Author: RR

VIJOICE® (Alpelisib)

RR

The FDA on April 5, 2022, granted accelerated approval to VIJOICE® for adult and pediatric patients two years of age and older with severe manifestations of PIK3CA-Related Overgrowth Spectrum (PROS) who require systemic therapy. VIJOICE® is a product of Novartis Pharmaceuticals Corporation.

KEYTRUDA® (Pembrolizumab)

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The FDA on March 21, 2022, approved KEYTRUDA® (Pembrolizumab) as a single agent, for patients with advanced endometrial carcinoma that is MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting, and who are not candidates for curative surgery or radiation. KEYTRUDA® is a product of Merck & Co., Inc.

Late Breaking Abstract – ASCO 2022: FOLFOXIRI Plus Bevacizumab in Unresectable Colorectal Cancer with Liver Metastases

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 151,030 new cases of CRC will be diagnosed in the United States in 2022 and about 52,580 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations and BRAF V600E is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease and do not respond as well to standard treatment intervention. Approximately 20% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Colorectal cancer patients with unresectable liver-only metastases at the time of initial presentation may potentially be cured, after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined.

CAIRO5 is a prospective, randomized, multicentre, Phase III trial, conducted to investigate the optimal systemic induction therapy for patients with initially unresectable, liver-only colorectal cancer metastases. In this study, 294 patients were randomized to receive either FOLFOX or FOLFIRI plus Bevacizumab (N=148), or FOLFOXIRI plus Bevacizumab (N=146) for up to 12 cycles. Bevacizumab was given at a dose of 5 mg/kg IV. FOLFOX/FOLFIRI regimen consisted of either Oxaliplatin 85 mg/m2 IV or Irinotecan 180 mg/m2 IV, given along with Leucovorin 400 mg/m2 IV over 120 minutes, 5-Flourouracil (5-FU) 400 mg/m2 IV, followed by 5-FU 2400 mg/m2 given as an IV infusion over 46 hours. FOLFOXIRI regimen consisted of Oxaliplatin 85 mg/m2 IV, Irinotecan 165 mg/m2 IV, given along with Leucovorin 400 mg/m2 IV over 120 minutes, followed by 5-FU 3200 mg/m2 given as an IV infusion over 46 hours. Treatment was given every 2 weeks for a maximum of 12 cycles, followed by 5-FU, Leucovorin and Bevacizumab maintenance until disease progression. Enrolled patients had metastatic CRC with previously untreated liver-only metastases, (un)resectability status was prospectively assessed by a central panel consisting of radiologists and liver surgeons, according to predefined criteria, and patients were assessed for resectability every 2 months. Eligible patients had right-sided primary tumor and/or RAS or BRAF V600E mutated tumor. Both treatment groups were well balanced. The median age was 63 years, 41% had right-sided primary tumor, 86% of tumors had RAS mutation, 7% had BRAF V600E mutation, 5% had prior adjuvant chemotherapy, the median number of colorectal liver metastases was 12, and 87% had potentially resectable colorectal metastases. Patients were stratified by potentially resectable versus permanently unresectable colorectal liver metastases, BRAFV600E mutation, sidedness and choice of Irinotecan versus Oxaliplatin. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included R0/1 resection, Overall Survival (OS), Overall Response Rate (ORR), toxicity, pathologic response and postoperative morbidity.

At a median follow up of 41 months, the median PFS was 9.0 months with doublet regimen FOLFOX/FOLFIRI plus Bevacizumab versus 10.6 months with the triplet regimen of FOLFOXIRI plus Bevacizumab. (HR=0.74; P=0.02). The ORR was 32% in the FOLFOX/FOLFIRI plus Bevacizumab group versus 52.1% in the FOLFOXIRI plus Bevacizumab group (P<0.001), R0/1 resection/ ablation rates were 37.4% versus 51.4% (P=0.02), and postoperative complications occurred in 38.2% versus 51.2% (P=0.14), respectively. Overall Survival data was immature at the time of data cutoff. Grade 3 or more adverse events, including neutropenia and diarrhea, were more common in the FOLFOXIRI plus Bevacizumab group.

