Category: Hem/Onc Updates

AI Derived Molecular Signature Predicts First-line Oxaliplatin-Based Chemotherapy Benefit in Advanced CRC

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SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the overall death rate has continued to drop, deaths from CRC among people younger than 55 years have increased 1% per year from 2008 to 2017, with 12% of CRC cases diagnosed in people under age 50. 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 ( FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. However numerous studies have failed to clearly establish that any of these combination regimens would be superior for any given patient based on clinical factors. In the TRIBE2 Phase III study, upfront FOLFOXIRI plus Bevacizumab and reintroduction after progression resulted in significant improvement in median Overall Survival (OS), compared to mFOLFOX6 plus Bevacizumab followed by FOLFIRI plus Bevacizumab, in patients with metastatic CRC. Majority of patients with mCRC receive FOLFOX-based first-line treatment, even though neuropathy almost always limits its use beyond 4 months. Oxaliplatin has also become a first line treatment option as part of FOLFOXIRI in mCRC, as part of FOLFIRINOX in advanced Pancreatic cancer and as a part of FOLFOX for other cancers such as GE Junction and Gastric cancer. A biomarker predicting the relative efficacy of these regimens is presently lacking. However, the availability of large, combined clinical and molecular datasets has enabled the development of a machine-learning approach.

The authors conducted this study to determine a patients’ likelihood of benefit from first-line treatment with FOLFOX followed by FOLFIRI versus FOLFIRI followed by FOLFOX, by taking advantage of an advanced machine-learning approach, to identify a molecular signature (FOLFOXai), predictive of treatment benefit from FOLFOX chemotherapy, by analyzing a combined dataset of comprehensive molecular profiling results and clinical outcomes data.

The researchers leveraged AI algorithms and comprehensive molecular profiling data to develop a machine-learning approach, and identified a 67-gene molecular signature (FOLFOXai), predictive of clinical benefit from FOLFOX chemotherapy, in previously untreated patients with mCRC. The molecular signature included genes involved in mediating WNT signaling (BCL9 and CDX2), epithelial-to-mesenchymal transition (EMT; INHBA, PRRX1, PBX1, and YWHAE), chromatin remodeling (EP300, ARID1A, SMARC4, and NSD3), DNA repair (WRN and BRIP1), NOTCH signaling (MAML2), and cell-cycle regulation (CNTRL and CCNE1). They then validated the putative molecular signature from a large Real World Evidence (RWE) database, a subset of cases from the randomized controlled Phase III TRIBE2 study, as well as RWE data from patients with advanced Esophageal/Gastro Esophageal Junction cancers (EC/GEJ cancers) or Pancreatic Ductal AdenoCarcinoma (PDAC) who received first-line treatments with Oxaliplatin-containing regimens.

The researchers utilized Real World Evidence (RWE) outcomes dataset from the Caris Life Sciences Precision Oncology Alliance registry, and insurance claims data from more than 10,000 physicians. The training cohort or dataset included patients who had a diagnosis of mCRC, received treatment with FOLFOX-based combination therapy, completed at least one full cycle of therapy, and completed Next-Generation DNA analysis of at least one colorectal cancer sample using a 592-gene panel. Patients were excluded if they had prior chemotherapy, including adjuvant therapy.

Two separate RWE validation cohorts were also generated, and patients in these cohorts had a diagnosis of mCRC, received first-line treatment with FOLFOX/Bevacizumab (FOLFOX/Bevacizumab cohort) or FOLFIRI-based treatment (FOLFIRI cohort), completed at least one full cycle of therapy, completed Next-Generation DNA analysis of at least one CRC sample using a 592-gene panel, and switched to an Irinotecan-containing regimen (FOLFOX/bevacizumab cohort) or to FOLFOX (FOLFIRI cohort).

