Author: RR

The Evolution of Therapeutics for Patients with aRCC

RR

Written by Dr. Thomas Hutson, Texas Oncology

Renal cell carcinoma (RCC) is one of the most frequently diagnosed cancers with an incidence of around 400,000 cases worldwide.1 In the United States alone, RCC accounted for 73,820 new cases and 14,770 deaths in 2019.2 In patients with RCC, about 30% present with metastatic disease at the time of initial diagnosis typically requiring systemic therapy, and of those treated for localized RCC, almost 30% develop recurrent disease during the follow-up.3 To address this patient population, multiple targeted therapies focused predominantly on two major molecular pathways, namely angiogenesis and intracellular signal transduction pathways, have gained increasing attention in recent years as prospective therapies for advanced RCC (aRCC).4

The Advent of New Therapeutics for RCC

After the approval of high-dose IL2, there was remarkable progress in the treatment of RCC with approval of VEGF inhibitors, as well as mammalian target of rapamycin (mTOR) pathway inhibitors. These agents have gained regulatory approval and have drastically improved the outcome of patients with advanced RCC.5 More recently, key insights obtained in regard to the Von Hippel-Lindau (VHL) pathway provided the basis for the development of the VHL-hypoxia pathway-based therapeutic landscape in renal cancers.6 For instance, the newer generation tyrosine kinase inhibitors (TKIs) block not only vascular endothelial growth factor receptor (VEGFR) but also fibroblast growth factor receptor (FGFR), and hepatocyte growth factor receptor (C-Met) and Axl, respectively.6 These additional targets have been implicated to help escape angiogenesis blockade which may explain their incremental improvement in efficacy demonstrated in pivotal clinical trials.6 While significant progress has occurred, there is still room for improvement for targeted therapies as current drug interventions for metastatic RCC (mRCC) have yet to demonstrate the ability to circumvent recurrence and several therapies are accompanied by severe adverse events.5

Given that RCC is considered immune-responsive in nature with high numbers of immune cells present in the tumor microenvironment (TME), targeted immunotherapy (IO) was more recently approved as another potential therapy in RCC.7 One strategy involves the use of immune checkpoint inhibitors (ICI). In particular, the use of sophisticated ICIs – anti-programmed death receptor-1 (PD-1), anti-programmed death receptor ligand-1 (PD-L1), and anti-cytotoxic T lymphocytes antigen-4 (CTLA-4) – have been studied in large international phase 3 trials demonstrating significant and clinically relevant improvements in efficacy.4,8 As such, these new therapies have quickly been integrated into the RCC landscape with PD-1 and PD-L1 antibody-based novel ICIs now approved by the FDA as the standard second-line treatment for mRCC as well as in the first-line for moderate to high risk mRCC.9,10

Recently reported and FDA-approved combinations of ICI or ICI with TKI therapy have been rapidly integrated into the first-line treatment setting based upon recent international phase 3 trials.4 It has been proposed that anti-VEGF therapies used in combination with targeted immunotherapies may overcome resistance by modulating the TME. Moreover, inhibition of the VEGF pathway was shown to facilitate access of T-cell population into the TME and decrease the activity of T-regulatory cells and myeloid-derived suppressor cells, thereby enhancing responsiveness to immunotherapy.9,11,12

Strategizing Therapeutic Approach

When patients with mRCC progress through first-line therapies (TKI-ICI, TKI, ICI-ICI), there are many second-line choices to choose from, including ICI, mTOR pathway inhibitors and TKI-mTOR inhibitor combinations.