It was concluded that in patients with initially unresectable colorectal cancer liver metastasis and right-sided and/or RAS or BRAF-mutated primary tumor, the triplet regimen of FOLFOXIRI plus Bevacizumab resulted in superior Progression Free Survival, a higher Objective Response Rate, and a greater chance for R0/R1 hepatic metastasectomy with or without ablation, compared to doublet chemotherapy with FOLFOX or FOLFIRI plus Bevacizumab. This benefit with the triplet regimen was achieved at the cost of increased toxicity, suggesting that careful patient selection should be made for the triplet regimen.

FOLFOXIRI + bevacizumab versus FOLFOX/FOLFIRI + bevacizumab in patients with initially unresectable colorectal liver metastases (CRLM) and right-sided and/or RAS/BRAFV600E-mutated primary tumor: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group. Punt CJA, Bond MJG, Bolhuis K, et al. J Clin Oncol. 2022;40(suppl 17):LBA3506.

Late Breaking Abstract – ASCO 2022: RVd Plus Autologous Stem Cell Transplantation and REVLIMID® Maintenance Improves PFS in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, Multiple Myeloma (MM) in 2022 remains an incurable disease.

In patients with newly diagnosed Myeloma who are eligible for transplant, the optimal use of triplet/quadruplet induction regimens, Autologous Stem Cell Transplantation (ASCT), and REVLIMID® (Lenalidomide)-based maintenance, continues to evolve. In the IFM 2009 French trial, REVLIMID® maintenance treatment was admininstered for one year and after a median follow-up of 89.8 months, the median Progression Free Survival (PFS) was 47.2 months with RVd plus ASCT and 35 months with RVd alone, but there was no Overall Survival (OS) benefit.

DETERMINATION ((Delayed vs Early Transplant with Revlimid Maintenance and Antimyeloma Triple Therapy) trial is a randomized Phase III trial, conducted to determine whether Autologous Stem Cell Transplantation (ASCT) enhances the efficacy of first line triplet induction therapy or whether it should be kept in reserve for select group of patients. In this study, 722 patients with symptomatic newly diagnosed Myeloma were enrolled. All patients received 3 cycles of RVd followed by stem cell mobilization (for possible ASCT if disease progressed). Patients were then randomly assigned to receive 5 additional cycles of RVd (RVd-alone arm, N=357) or Melphalan at 200 mg/m2, followed by ASCT and 2 additional cycles of RVd (RVd+ASCT arm, N=365). Each RVd cycle consisted of REVLIMID® 25 mg orally on days 1-14, VELCADE® (Bortezomib) 1.3 mg/m2 IV or SC on days 1, 4, 8, 11, and Dexamethasone given orally on days 1, 2, 4, 5, 8, 9, 11, 12, given as 21 day cycles. Dexamethasone was dosed at 20 mg/day for first 3 cycles and 10 mg/day for remaining cycles. Both treatment groups then received REVLIMID® maintenance at 10-15 mg orally daily, until disease progression or drug related toxicities. Both treatment groups were well balanced. The median age of enrolled patients was 56 years, approximately 14% of patients had ISS Stage III Multiple Myeloma and 18% had high-risk cytogenetics such as t(4;14), t(14;16), del17p. Approximately 19% of trial participants were African American, which is the highest representation of this subset of patients in any Phase III Myeloma trial. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Response Rates, Duration of Response (DOR), time to progression, Overall Survival (OS), Quality of Life, and Safety.

At a median follow up of 76 months, the median PFS was 46.2 months in the RVd alone group versus 67.6 months in the RVd plus ASCT group (HR=1.53; P<0.0001). The estimated 5-year PFS rates were 41.5% and 55.6% respectively. The 5 year Overall Survival was similar and not statistically different and was 79.2% and 80.7% respectively. The authors attributed the lack of Overall Survival in the RVd plus ASCT group to the availability of many highly effective treatment options now available after first-line therapy including salvage ASCT, next-generation immunomodulatory drugs, Proteasome Inhibitors, and monoclonal antibodies.