For algorithm training, a TTNT (Time To Next Treatment) of 270 days was chosen to define whether a patient benefitted from receiving first-line FOLFOX. Patients with TTNT of less than 270 days were referred to as having decreased benefit to FOLFOX and others were referred to as having increased benefit. Validation studies used Time To Next Treatment (TTNT), Progression Free Survival (PFS), and Overall Survival (OS) as the primary endpoints.

A total of 105 patients with mCRC from the RWE dataset who had received first-line FOLFOX-based treatment and who had been profiled by Caris Life Sciences, were included in the training cohort. The first validation cohort included 412 patients (with RWE data on treatments and death dates) treated with FOLFOX/Bevacizumab and 55 patients who had received FOLFIRI as first-line treatments. Additional RWE datasets included 333 patients with advanced PDAC and EC/GEJC treated in first line with Oxaliplatin-containing regimens, and blinded retrospective-prospective analysis of samples from patients enrolled in the Phase III TRIBE2 study, with completed Next Generation Sequencing (NGS) analysis.

The researchers noted that
1) A 67-gene signature was cross-validated in a training cohort (N=105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit.
2) The gene signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI.
3) Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of overall survival in both Oxaliplatin-containing arms (FOLFOX HR=0.629; P=0.04 and FOLFOXIRI HR=0.483; P=0.02).
4) FOLFOXai was also predictive of benefit from Oxaliplatin-containing regimens in advanced Esophageal/Gastro Esophageal Junction cancers, as well as Pancreatic Ductal AdenoCarcinoma.

It was concluded from this analysis that application of FOLFOXai molecular signature could lead to improvements of treatment outcomes for patients with mCRC and other cancers, because patients predicted to have less benefit from Oxaliplatin-containing regimens might benefit from alternative regimens, thus providing critical guidance for the choice of first line therapy. The authors added that this is the first clinically validated, machine-learning powered molecular predictor of chemotherapy efficacy in these diseases, with immediate relevance for the initial therapeutic decision-making process.

Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer. Abraham JP, Magee D, Cremolini C, et al. Clin Cancer Res 2021;27:1174-1183.

70-Gene Risk Signature May Determine Long Term Benefit of Endocrine Therapy in Premenopausal Breast Cancer Patients

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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 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Approximately 75% of patients with breast cancer are Hormone Receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.

ZOLADEX® (Goserelin) is a potent synthetic analogue of Luteinizing Hormone-Releasing Hormone (LHRH), also known as a Gonadotropin Releasing Hormone (GnRH) agonist analogue. It stimulates the production of the sex hormones Testosterone and Estrogen in a non-pulsatile (non-physiological) manner, resulting in the disruption of the endogenous hormonal feedback systems, and down-regulation of Testosterone and Estrogen production. Given that premenopausal patients with breast cancer have their disease diagnosed earlier in life, they are at an increased risk of fatal disease during their lifetime. The long term benefit of endocrine therapy, including ovarian suppression, has not been studied in this patient population.

Zipp-trial (STO-5) in one of three well defined randomized, controlled, clinical studies of adjuvant endocrine therapy, conducted between 1990 and 1997 by the Stockholm Breast Cancer Study Group. This trial included premenopausal patients with invasive breast cancer treated with a modified radical mastectomy or breast conserving surgery and axillary lymph node dissection or biopsy. Patients undergoing breast conserving surgery also received adjuvant radiotherapy to the breast (50 Gy over 5 weeks). Patients were included in study irrespective of ER status. All patients with node positive disease electively received adjuvant cytotoxic chemotherapy and those with four or more lymph node metastases received radiotherapy as well.

The Stockholm part of the Zoladex In Premenopausal Patients (ZIPP-trial, STO-5) included 924 patients and the purpose of this analysis was to examine the long-term 20-year benefit of ZOLADEX® and Tamoxifen, stratified by the molecular 70-gene risk prediction signature in this patient population. Patients were stratified by lymph node status and divided into 3 groups: patients with lymph node-negative status, those with 1-3 positive lymph nodes who had received chemotherapy, and those with 4 or more positive lymph nodes who received chemotherapy and locoregional radiotherapy. All of these patients were included in a 2X2 factorial randomization to receive ZOLADEX® 3.6 mg Subcutaneously every 28 days (N=230), Tamoxifen 40 mg orally daily (N=231), ZOLADEX® plus Tamoxifen (N=230), or no endocrine therapy (N = 233), for 2 years. Node-positive patients received adjuvant chemotherapy in addition to endocrine therapy. The median age was 46 years.

