational cohort. A statistically significant ELT benefit for DFS was observed in the MP-LR group (HR, 0.67; 95% CI, 0.52-0.85; 

< .001) but not in the MP-HR group (HR, 1.10; 95% CI, 0.82-1.47; 

 = .55). Furthermore, a 7.8% improvement was observed in patients undergoing ELT for MP-LR tumors vs placebo, contrasting with a –1.6% difference reported in patients undergoing ELT for MP-HR tumors compared with placebo.

In BCFI, the assumption of hazards proportionality was not satisfied between treatment groups for the MP-HR subgroup; a change point of 5.2 years identified a distinguishable statistically significant difference in ELT effect between MP-HR (HR, 2.77; 95% CI, 1.28-5.99; 

= .01) and MP-LR (HR, 0.37; 95% CI, 0.21-0.66; 

< .001) subgroups. Prior to 5.2 years, ELT benefit was similar between MP-HR and MP-LR subgroups.

Rastogi P, Bandos H, Lucas PC, et al. Utility of the 70-Gene MammaPrint assay for prediction of benefit from extended letrozole therapy in the NRG Oncology/NSABP B-42 trial. 

 Published online July 24, 2024. doi:10.1200/JCO.23.01995

Letrozole in treating postmenopausal women who have received hormone therapy for hormone receptor-positive breast cancer. ClinicalTrials.gov. Accessed August 14, 2024. https://tinyurl.com/2dhreevh

NSABP B-42 trial results show that the assay was predictive of extended letrozole therapy response, identifying a patient subset with improved outcomes.

Gene Assay May Predict Extended Letrozole Benefits in Breast Cancer Subsets

An overall survival benefit was observed when patients with resectable esophageal cancer were given perioperative chemotherapy with docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) vs neoadjuvant chemoradiation (CROSS), according to results from the phase 3 ESOPEC trial (NCT02509286) presented during the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting

At a median follow-up of 55 months, patients in the intention-to-treat population who received the FLOT protocol (n = 221) achieved a median OS of 66 months (95% CI, 36-not evaluable [NE]) compared with 37 months (95% CI, 28-43) among those who were treated with the CROSS protocol (n = 217; HR, 0.70; 95% CI, 0.53-0.92; 

 = .012). The 3-year OS rates were 57.4% vs 50.7%, respectively, and the 5-year OS rates were 50.6% vs 38.7%, respectively.

Additionally, the median progression-free survival (PFS) was 38 months (95% CI, 21-NE) in the FLOT arm compared with 16 months (95% CI, 12-22) in the CROSS arm (HR, 0.66; 95% CI, 0.51-0.85; 

 = .001). The 3-year PFS rates were 51.6% vs 35.0%, respectively, and the 5-year PFS rates were 44.4% vs 30.9%, respectively.

“Many patients in the US and Europe are still treated with the CROSS radiochemotherapy protocol. Our study shows that patients with resectable esophageal cancer should have FLOT chemotherapy before and after the operation in order to optimize the chance of curing their tumors in the long term,” Jens Hoeppner, FAChirg, FACS, MD, the director of the Department of Surgery at University Medical Center, University of Bielefeld, in Detmold, Germany, stated in a press release.

ESOPEC was a prospective multicenter study that enrolled patients with esophageal adenocarcinoma across 25 sites in Germany between February 2016 and April 2020. Eligible patients needed to be at least 18 years old, have received no prior abdominal or thoracic radiotherapy, have an ECOG performance status of 2 or less, and have adequate organ function. Patients were also required to have pretreatment stage cT1N+, M0 or cT2-4a, N0/+, M0 disease. The presence of squamous or other non-adenocarcinoma histology, gastric cancer, clinical stage cT1cN0 and cT4b disease, or metastatic disease excluded patients from enrollment.

Patients were randomly assigned 1:1 to receive either the FLOT or CROSS protocol. Those in the FLOT arm received repeated doses of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel every 2 weeks over 4 neoadjuvant cycles prior to surgery and 4 adjuvant cycles after surgery. In the CROSS arm, patients received neoadjuvant radiation therapy and concurrent chemotherapy with carboplatin and paclitaxel for 5 cycles in 5 weeks prior to surgery. Following neoadjuvant treatment, patients in both arms waited 4 to 6 weeks before proceeding to surgery.

The primary end point was OS. Secondary end points included PFS, recurrence-free survival, postoperative pathological stage, postoperative complications, and postsurgical quality of life.