When evaluated by cytogenetic risk, for the standard risk group, the median PFS was 82.3 months in the RVd plus ASCT group versus 53.2 months in the RVd alone group, whereas for patients with high risk cytogenetics, the median PFS was 55.5 versus 17.1 months, respectively. Further, patients with t(4;14) derived more PFS benefit from RVd plus ASCT than those with del(17p). The PFS benefit with RVd plus ASCT was inferior among the African American enrollees and individuals with a Body Mass Index greater than 25 kg/m2.

Even though the Response Rates and quality of responses were similar between the two treatment groups, the Duration of Response was longer in the RVd plus ASCT group at 56.4 months, compared to 39.9 months in the RVd alone group.

More patients in the RVd plus ASCT group achieved MRD (Minimal Residual Disease) negativity compared to RVD alone (54.4% versus 39.8%), despite similar Complete Response Rates in both treatment groups. These MRD negative patients had favorable 5-year PFS, regardless of their treatment assignment. However, RVd plus ASCT improved PFS by 67% among the MRD positive patients.

Grade 3 or greater treatment-related adverse effects including mucositis, fatigue, and infections were less common without ASCT than with, at 78% versus 94% respectively. Secondary malignancies occurred in 10% of the RVd-alone group and 11% of the RVd plus ASCT group. Following RVd plus ASCT, 10 patients developed Myelodysplastic syndrome and/or Acute Myeloid Leukemia, compared with none in the RVd-alone group, and this was statistically significant (P=0.002).

The authors concluded that a combination of REVLIMID®, VELCADE® and Dexamethasone (RVd) plus ASCT as initial therapy followed by REVLIMID® maintenance until progression, demonstrated a significant improvement in PFS compared to RVd alone, followed by REVLIMID® maintenance, in patients with newly diagnosed Multiple Myeloma. There was no Overall Survival advantage observed to date. The researchers added that given the lack of benefit in OS and potential toxicities associated with ASCT, these data provide support for personalized treatment approaches, and helps patients make informed decision to delay transplant. Additionally, the significantly longer PFS for both treatment groups in the DETERMINATION study compared to the IFM 2009 (preplanned comparison), suggests that there is a clear benefit to continuous REVLIMID® maintenance until disease progression.

Lenalidomide, bortezomib, and dexamethasone (RVd) ± autologous stem cell transplantation (ASCT) and R maintenance to progression for newly diagnosed multiple myeloma (NDMM): The phase 3 DETERMINATION trial. Richardson PG, Jacobus SJ, Weller E, et al. J Clin Oncol. 2022;40(suppl 17):LBA4. doi:10.1200/JCO.2022.40.17_suppl.LBA4

Late Breaking Abstract – ASCO 2022: ENHERTU® for HER2-Low Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

It is estimated that approximately 60% of metastatic breast cancers categorized as HER2-negative express low levels of HER2, defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). These HER2-low breast cancer tumors are treated as HER2-negative, as currently available HER2-directed therapies have resulted in poor outcomes. These patients have limited targeted treatment options and are often treated with single agent palliative chemotherapy following progression on first line chemotherapy.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure. The potential activity of ENHERTU® in HER2-low breast cancer tumors is driven by the bystander antitumor effect, offered by the optimized ADC technology. Previously published Phase I and II trials have shown that ENHERTU® in heavily pretreated patients with HER2-low metastatic breast cancer resulted in an Overall Response Rate of 37%, and median Progression Free Survival ranging from 6.3 to 11.1 months.