The researchers identified clinically relevant breast cancer markers by immunohistochemistry in 729 patients, of whom 610 patients had Hormone Receptor-positive tumors. Molecular risk classification data were available in 465 patients and the 70-gene signature classified patients into groups with either Low risk (N=306) or High risk of disease recurrence (N=159). Of the 610 patients with Hormone Receptor-positive tumors, 160 received ZOLADEX®, 142 received Tamoxifen, 156 received the combination, and 152 received no endocrine therapy (control group).

The researchers noted that the 20-year risk for distant recurrence was significantly reduced in the patients who received ZOLADEX®, Tamoxifen or both, compared with those who did not receive endocrine therapy. The respective Hazard Ratios (HRs) were 0.48, 0.59, and 0.67 after adjusting for prior therapy and tumor characteristics. Stratification by the 70-gene signature demonstrated that Low risk patients derived a significant benefit from Tamoxifen therapy (HR=0.38), whereas ZOLADEX® plus Tamoxifen provided less benefit to these patients ((HR=0.80 and 0.72, respectively). In contrast, patients at High risk had significant benefit from ZOLADEX® therapy (HR=0.22), whereas less benefit was observed with Tamoxifen or ZOLADEX® plus Tamoxifen (HR=0.69 and 0.64, respectively).

The authors concluded that long term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification, with significant benefit from ZOLADEX® noted in High risk patients, whereas Low risk patients benefit from Tamoxifen.

LBA1 – 20-year benefit of endocrine therapy in premenopausal breast cancer patients by the 70-gene risk signature. Johansson A, Dar H, Van ‘T Veer L, et al. DOI:https://doi.org/10.1016/j.annonc.2021.03.210

Final Analysis Confirms Superior OS Benefit with ERLEADA® in Metastatic Castrate Sensitive Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second generation anti-androgen agents, which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. ERLEADA® inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. ERLEADA® is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer (CSPC) and non-metastatic Castration Resistant Prostate Cancer (CRPC).

TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) is an international, randomized, placebo-controlled, double-blind, Phase III trial, conducted to determine whether treatment with ERLEADA® would result in longer radiographic Progression Free Survival (PFS) and Overall Survival (OS) than placebo, with an acceptable Safety profile and Health-Related Quality of Life, among patients with metastatic CSPC, who were receiving concomitant ADT. In this study a 1052 patients were randomly assigned 1:1 to receive ERLEADA® plus ADT (N=525) or placebo plus ADT (N=527). Patients received ERLEADA® 240 mg orally once daily, in addition to continuous ADT. The median age was 68 years and eligible patients had adenocarcinoma of the prostate with distant metastatic disease and were castration sensitive (patients were not receiving ADT at the time of disease progression). Previous treatment for prostate cancer was limited to no more than 6 cycles of Docetaxel, with no evidence of progression during treatment. A total of 16% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 11% had received previous Docetaxel therapy and 63% had high-volume disease. The co-Primary end points were OS and radiographic PFS (rPFS).

At the first interim analysis, with a median follow up of 22.7 months, ERLEADA® significantly improved dual Primary end points of OS (HR for death=0.67; P=0.005) and rPFS (HR for radiologic progression or death=0.48; P<0.001; Chi et al. NEJM. 2019). When this data was reported, OS information was from the first planned interim analysis, whereas rPFS data was final. TITAN study was then unblinded, allowing patients without progression who were still receiving placebo, to cross over to ERLEADA®. The authors in this publication reported the final analysis of efficacy and safety results from TITAN study.