Before starting therapy, it is necessary to educate the patient about the possibility of adverse reactions that may ensue in the weeks and months after therapy begins. Setting expectations of therapy will serve to maximize patient compliance through early intervention as adverse reactions emerge. This will require close communication between the clinical treatment team, the patient, and their caregivers. Withholding therapy and dose adjustments may be required in some cases to enable patients to remain on therapy.13,14

References
1. Bray F, Ferlay J, Soerjomataram I, et al. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2018;68:394-424
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
3. Abara E, Chivulescu I, Clerk N, et al. Recurrent renal cell cancer: 10 years or more after nephrectomy. Canadian Urological Association. 2010;4(2):E45-E49.
4. Wang J, Li X, Wu X, et al. Role of immune checkpoint inhibitor-based therapies for metastatic renal cell carcinoma in the first-line setting: A Bayesian network analysis. EBioMedicine. 2019;47:78-88.
5. Barata P, Ornstein M, Garcia J. The Evolving Treatment Landscape of Advanced Renal Cell Carcinoma in Patinents Progressing after VEGF Inhibition. J Kidney Cancer VHL 2017;4(2):10-18.
6. Jonasch E. Implications of VHL-HIF pathway dysregulation in renal cell carcinoma: current therapeutic strategies and challenges. Kidney Cancer Journal. 2020;18(1):6-10.
7. Leite KR, Reis ST, Junior JP, et al. PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn Pathol. 2015;10:189.
8. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813.
9. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115.
10. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-1290.
11. Rini B.I, Plimack E.R, Stus V, et al. Pembrolizumab plus Axitinib versus
Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380:1116-27
12. Suk Lee W, et al. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Experimental and Molecular Medicine. 2020; 52:1475-1485
13. Philip L. Management of Targeted Therapy Adverse Effects. Pharmacytimes. 2020. https://www.pharmacytimes.com/publications/Directions-in-Pharmacy/2019/December2019/featured-article-management-of-targeted-therapy-adverse-effects. Accessed 10/27/2020.
14. Barber FD. Adverse Events of Oncologic Immunotherapy and Their Management. Asia Pac J Oncol Nurs. 2019;6:212-26

This article is sponsored by Eisai Inc.

LENV-US4722

Chemotherapy Can Be Spared in Majority of Postmenopausal Women with Node Positive Early Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer were diagnosed in 2020 and about 42,170 women died of the disease. Approximately 25% of patients with Hormone Receptor (HR)-positive, HER2-negative early breast cancer have metastatic lymph node involvement and two third of these patients are postmenopausal. Majority of these patients currently receive chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early stage breast cancer. Chemotherapy recommendations for early stage, HR-positive, HER-negative, early stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay.

In the ground-breaking TAILORx (Trial Assigning Individualized Options for Treatment) study which enrolled 10,273 patients with HR-positive, HER2-negative, axillary node-negative breast cancer, patients were divided into three groups based on their Recurrence Score. Patient with Intermediate Recurrence Score of 11-25 were randomly assigned to receive endocrine therapy alone or endocrine therapy and adjuvant chemotherapy. There was no benefit noted from adding chemotherapy to endocrine therapy, for women older than 50 years in this Intermediate RS group, suggesting that a significant percentage of women with node-negative breast cancer do not achieve substantial benefit from chemotherapy. Whether the results of TAILORx can be extrapolated to women with node-positive breast cancer has remained unclear. It is estimated that approximately 85% of women with node-positive disease have Recurrence Score results of 0-25.

The RxPONDER trial was designed to determine the benefit of chemotherapy, in patients who had a Recurrence Score of 0-25. This trial did not include pre and postmenopausal women with Recurrence Score results 26-100 based on previously published studies suggesting that this patient group benefited from chemotherapy. SWOG S1007 (RxPONDER) is an multicenter, international, prospective, randomized, Phase III trial, in which patients with HR-positive, HER2-negative breast cancer with 1-3 positive axillary lymph nodes were included, to determine which patients would benefit from chemotherapy and which patients could safely avoid it. In this study, a total of 5083 HR-positive, HER2-negative breast cancer patients with 1-3 positive lymph nodes and Oncotype DX Recurrence Score of less than 25 were randomly assigned 1:1 to receive chemotherapy plus endocrine therapy or endocrine therapy alone. Approximately two-thirds of patients were postmenopausal and one-third were premenopausal and had no contraindications to taxane and/or anthracycline based chemotherapy. Patients were stratified by Recurrence Score (0-13 versus 14-25), menopausal status, and axillary nodal dissection versus sentinel node biopsy. The Primary endpoint was Invasive Disease Free Survival (IDFS), defined as local, regional, or distant recurrence, any second invasive cancer, or death from any cause, and whether the effect depended on the Recurrence Score. Secondary endpoints included Overall Survival (OS).