DESTINY-Breast04 is a multicenter, randomized, open-label, Phase III trial, conducted to evaluate the efficacy and safety of ENHERTU® as compared with the physician’s choice of chemotherapy, in patients with HER2-low metastatic breast cancer. In this study, patients were randomly assigned in a 2:1 ratio to receive ENHERTU® 5.4 mg/kg IV every 3 weeks (N=373) or the physician’s choice of Capecitabine, Eribulin, Gemcitabine, Paclitaxel, or Nab-paclitaxel (N=184). Low expression of HER2 was defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). Randomization was stratified according to HER2-low status (IHC 1+ versus IHC 2+ and ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one versus two), and Hormone Receptor (HR) status (positive versus negative) and if positive, previous CDK4/6 inhibitor therapy versus no CDK4/6 inhibitor therapy. IHC scores for HER2 expression were determined through central testing with the use of VENTANA HER2/neu investigational assay system, according to an algorithm adapted from the 2018 ASCO/CAP testing guidelines. Eligible patients must have received chemotherapy for metastatic disease or have had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with Hormone Receptor positive (HR-positive) disease must have received at least one line of endocrine therapy. Patients with treated, stable brain metastases were eligible. Patients were ineligible if they had a history of noninfectious interstitial lung disease treated with steroids or had suspected interstitial lung disease on imaging at screening. Both treatment groups were well balanced and approximately 89% in the ENHERTU® group and 90% in the chemotherapy group were HR-positive. The Primary end point was Progression Free Survival (PFS) among patients with HR-positive disease. Secondary end points included PFS among all patients, Overall Survival (OS) in the HR-positive cohort and among all patients, Objective Response Rate (ORR), Duration of Response, and efficacy in the HR-negative cohort. The median duration of follow up for survival was 18.4 months.

At the time of the primary efficacy analysis, the median PFS in the HR-positive cohort was 10.1 months in the ENHERTU® group and 5.4 months in the physician’s choice group (HR for disease progression or death=0.51; P<0.001). This benefit with ENHERTU® was seen consistently across all analyzed subgroups which included HER2 IHC 1+, HER2 IHC 2+ and ISH-negative, as well as those who had received previous treatment with CDK4/6 inhibitors. The median PFS among all patients was 9.9 months in the ENHERTU® group and 5.1 months in the physician’s choice group (HR for disease progression or death=0.50; P<0.001). The median PFS in the HR-negative cohort was 8.5 months in the ENHERTU® group and 2.9 months in the physician’s choice group (HR=0.46).

The median OS in the HR-positive cohort was 23.9 months in the ENHERTU® group and 17.5 months in the physician’s choice group (HR for death=0.64; P=0.003). The median OS among all patients was 23.4 months in the ENHERTU® group and 16.8 months in the physician’s choice group HR=0.64; P=0.001). The median OS in the HR-negative cohort was 18.2 months in the ENHERTU® group and 8.3 months in the physician’s choice group (HR=0.48).

The ORR in the HR-positive group was 52.6% in the ENHERTU® group and 16.3% in the physician’s choice group, and the median duration of response was 10.7 months in the ENHERTU® group and 6.8 months in the physician’s choice group. The ORR among all patients was 52.3% in the ENHERTU® group and 16.3% in the physician’s choice group. Among HR-negative cohort, the ORRs were 50% and 16.7% respectively.

Grade 3 or higher adverse events occurred in 53% of the patients who received ENHERTU® and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related Interstitial Lung Disease or pneumonitis occurred in 12.1% of the patients who received ENHERTU®.

The authors concluded that this is the first Phase III, practice-changing trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer, to show a statistically significant and clinically meaningful benefit in PFS and OS, compared to standard chemotherapy, regardless of Hormone Receptor status, with a generally manageable safety profile. The authors added that the strong efficacy of ENHERTU® in this HER2-low patient population, with approximately 50% lower risk of disease progression and 36% lower risk of death with ENHERTU® compared to standard chemotherapy, supports the need to reclassify HER2-low as a new targetable category of metastatic breast cancer.

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. Modi S, Jacot W, Yamashita T, et al. for the DESTINY-Breast04 Trial Investigators. N Engl J Med 2022; 387:9-20.

Screening for Pancreatic Cancer Results in Early Detection and Improved Overall Survival

RR

SUMMARY: The American Cancer Society’s estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 10%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States

Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and is typically detected when the disease is advanced. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is not recommended by the FDA for screening, as it may be elevated in several benign conditions.