At a median follow up was 44.0 months, the previous efficacy data was confirmed even after 39.5% of patients in the placebo group crossed over to receive ERLEADA®. Median treatment durations were 39.3 months with ERLEADA® in the ERLEADA® group, 20.2 months with placebo in the placebo group, and 15.4 months with ERLEADA® in placebo-treated patients who crossed over. In the intention-to-treat population, including patients who crossed over from the placebo group, the median Overall Survival was Not Reached in the ERLEADA® group versus 52.2 months in the placebo group (HR=0.65, P < 0.0001). The OS was superior in the ERLEADA® group compared with the placebo group despite crossover and the 4-year survival rates were 65% with ERLEADA® versus 52% with placebo. When the analysis was adjusted for crossover, the Hazard Ratio further improved to 0.52 (P<0.0001). At final analysis, cytotoxic chemotherapy had been initiated in 13.1% of ERLEADA®-treated patients versus 23.9% of placebo-treated patients (HR=0.47, P<0.0001). Secondary endpoints including second PFS (PFS2) was also in favor of ERLEADA®, and Health-Related Quality of Life (HRQoL) was maintained in the ERLEADA® group throughout the study and was not different from the placebo group. Safety was consistent with previous reports.

The authors concluded that with close to 4 years of follow up, the final analysis of the TITAN study demonstrated that among patients with metastatic Castrate Sensitive Prostate Cancer, ERLEADA® plus ADT provided an improvement in Overall Survival with a 35% reduction in risk of death, which further increased to 48% reduction, after adjusting for patients who had crossed over from placebo to ERLEADA®. Further, ERLEADA® also delayed castration resistance, and maintained Quality of Life.

Apalutamide in Patients with Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. Chi KN, Chowdhury S, Bjartell A, et al. J Clin Oncol. 2021 Apr 29;JCO2003488. doi: 10.1200/JCO.20.03488. Online ahead of print.

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

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SUMMARY: The American Cancer Society estimates that 45,230 new cases of rectal cancer will be diagnosed in the US in 2021. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined, is 67%. The current standard of care for patients with locally advanced rectal cancer (Stages T3, T4, or N+) consists of Chemoradiation followed by Total Mesorectal Excision (TME), which provides good local disease control, although distant metastases can still occur. Adjuvant chemotherapy after preoperative Chemoradiation remains controversial, as it has not shown an improvement in Overall Survival (OS). This has been attributed in part to poor treatment compliance. Phase II trials of total neoadjuvant therapy have yielded promising results but there is presently no data from Phase III trials.

The Phase III PRODIGE 23 trial sponsored by the French UNICANCER GI group, investigated the role of neoadjuvant modified FOLFIRINOX before standard preoperative chemoradiotherapy, in patients with locally advanced rectal cancer. The aim of the study was to assess whether administering neoadjuvant chemotherapy before preoperative Chemoradiation could reduce the risk of distant recurrences. In this study, 461 patients were randomly assigned 1:1 to either the neoadjuvant chemotherapy group (N=231) or the standard-of-care Chemoradiation group (N=230). Eligible patients had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a Performance Status of 0-1. The neoadjuvant chemotherapy group received preoperative chemotherapy with FOLFIRINOX (Oxaliplatin 85 mg/m2 IV, Irinotecan 180 mg/m2 IV, Leucovorin 400 mg/m2 IV, and Fluorouracil 2400 mg/m2 IV as a continuous infusion over 46 hours every 14 days for 6 cycles), followed by Chemoradiation (50 Gy over 5 weeks along with concurrent Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed by Total Mesorectal Excision, and adjuvant chemotherapy which consisted of modified FOLFOX6 (Oxaliplatin 85 mg/m2 IV and Leucovorin 400 mg/m2 IV, followed by Fluorouracil 400 mg/m2 IV bolus and then Fluorouracil 2400 mg/m2 continuous infusion over 46 hours) every 14 days for six cycles or Capecitabine 1250 mg/m2 orally twice daily on days 1-14 every 21 days.