At a median follow up of 5.1 years, there was no association noted between Recurrence Score (RS) values and chemotherapy benefit for the entire study population (P=0.30). However, a prespecified analysis did show a significant association between chemotherapy benefit and menopausal status. Premenopausal women (N=1665) with an RS between 0 and 25 had an IDFS benefit with the addition of chemotherapy to endocrine therapy compared with endocrine therapy alone (94.2% versus 89%, HR=0.54; P=0.0004). This absolute 5.2% benefit in the premenopausal subset was highly significant. The relative risk reduction with the addition of chemotherapy to endocrine therapy for the two RS risk groups 0-13 and 14-25 was consistent in the premenopausal population, with an overall Hazard Ratio of 0.54. The absolute benefit was numerically higher in those with RS 14-25. Consistent benefit was again noted regardless of number of involved lymph nodes, although there was slight variation in the absolute benefit. Postmenopausal women (N=3350) did not benefit with the addition of chemotherapy to endocrine therapy when compared endocrine therapy alone, regardless of Recurrence Score (91.9% versus 91.6%, HR=0.97; P=0.82). Chemotherapy also improved Overall Survival in the premenopausal cohort, although the follow up is limited.

It was concluded from this practice-changing outcomes that postmenopausal women with HR-positive, HER2-negative breast cancer with 1-3 positive nodes and Oncotype DX Recurrence Score of 25 or less can safely avoid receiving adjuvant chemotherapy, whereas premenopausal patients with 1-3 positive nodes and a Recurrence Score of 25 or less should consider adjuvant chemotherapy. The authors added that these finding demonstrate that the great majority of postmenopausal women can be spared unnecessary chemotherapy and receive only endocrine therapy.

First results from a phase III randomized clinical trial of standard adjuvant endocrine therapy ± chemotherapy in patients with 1-3 positive nodes, hormone receptor-positive and HER2-negative breast cancer with recurrence scores ≤ 25: SWOG S1007 (RxPONDER). Kalinsky K, Barlow WE, Meric-Bernstam F, et al. 2020 San Antonio Breast Cancer Symposium. Presented December 10, 2020. Abstract GS3-00.

Osteonecrosis of the Jaw with Zoledronic Acid Treatment

RR

SUMMARY: OsteoNecrosis of the Jaw (ONJ) is defined as progressive bone destruction in the maxillofacial region resulting in exposed bone, or bone that can be probed through an intraoral or extraoral fistula (or fistulae) in the maxillofacial region and that does not heal within 8 weeks, occurring in a patient who has received a Bone-Modifying Agent (BMA) or an angiogenic inhibitor agent and with no history of head and neck radiation. The condition may involve the mandible or the maxilla and can be challenging to treat and can cause significant pain, impacting patients quality of life. The true incidence ONJ is unknown.

Bone Modifying Agents that have been linked with ONJ principally include bisphosphonates such as Zoledronic acid and Pamidronate and Rank Ligand inhibitor, Denosumab. BMAs are an integral part of cancer management and have essential roles in supportive oncology for the treatment of hypercalcemia of malignancy and bone metastases, and prevention of Skeletal-Related Events (SREs) such as pathologic fractures and reduce the need for radiation or surgical intervention. BMAs disrupt the bone remodeling cycle by reducing osteoclast survival and function.