NCCN guideline recommends that germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.

Screening for pancreatic cancer has been recommended for individuals considered to be at high risk of developing pancreatic ductal adenocarcinoma (5% or higher estimated lifetime risk). The risk increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene. The goals of screening for pancreatic cancer are to reduce mortality from pancreatic cancer through early detection, at a stage when the disease is most curable (Stage I), or when there is only a noninvasive neoplasm with high-grade dysplasia.

The Cancer of the Pancreas Screening Study (CAPS) is a research program developed at Johns Hopkins in 1998, to evaluate the effectiveness of early detection screening in high risk individuals of pancreatic cancer, and to progress the discovery of new biomarkers to improve early detection. The screening consortium agreed that to be successful, a screening program should detect and treat T1N0M0 margin-negative pancreatic cancer and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). CAPS 1–4 studies were single-institution studies, whereas CAPS 5 is a multicenter, prospective cohort study involving eight academic medical centers in the United States that opened to enrollment in 2014. The goal of CAPS 5 was to report pancreas surveillance outcomes of high-risk individuals within the CAPS 5 study, and to update outcomes of patients enrolled in prior CAPS studies, initiated more than 20 years ago. .

CAPS 5 prospectively enrolled 1,461 high-risk individuals for pancreas surveillance. High Risk Individuals included those with hereditary syndromes or germline variant carriers such as BRCA2, ATM, BRCA1, PALB2 or Lynch syndrome associated genes with a family history of pancreatic ductal adenocarcinoma, FAMMM-Familial Atypical Multiple mole Melanoma (CDKN2A) and Peutz-Jeghers syndrome (STK11). Also included in the high risk group were individuals with a family history of at least one first-degree and one second-degree relative with pancreatic ductal adenocarcinoma. High risk individuals should have met age criteria for surveillance. Surveillance protocol included annual surveillance with endoscopic ultrasound and or MRI/MRCP, often alternating between these two methods. Surveillance interval was modified when suspicious lesions were detected.

The Primary outcome of this study was the early detection of Stage I pancreatic duct adenocarcinoma or a noninvasive neoplasm with high grade dysplasia among high risk individuals undergoing surveillance. The study’s secondary outcome was Overall Survival after a diagnosis of pancreatic ductal adenocarcinoma or high grade dysplasia for high risk individuals enrolled in all CAPS studies (CAPS1-5), estimated using the Kaplan-Meier method.

Among the 1461 high risk individuals undergoing surveillance in the CAPS 5 study, 77.8% of pancreatic cancers were surgical pathology Stage I at diagnosis, 88.9% had resectable disease and the median survival for these patients was 9.8 years. This is in contrast to pancreatic ductal adenocarcinoma diagnosed outside surveillance where more than 50% present with metastatic disease, less than 20% have localized resectable disease and less than 5% have surgical Stage I disease.

In the entire CAPS cohort (CAPS 1-5) to date, the 5-year Overall Survival among screen-detected pancreatic ductal adenocarcinoma was 73.3%. The patients who progressed to pancreatic ductal adenocarcinoma in this study included carriers with germline pathogenic variants and those who met familial-risk criteria only. These results support current CAPS surveillance recommendations and argue against limiting pancreatic surveillance to those high-risk individuals with known pathogenic mutations. The median survival in the entire CAPS cohort for the patients with a screen-detected pancreatic ductal adenocarcinoma was 9.8 years, compared with 1.5 years for patients whose pancreatic ductal adenocarcinoma were diagnosed outside surveillance (HR=0.13; P=0.003).

The researchers concluded that screening for pancreatic cancer in high risk individuals can result in early detection, at a stage when the disease is most curable (Stage I).

The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival. Dbouk M, Katona BW, Brand RE, et al., J Clin Oncol. 2022 Jun 15;JCO2200298. doi: 10.1200/JCO.22.00298. Online ahead of print.