At baseline, the mean age of patients in the FLOT and CROSS arms was 63.1 years (standard deviation [SD], 8.6) vs 62.6 years (SD, 9.8), respectively. Most patients in both arms were male (89.1% vs 89.4%), had clinical T-stage cT3-4 disease (79.1% vs 81.9%), and had clinical N-stage cN+ disease (77.8% vs 81.6%). Overall, 191 patients in the FLOT arm underwent surgery compared with 180 patients in the CROSS arm.

Additional findings from ESOPEC showed that the pathological complete remission rates among patients who underwent surgery in the FLOT arm was 16.8% compared with 10.0% in the CROSS arm. In both arms, complete regression (18.3% vs 13.3%) or near complete regression (25.1% vs 39.4%) was observed. Most patients across both arms underwent an R0 resection (94.2% vs 95.0%).

Patients in the predefined protocol population in the FLOT (n = 207) and CROSS (n = 196) arms achieved a median OS of 66 months (95% CI, 38-NE) vs 39 months (95% CI, 29-45), respectively (HR, 0.72; 95% CI, 0.54-0.96; 

 = .023). The 3-year OS rates were 58.1% vs 52.6%, respectively, and the 5-year OS rates were 51.8% vs 40.5%, respectively.

Results from an exploratory subgroup analysis demonstrated that the OS benefit in favor of FLOT vs CROSS was observed in all subgroups examined. The most pronounced benefit was reported in patients aged less than 60 years (HR, 0.57; 95% CI, 0.34-0.95) and those with clinical T-stage T3-4 disease (HR, 0.68; 95% CI, 0.50-0.92).

Most patients in both the FLOT and CROSS arms started neoadjuvant treatment; these patients comprised the predefined protocol population. A majority of patients in both arms completed neoadjuvant treatment (87.3% vs 67.7%) and received neoadjuvant treatment plus surgery (86.0% vs 82.9%). In the FLOT arm, 63.3% of patients received adjuvant treatment and 52.5% completed adjuvant treatment.

In the 90 days post-surgery, 3.2% of patients in the FLOT arm died compared with 5.6% in the CROSS arm. The 30-day postoperative mortality rates were 1.0% vs 1.7%, respectively At the data cutoff, 97 and 121 patients died in these respective arms.

“Perioperative chemotherapy with FLOT plus surgery improves OS compared with neoadjuvant chemoradiation with CROSS plus surgery in patients with locally advanced, resectable esophageal adenocarcinoma. ESOPEC found that perioperative chemotherapy with FLOT should be preferred over neoadjuvant chemoradiation with the CROSS protocol for improving survival in resectable esophageal adenocarcinoma,” Hoeppner concluded in an oral presentation.

Hoeppner J, Brunner T, Lordick F, et al. Prospective randomized multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (ESOPEC trial).

. 2024;42(suppl 17):LBA1. doi:10.1200/JCO.2024.42.17_suppl.LBA1

Chemotherapy before and after surgery may be new standard treatment for some patients with esophageal cancer. News Release. ASCO. June 2, 2024. Accessed June 2, 2024. https://society.asco.org/about-asco/press-center/news-releases/chemotherapy-and-after-surgery-may-be-new-standard-treatment

Perioperative chemotherapy compared to neoadjuvant chemoradiation in patients with adenocarcinoma of the esophagus (ESOPEC). ClinicalTrials.gov. Updated May 8, 2024. Accessed June 1, 2024. https://clinicaltrials.gov/study/NCT02509286

study was published on June 2, 2024, from the press briefing, and was updated on June 4, 2024, with additional information/data from the oral session.

The combination of perioperative chemotherapy plus FLOT improved overall survival vs neoadjuvant chemoradiation in patients with resectable esophageal cancer. 


Conference

OS Prolonged With Perioperative Chemo Vs Neoadjuvant CRT in Esophageal Cancer 

The FDA has accepted a biologics license application (BLA) for a subcutaneous formulation including nivolumab (Opdivo) and hyaluronidase (rHuPH20) for adult patients with solid tumors for which standard intravenous nivolumab has already received approval, according to a press release from the developers, Bristol Myers Squibb.

If approved, patients would be eligible to receive subcutaneous nivolumab as monotherapy, monotherapy maintenance after receiving prior nivolumab plus ipilimumab (Yervoy), or as part of a combination regimen including chemotherapy or cabozantinib (Cabometyx). The regulatory agency has set a Prescription Drug User Fee Act date of February 28, 2025, for its decision on approving the subcutaneous formulation of the agent.