The SWOG Cancer Research Network designed this trial to prospectively assess the incidence of and predictive factors associated with OsteoNecrosis of the Jaw (ONJ), in patients with cancer receiving Zoledronic acid. The Primary objective was to prospectively assess the cumulative incidence of ONJ at 3 years. SWOG S0702 is a multicenter, prospective observational cohort study which enrolled 3491 patients with Metastatic Bone Disease (MBD) with either limited or no prior exposure to Bone Modifying Agents, who had received Zoledronic acid (ZOMETA®) within 30 days of registration. The median patient age was 63 years of whom 32% had breast cancer, 17% had myeloma, 20% had prostate cancer, 19% had lung cancer, and 12% had other malignancies. A baseline dental examination was performed in 65% of the patients. Over 65% of patients reported no alcohol use, 12% were current smokers and complete or partial dentures were observed in 22% of patients. The Primary end point was the diagnosis of confirmed ONJ, defined as an area of exposed bone in the maxillofacial region that had been present for at least 8 weeks in a patient receiving or previously exposed to a bisphosphonate, and who had not had radiotherapy to the craniofacial region. A suspected case of ONJ was defined by the same ONJ criteria but present for less than 8 weeks. All suspected and confirmed cases of ONJ were adjudicated by the study team. The median follow up was 3 years.

The cumulative incidence of confirmed ONJ at year 1 was 0.8%, at year 2 was 2% and at year 3 was 2.8%. The cumulative incidence at 3 years was highest in patients with myeloma (4.3%) and lowest in those with breast cancer (2.4%). ONJ risk was higher among patients with planned Zoledronic acid dosing intervals of less than 5 weeks versus those with planned intervals of 5 weeks or longer (cumulative incidence 3.2% versus 0.7%; P=0.009). ONJ risk was higher among patients with any dentures (cumulative incidence, 5% versus 2.9%; P=0.02) and removable dentures (cumulative incidence 6.5% versus 3%; P=0.03), and were about twice as likely to experience ONJ compared with patients without any dentures or without removable dentures, respectively. A higher rate of ONJ was associated with fewer total number of teeth (less than 25 versus more than 25), with a 3 year ONJ incidence of 4.4% versus 2.4% respectively (HR=0.51; P=0.006). Current smokers were more likely to experience ONJ than patients who were not current smokers (3.7% versus 2.4%; P=0.02)

The authors concluded that this prospective study of patients treated with Zoledronic acid provides clinicians with critical information about the overall risk and risk factors for developing ONJ. The authors added that when clinically appropriate, consideration should be given to use of Zoledronic acid dosing intervals of greater than 5 weeks to reduce the risk of ONJ.

Association of Osteonecrosis of the Jaw With Zoledronic Acid Treatment for Bone Metastases in Patients With Cancer. Van Poznak CH, Unger JM, Darke AK, JAMA Oncol. Published online December 17, 2020. doi:10.1001/jamaoncol.2020.6353.

ASCO Guideline: PARP Inhibitors in the Management of Ovarian Cancer

RR

SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

Germline mutations in BRCA1 and BRCA2 genes account for about 17% of ovarian cancers (mutations present in all individual cells), whereas somatic mutations are found in an additional 7% (mutations present exclusively in tumor cells). BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

This systematic review-based guideline was developed by a multidisciplinary ASCO Expert Panel to provide clinicians and other health care practitioners, recommendations on the use of PARP inhibitors for management of Epithelial Ovarian, tubal, or Primary Peritoneal Cancer (herein referred to as EOC), based on best available evidence. The recommendations were developed following a systematic review of the literature which identified 17 randomized controlled trials published from 2011 through 2020, that included patients who have not previously received a PARP inhibitor.