The Chemoradiotherapy group received preoperative Chemoradiation (50.4 Gy over 5 weeks along with Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed 7 weeks later by Total Mesorectal Excision and adjuvant chemotherapy, which consisted of 6 months (12 cycles) of modified FOLFOX or 6-8 cycles of Capecitabine. It should be noted that patients received the same schedule of Chemoradiation, the same surgery, and the same total duration of chemotherapy (6 months) in both groups.

The Primary endpoint was Disease Free Survival (DFS) at 3 years. Secondary endpoints included Overall Survival (OS), Metastasis-Free Survival (MFS), and Cancer-Specific Survival (CSS). Safety analyses were performed on treated patients. More than 90% of patients received all planned cycles of FOLFIRINOX.

At a median follow-up of 46.5 months, the 3-year DFS rates were 76% in the neoadjuvant chemotherapy group and 69% in the standard-of-care group (HR=0.69; P=0.034). This represented a 31% reduction in the DFS hazard in the neoadjuvant group. Metastasis-Free-Survival at 3 years was significantly improved in the neoadjuvant group (79% vs 72%, P=0.017) and the pathologic Complete Responses were also significantly higher in the neoadjuvant group (28% versus 12%; P<0.001).
FOLFIRINOX was reported to be well tolerated with 92% compliance rate with this regimen. There were significantly more grade 3 or 4 adverse events in the Chemoradiation group, especially neutropenia and neuropathy. There were significantly more Grade 3 or 4 adverse events associated with adjuvant chemotherapy in the Chemoradiation control group (79% versus 45%, P<0.0001). Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and neuropathy, all occurred significantly more often in the patients who received 6 months of adjuvant therapy (Chemoradiation group), suggesting that for the same duration of chemotherapy, the perioperative approach was better tolerated than adjuvant chemotherapy.

The authors concluded that chemotherapy intensification using FOLFIRINOX before preoperative Chemoradiation significantly improved outcomes, with better tolerance and decreased neurotoxicity, compared with standard-of-care preoperative Chemoradiation, among patients with cT3 or cT4 M0 rectal cancer.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Conroy T, Bosset J-F, Etienne P-L, et al. Lancet Oncol. 2021;22:702-715.

Somatic Tumor Mutations and Risk for Thrombosis

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.

The researchers conducted this study to assess potential associations between tumor molecular signatures and Cancer Associated Thrombosis, including tumor-specific mutations, and the presence of Clonal Hematopoiesis. The authors analyzed deep-coverage targeted DNA-sequencing data of more than 14,000 solid tumor samples from 11,695 patients, using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform, to identify somatic alterations associated with Venous ThromboEmbolism (VTE). Among the patients included, more than 15 different solid tumor types were represented and 72% had metastatic disease at time of analysis.
Among these patients, there were 693 episodes of Cancer Associated Thrombosis, and the authors in addition to looking for associations with standard clinical variables such as diagnosis, stage and therapy, also assessed potential linkage of Cancer Associated Thrombosis with oncogenic mutations. The Primary endpoint was defined as the first instance of cancer-associated Pulmonary Embolism and/or proximal/distal lower extremity Deep Vein Thrombosis.

It was noted that several genes were found to be significantly associated with the VTE risk, regardless of tumor type. Independent of tumor type, the following mutations were associated with increased risk of Cancer Associated Thrombosis: KRAS (HR=1.34 suggesting 1.34 times higher risk), STK11 (HR=2.12), KEAP1 (HR=1.84), CTNNB1 (HR=1.73), CDKN2B (HR=1.45) and MET (HR=1.83). Mutations in SETD2 were associated with a decreased risk of Cancer Associated Thrombosis (HR=0.35). Clonal Hematopoiesis (CH) is an aging associated biologic state, with genetic mutations occurring in the background of active malignancies. The presence of Clonal Hematopoiesis was not associated with an increased risk of Cancer Associated Thrombosis.