(Editor's Note: As of May 21, 2024, the FDA updated the Prescription Drug User Fee Act date for subcutaneous nivolumab to December 29, 2024.)

“We believe subcutaneous nivolumab has the potential to make a significant difference in the lives of patients, which is reinforced by the FDA’s acceptance of our application,” Gina Fusaro, PhD, vice president and global program lead at Bristol Myers Squibb, said in the press release.

“[Nivolumab] is a foundational PD-1 inhibitor approved for many different types of cancer, and our continued investment in research that puts patients first remains a priority. If approved by the FDA, the subcutaneous administration of nivolumab would provide patients and their physicians with a new option that delivers the same well-known benefits as [intravenous nivolumab] but with the improved convenience of an injection administered in 3-to-5 minutes rather than a 30-to-60-minute infusion.”

Supporting findings for the BLA came from the 

phase 3 CheckMate-67T trial (NCT04810078),

 in which investigators compared treatment with intravenous vs subcutaneous nivolumab in previously treated patients with advanced or metastatic clear cell renal cell carcinoma (RCC). Updated findings from the CheckMate-67T trial were presented at the 

In the CheckMate-67T trial, 495 patients were randomly assigned to receive either subcutaneous (n = 248) or intravenous (n = 247) nivolumab. ORR was a key secondary end point of the trial.

Regarding the coprimary end point of time-averaged nivolumab serum concentration over 28 days (Cavgd28), treatment with subcutaneous nivolumab demonstrated noninferiority compared with the intravenous formulation with a geometric mean ratio of 2.098 (90% CI, 2.001-2.200).

 Additionally, the subcutaneous formulation exhibited noninferiority with respect to the coprimary end point of trough serum concentration at steady state (Cminss) with a geometric mean ratio of 1.774 (90% CI, 1.633-1.927).

The objective response rate (ORR) was 24.2% with subcutaneous nivolumab vs 18.2% with the intravenous formulation (relative risk, 1.33; 95% CI, 0.94-1.87). Additionally, the median progression-free survival according to blinded independent central review was 7.23 months vs 5.65 months, respectively.

Grade 3/4 adverse effects (AEs) occurred in 35.2% of patients in the subcutaneous arm vs 40.8% of those in the intravenous arm. Additionally, 9.7% and 14.7% of patients in each respective arm had treatment-related AEs, 21.1% and 22.9% had serious AEs, and 6.5% and 6.5% experienced treatment-related serious AEs.

Investigators concluded that the safety profile of subcutaneous nivolumab was comparable with prior reports of the intravenous formulation.

“The data from CheckMate-67T with the subcutaneous formulation of nivolumab co-formulated with recombinant human hyaluronidase represent a groundbreaking advancement in oncology research for physicians and our patients,” Saby George, MD, FACP, a professor of Oncology and Medicine and the director of Network Clinical Trials in the Department of Medicine at Roswell Park Comprehensive Cancer Center said in a press release about these data.

“Having the option to administer immunotherapy subcutaneously could undoubtedly reduce the treatment burden that patients diagnosed with cancer currently [have], as well as help maximize efficiencies within healthcare systems. As it stands, intravenous immunotherapy infusion can take precious time, which we know is an important commodity for patients and the doctors who treat them. That’s why these results indicating noninferiority with subcutaneous nivolumab have the potential to be practice-changing and to improve patients’ treatment experience with one injection that can be given in under five minutes and, in some cases, outside of the infusion center,” George concluded.

U.S. Food and Drug Administration accepts Bristol Myers Squibb’s application for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 6, 2024. Accessed May 6, 2024. https://bit.ly/3JL8yY1

Bristol Myers Squibb announces updated action date by the U.S. Food and Drug Administration for subcutaneous nivolumab (nivolumab and hyaluronidase). News release. Bristol Myers Squibb. May 21, 2024. Accessed May 21, 2024. https://tinyurl.com/3emkwdk2

Subcutaneous nivolumab (nivolumab and hyaluronidase) shows noninferiority compared to intravenous Opdivo (nivolumab) in advanced or metastatic clear cell renal cell carcinoma in CheckMate -67T trial. News release. Bristol Myers Squibb. January 27, 2024. Accessed May 6, 2024. https://bit.ly/4dvCMvQ

Data from the CheckMate-67T trial support the biologics license application for subcutaneous nivolumab in multiple solid tumors.