ASCO Guideline Questions:
1) Should PARP inhibitor therapy for EOC be repeated over the course of treatment?
2) In which patients with newly diagnosed EOC are PARP inhibitors recommended?
a. What are the histologic types of EOC for which PARP inhibitors are recommended?
b. What are the biomarker subsets for which PARP inhibitors are recommended?
3) Is PARP inhibitor monotherapy recommended for recurrent EOC? If so,
a. In which settings (eg, second-line maintenance or treatment of recurrent disease)?
b. At what dose and duration?
4) Are there settings where PARP inhibitors in combination with chemotherapy or other targeted therapy are recommended?
5) How should clinicians manage the specific toxicities of the various PARP inhibitors?

Recommendations: The following recommendations pertain only to patients with EOC who have not previously received a PARP inhibitor.

Repeating PARP Inhibitor

Recommendation 1.0: Repeating therapy with a PARP inhibitor in the treatment of EOC is not recommended at this time. Consideration should be made as to the best time in the life cycle of an individual patient’s EOC in which to use PARP inhibitor. Clinical trial participation is encouraged.

Newly Diagnosed Ovarian Cancer

Recommendation 2.0: PARP inhibitors are not recommended for use in initial treatment of early stage (Stage I-II) EOC because there is insufficient evidence to support use in this population.

Recommendation 2.1: Women with newly diagnosed Stage III-IV EOC that is in Complete or Partial Response to first-line platinum-based chemotherapy should be offered PARP inhibitor maintenance therapy with Olaparib (for those with germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes) or Niraparib (all women) in High-Grade Serous or endometrioid ovarian cancer.
PARP inhibitor maintenance therapy should consist of Olaparib (300 mg orally every 12 hours for 2 years) or Niraparib (200-300 mg orally daily for 3 years). Longer duration could be considered in selected individuals.

Recommendation 2.2: The addition of Olaparib to Bevacizumab maintenance may be offered to patients who have Stage III-IV High-Grade Serous or endometrioid ovarian cancer and germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, as determined by Myriad myChoice CDx, and who have had a Partial or Complete Response to chemotherapy plus Bevacizumab combination.

Recommendation 2.3: Inclusion of the PARP inhibitor Veliparib with combination chemotherapy followed by Veliparib maintenance therapy cannot be recommended at this time. There are no data that this approach is superior, equal, or less toxic than a switch maintenance.
Note: Veliparib is not commercially available at the time of these recommendations.

Recurrent Ovarian Cancer: Second-Line or Greater Maintenance and Treatment

Recommendation 3.0: PARP inhibitor monotherapy maintenance (second-line or more) may be offered to patients with EOC who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status. Treatment is continued until disease progression or toxicity despite dose reductions and best supportive care. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.1: Treatment with a PARP inhibitor should be offered to patients with recurrent EOC who have not already received a PARP inhibitor and have a germline or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes. Options include Olaparib 300 mg every 12 hours, Rucaparib 600 mg every 12 hours or Niraparib 200-300 mg once daily.

Recommendation 3.2: Treatment with a PARP inhibitor monotherapy should be offered to patients with recurrent EOC who have not already received a PARP inhibitor, and whose tumor demonstrates genomic instability, as determined by Myriad myChoice CDx, and has not recurred within 6 months of platinum-based therapy

Recommendation 3.3: PARP inhibitors are not recommended for treatment of BRCA wild-type or platinum-resistant recurrent EOC

PARP Inhibitors in Combination

Recommendation 4.0: PARP inhibitors are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents in the recurrent setting outside the context of a clinical trial. Clinical trial participation is encouraged.

Management of Adverse Events

Recommendation 5.0 Anemia: Patients requiring a blood transfusion for symptom relief and/or hemoglobin level less than 8 g/dL should be monitored. PARP inhibitor dose should be reduced with evidence of repeated anemia to avoid multiple transfusions. Patients with progressive anemia may be offered growth factor per ASCO guidelines and physician and patient comfort.

Recommendation 5.1 Neutropenia: Growth factor is not indicated for use in patients receiving daily PARP inhibitor. Neutropenia (grade 4 lasting at least 5-7 days or associated with fever) should result in dose hold until recovery of infection and granulocyte count, followed by dose reduction. Growth factor support may be used in this setting to support patient safety during the drug hold period.