Late Breaking Abstract – ASCO 2022: KISQALI® with Switch Endocrine Therapy Following Progression on a Prior CDK4/6 Inhibitor in HR+/HER2-negative Metastatic Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation and associated with increased expression of CDK4. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.

KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest.

MAINTAIN trial is an investigator-initiated, multicenter, Phase II, double-blind, placebo-controlled, prospective randomized study, conducted to evaluate the efficacy of Fulvestrant or Exemestane with or without KISQALI®, in patients with HR+/HER2-negative metastatic breast cancer, who had previously progressed on any CDK 4/6 inhibitor plus any endocrine therapy. In this study, 119 evaluable patients were randomized 1:1 to receive either KISQALI® 600mg orally once daily given 3 weeks on and 1 week off plus switch endocrine therapy (N= 60) or placebo plus switch endocrine therapy (N=59). Patients treated with prior Fulvestrant received Exemestane as endocrine therapy in the randomization, whereas if prior Exemestane was endocrine therapy, patients received Fulvestrant. If patients received neither as prior endocrine therapy, Fulvestrant or Exemestane was given per investigator discretion, although Fulvestrant was encouraged. Ultimately, 83% of patients received Fulvestrant and 17% received Exemestane. Eligible patients were postmenopausal, had HR+/HER2- negative metastatic breast cancer and had progressed on prior endocrine therapy and any CDK4/6 inhibitor. With regards to prior CDK 4/6 inhibitor treatment, 84% received IBRANCE® (Palbociclib), 11% received KISQALI®, 2% received VERZENIO® (Abemaciclib) and 3% received IBRANCE® and another CDK 4/6 inhibitor. The median duration of treatment with the prior CDK4/6 inhibitor was 15.5 months in the KISQALI® group and 17 months in the placebo group. Approximately 60% of patients had visceral metastasis, 45% had de novo metastasis at diagnosis, 18% had bone-only disease, 18% had received 2 or more prior endocrine therapies for metastatic disease, and 9% had received chemotherapy. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Response Rate (ORR), Clinical Benefit Rate, safety, and tumor and blood biomarkers. The median follow up was 18.2 months.

There was a statistically significant PFS improvement for patients randomized to KISQALI® plus endocrine therapy and the median PFS for patients in the KISQALI® plus endocrine therapy was 5.33 months, compared with 2.76 months for patients receiving placebo and endocrine therapy (HR=0.56;; P=0.004). At 12 months, the PFS rates were 24.6% in the KISQALI® group versus 7.4% in the placebo group. Similar results were noted in the subset of patients treated with Fulvestrant and KISQALI®, and the median PFS for those randomized to KISQALI® was 5.29 months versus 2.76 months in the placebo group (HR=0.59; P=0.02). The PFS benefit was more evident in KISQALI® group compared to the placebo group, especially among those who received a shorter duration of therapy with a prior CDK4/6 inhibitor (HR=0.36) and among those over age 65 years (HR=0.31). The Overall Response Rate in the KISQALI® group was 20%, compared to 11% in the placebo group, and the median Duration of Response was 18.8 months in those treated with KISQALI® and endocrine therapy, compared with 14.8 months for those treated with placebo plus endocrine therapy. There was also a significant improvement in the Clinical Benefit Rate (CBR), defined as patients who achieved Complete Response, Partial Response, or stable disease lasting at least 24 weeks. The CBR was significantly improved in the KISQALI® group, compared with the placebo group, and was 43% versus 25%, respectively (P=0.06). The most common adverse event in the KISQALI® group was neutropenia at 72%, compared to 15% in the placebo group.

It was concluded from this randomized, placebo-controlled trial that, treatment with KISQALI® and an alternate endocrine therapy, after progression on a prior CDK4/6 inhibitor, showed a 43% reduction in the risk of progression or death, compared with placebo and endocrine therapy, in patients with HR+/HER2-negative metastatic breast cancer.

A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. Kalinsky K, Accordino MK, Chiuzan C, et al. J Clin Oncol 40, 2022 (suppl 17; abstr LBA1004). DOI: 10.1200/JCO.2022.40.17_suppl.LBA1004.