FDA Accepts BLA for Subcutaneous Nivolumab in Solid Tumor Indications

For the duration of an extended cisplatin shortage beginning February 10, 2023, utilization of chemotherapy shifted to the use of alternative therapies, including carboplatin and cetuximab (Erbitux), for patients with head and neck cancers, according to a study presented at the 2024 American Society of Clinical Oncology (ASCO) Quality Care Symposium.

Additionally, the increase of the overall cost of cisplatin has persisted even after the resolution of the shortage, highlighting a shift in treatment and a more pronounced financial burden for this patient group.

“Drug shortages have become an all-too-common occurrence in oncology care, disrupting patient treatment, impacting where and how health care providers spend their time, and causing broad-ranging effects on the health care system. These results show the multi-faceted consequences of drug shortages and serve to provide evidence in the call-to-action for all health care and participating supply chain stakeholders to resolve the problem of drug shortages,” Puneeth Indurlal, MD, MS, MBBS, vice president of Practice Operations at The American Oncology Network, said in a press release on the study findings.

Results from the ASCO presentation reveal that from May to August 2023, cisplatin use decreased by 15%, with increases of carboplatin by 40%, paclitaxel by 24%, cetuximab by 15%, and fluorouracil by 5% were observed over the same period. The investigators highlighted that these results were profound for new treatment starts in the same timeframe, with the majority of treatment changes occurring among patients undergoing treatment for curative intent.

Additionally, the average drug cost per administration has increased during and after the shortage period, an increase of more than $150 from July 2022 before the shortage to March 2024 after the shortage. Additionally, by March 2024, the average cost per administration had exceeded the August 2023 amount by roughly $25, despite the shortage having concluded more than 6 months prior.

Another key finding revealed that the use of category 2B National Comprehensive Cancer Network treatment recommendations in the absence of the category 1 recommended cisplatin alone or as a combination therapy often incurred greater impacts on the cost of care. The most pronounced impact is seen with cetuximab, which, on average, costs more than the cost of cisplatin per administration, with Medicare average sale price-based reimbursements of $18 for cisplatin and $2607 for cetuximab.

If patients had medicare without secondary insurance, cisplatin costs $3.60 and cetuximab costs $521.40. Additionally, if patients had commercial insurance with a $3000 deductible, 20% coinsurance, and $6000 out of pocket, cisplatin cost $21.60 and cetuximab cost $3025.68.

The study sought to describe the effects of the cisplatin shortage on The US Oncology Network practices for the treatment of patients with head and neck cancers. Specifically, the study aimed to assess chemotherapy utilization trends leading up to the shortage, during the shortage, and after the shortage concluded by overall use and new treatment starts as well as treatment intent. Additionally, the impact on costs was assessed, including payer impact and estimated patient responsibility.

The study period began in July 2022 and ended in March 2024. Pre-shortage occurred from July 2022 to January 2023, during the shortage occurred from February 2023 to August 2023, and post-shortage occurred from September 2023 to March 2024.

Chemotherapy evaluation was assessed through drug administration records from electronic health records (EHR). Costs associated with administered chemotherapy were evaluated through financial claims from a financial data warehouse.

Additionally, following the FDA announcement of the cisplatin shortage, cisplatin, paclitaxel, carboplatin, and fluorouracil were placed on the Fair Share Program, which is designed to allocate existing supply to practices based on historical use patterns while mitigating reactive product purchasing. Paclitaxel, fluorouracil, cisplatin, and carboplatin were kept on the Fair Share Program until April, September, and October 2023, and January 2024, respectively.

“Cancer drug shortages in the United States most commonly occur with chemotherapy agents that are generic and inexpensive. This study shows that switches to alternative regimens in patients with head and neck cancer during the 2023 cisplatin/carboplatin drug shortage crisis involved the use of more expensive substitutes (specifically the monoclonal antibody cetuximab), resulting in significant increases in the cost of care for payers and patients. Whether switches made during the recent drug shortages will ultimately be shown to result in equivalent or possibly poorer outcomes remains to be seen.” Julie R. Gralow, MD, FACP, FASCO, chief medical officer and executive vice president of ASCO stated in the press release.

Indurlal P, Garey JS, Albaugh J, et al. Prescription predicament: unveiling the financial fallout of drug shortages. 

 2024;20(suppl 10). doi:10.1200/OP.2024.20.10_suppl.1

While cisplatin was in shortage, clinicians were forced to prescribe costlier alternatives for patients with head and neck cancer. 

Barbara Ensoli, MD, PhD

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