Recommendation 5.2 Platelets: Thrombocytopenia is most common with Niraparib. Niraparib dosing guidelines should be used to lower starting dose (200 mg) based on weight and platelet count. Discontinue PARP inhibitor for persistent thrombocytopenia or significant bleeding despite dose reduction.

Recommendation 5.3 Persistent cytopenia: Evaluation for treatment-related Myelodysplastic Syndrome/Acute Myeloid Leukemia should be initiated in patients with persistent cytopenia that occurs despite drug hold.

Recommendation 5.4 Nausea: Many patients will have tachyphylaxis of nausea symptoms over the first cycle of therapy. Persistent nausea requiring daily antiemetic intervention, causing a reduction in performance status, and/or resulting in more than 5% weight loss, should result in dose reduction.

PARP Inhibitors in the Management of Ovarian Cancer: ASCO Guideline. Tew WP, Lacchetti C, Ellis A, et al. J Clin Oncol 2020;38:3468-3493.

FDA Approves XPOVIO® for Relapsed or Refractory Multiple Myeloma

RR

SUMMARY: The FDA on December 18, 2020 approved XPOVIO® (Selinexor) in combination with VELCADE® (Bortezomib) and Dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,270 new cases will be diagnosed in 2020 and 12,830 patients are expected to die of the disease. Multiple Myeloma (MM) in 2020 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). 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 or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Exportin 1 (XPO1) is an important nuclear export protein overexpressed in multiple myeloma. High XPO1 levels facilitate increased nuclear export of tumor suppressor proteins such as P53, P73, IkB and FOXO3a, pRb, BRCA1, as well as growth regulators such as Glucocorticoid Receptor and oncoprotein mRNA. This enables cancer cells to escape tumor suppressor protein mediated cell cycle arrest and apoptosis. XPOVIO® is an oral selective XPO1inhibitor that reactivates the tumor suppressor proteins by preventing nuclear transport, inhibits oncoprotein translation and reactivates Glucocorticoid Receptor signaling in the presence of Dexamethasone. In a Phase Ib/II study, the combination of XPOVIO® along with VELCADE® (a Proteasome Inhibitor) and Dexamethasone induced high response rates with low rates of peripheral neuropathy.

The present FDA approval for XPOVIO® was based on findings from the BOSTON trial, which is a multicenter, open-label, randomized, controlled Phase III study, conducted to evaluate the clinical benefit of weekly XPOVIO®, VELCADE® (Bortezomib), and Dexamethasone, versus standard VELCADE® and Dexamethasone, in patients with previously treated multiple myeloma. In this study, 402 patients were randomly assigned 1:1 to receive either XPOVIO® 100 mg PO once weekly, VELCADE® 1.3 mg/m2 SC once weekly, and Dexamethasone 20 mg PO twice weekly, or VELCADE® 1.3 mg/m2 SC twice weekly for the first 24 weeks and once weekly thereafter, and Dexamethasone 20 mg four times per week for the first 24 weeks and twice weekly thereafter. The median patient age was 67 years and 32% of the patients had 2 prior lines of therapy, including prior REVLIMID® (Lenalidomide) in 38% and prior VELCADE® in 69%. Approximately 48% of the patients had high-risk cytogenetics which included del(17p), t(4;14), t(14;16) or amp(1q21). The Primary endpoint was Progression Free Survival (PFS), and Secondary endpoints included Objective Response Rate (ORR), Duration of Response (DoR), Overall Survival (OS) and Safety.

It was noted that the median PFS was 13.9 months in the XPOVIO® group and 9.5 months for the control group (HR=0.70; P=0.0075). This represented a 30% reduction in the risk of progression or death with the XPOVIO® triplet combination. This benefit was consistently noted across all subgroups including those with high-risk cytogenetics. The ORR was 76.4% in the XPOVIO® group versus 62.3% in the control group (P=0.0012), and the significantly higher ORR again was noted across subgroups. The median Duration of Response was 20.3 months versus 12.9 months in the XPOVIO® group and the control group, respectively. The most common adverse events in the XPOVIO® group included cytopenias, fatigue, nausea, diarrhea, asthenia, decreased appetite and weight loss.

It was concluded that weekly regimen of XPOVIO® given along with VELCADE® and Dexamethasone, is a novel, effective, and convenient treatment option, for patients with multiple myeloma, who have received one to three prior lines of therapy.

Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Grosicki S, Simonova M, Spicka I, et al. Lancet. 2020;396:1563-1573.

FDA Approves MARGENZA® for HER2 Positive Metastatic Breast Cancer

RR

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2 oncoprotein is also expressed by tumor cells in gastroesophageal and other solid tumors.

HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (Ado-Trastuzumab Emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.MOA-of-MARGENZA

MARGENZA® (Margetuximab-cmkb) is an Fc-engineered, monoclonal antibody that binds to the HER2 oncoprotein with high specificity and affinity and inhibits tumor cell proliferation, and survival by mediating Antibody-Dependent Cellular Cytotoxicity (ADCC). It is postulated that the Fab portion of MARGENZA® has the same specificity and affinity to HER2 oncoprotein as Trastuzumab, with similar ability to disrupt signaling. However, the modified Fc region of MARGENZA® which binds Fc receptor expressing cells such as immune cells, has increased affinity for activating Fc receptor FCGR3A (CD16A) and decreases affinity for inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater ADCC and Natural Killer cell activation.

The SOPHIA study is a randomized, multicenter, open-label Phase III clinical trial, in which MARGENZA® plus chemotherapy was compared to Trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer, who have previously been treated with anti-HER2-targeted therapies. This study enrolled 536 patients who were randomized 1:1 to receive either MARGENZA® 15 mg/kg IV every three weeks (N=266) or Trastuzumab 6 mg/kg (or 8 mg/kg for loading dose) IV every three weeks (N=270), in combination with either Capecitabine, Eribulin, Gemcitabine or Vinorelbine, given at the standard doses. All study patients had previously received Trastuzumab, all but one patient had previously received PERJETA® (Pertuzumab), and 91% of patients had previously received KADCYLA®. Patients were stratified by choice of chemotherapy, number of lines of therapy in the metastatic setting and number of metastatic sites. The dual Primary endpoints of the study were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Additional efficacy outcome measures included Objective Response Rate (ORR) and Duration of Response (DOR) assessed by BICR.

This study demonstrated a statistically significant 24% reduction in the risk of disease progression or death with MARGENZA® plus chemotherapy compared with Trastuzumab plus chemotherapy (HR= 0.76; P=0.033), with a median PFS of 5.8 months versus 4.9 months respectively. Treatment benefit was more pronounced in patients with CD16A genotypes containing a 158F allele (median PFS 6.9 versus 5.1 months, HR=0.68; P=0.005). The ORR for MARGENZA® plus chemotherapy was 22%, with a median Duration of Response of 6.1 months, compared to an ORR of 16% and median Duration of Response of 6.0 months for Trastuzumab plus chemotherapy. The final Overall Survival (OS) analysis is expected in the second half of 2021. The most common adverse drug reactions occurring in more than 10% of patients receiving MARGENZA® plus chemotherapy included fatigue/asthenia, nausea, diarrhea, vomiting, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

It was concluded that MARGENZA® in combination with chemotherapy significantly improved PFS, compared to Trastuzumab plus chemotherapy, in pretreated patients with HER2 positive metastatic breast cancer. MARGENZA® along with chemotherapy represents the newest treatment option for patients who have progressed on available HER2-directed therapies.

SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy (C) versus trastuzumab + C in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. Rugo HS, Im SA, Shaw Wright GL, et al. J Clin Oncol 37, 2019 (suppl; abstr 1000)