The authors from this study concluded that this is the first large-scale study to explore the link between cancer genomics and thrombosis. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. It remains unclear whether drugs targeting these genetic alterations would alter the course of Cancer Associated Thrombosis.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors. Dunbar A, Bolton KL, Devlin SM, et al. Blood 2021;137:2103-2113.

Five-Year Efficacy Outcomes with KEYTRUDA® versus Chemotherapy in Metastatic NSCLC

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival across multiple tumor types. Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. High level of PD-L1 expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression, and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, Phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of Platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety. In an updated analysis of the KEYNOTE-024 study, after a median follow up of 25.2 months, the median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). This OS benefit was maintained even after adjusting for crossover.

The authors in this publication reported the 5-year efficacy and safety outcomes from this pivotal Phase III KEYNOTE-024 trial. The median time from randomization to data cutoff was 59.9 months. Among patients initially assigned to chemotherapy, 66% received subsequent anti PD-1 or PD-L1 therapy (66% cross over rate). In the KEYTRUDA® group, 52.9% received additional anticancer therapy.

The median OS was 26.3 months for KEYTRUDA® and 13.4 months for chemotherapy (HR=0.62). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the KEYTRUDA group and 16.3% for the chemotherapy group. The ORR was 46.1% among patients in the KEYTRUDA® group versus 31.1% in the chemotherapy group and the median Duration of Response was 29.1 months in the KEYTRUDA® group and 6.3 months in the chemotherapy group.

The authors concluded that first line KEYTRUDA® provides a durable and clinically meaningful long-term Overall Survival benefit, when compared to chemotherapy, in patients with metastatic NSCLC, with PD-L1 Tumor Proportion Score of at least 50%.They added that this is first 5-year follow up of any first line Phase III immunotherapy trial for Non Small Cell Lung Cancer.

Five-Year Efficacy Outcomes With Pembrolizumab vs Chemotherapy in Metastatic NSCLC With PD-L1 Tumor Proportion Score of at Least 50%: KEYNOTE-024 Trial. Reck M , Rodríguez–Abreu D, Robinson AG, et al. DOI: 10.1200/JCO.21.00174 Journal of Clinical Oncology. Published online April 19, 2021.

LENVIMA® Plus KEYTRUDA® for Advanced Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

SUTENT® (Sunitinib) is a MultiKinase Inhibitor (MKI) which simultaneously targets the tumor cell wall, vascular endothelial cell wall as well as the pericyte/fibroblast/vascular/smooth vessel cell wall, and is capable of specifically binding to tyrosine kinases inhibiting the earlier signaling events and thereby inhibits phosphorylation of VEGF receptor, PDGF receptor, FLT-3 and c-KIT. SUTENT® has been the standard first line intervention for treatment naïve patients with advanced RCC. In a large, multi-center, randomized, Phase III study, the median Progression Free Survival (PFS) with SUTENT® was 9.5 months, the Objective Response Rate (ORR) was 25%, and the median Overall Survival (OS) was 29.3 months, when compared with Interferon Alfa, in patients with treatment-naïve Renal Cell Carcinoma. This was however associated with a high rate of hematological toxicities.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

LENVIMA® (Lenvatinib) is an oral multitargeted TKI which targets Vascular Endothelial Growth Factor Receptor (VEGFR) 1-3, Fibroblast Growth Factor Receptor (FGFR) 1-4, Rearranged during Transfection tyrosine kinase receptor (RET), c-KIT, and Platelet Derived Growth Factor Receptor (PDGFR). LENVIMA® differs from other TKIs with antiangiogenesis properties by its ability to inhibit FGFR-1, thereby blocking the mechanisms of resistance to VEGF/VEGFR inhibitors. In addition, it controls tumor cell growth by inhibiting RET, c-KIT, and PDGFR beta and influences tumor microenvironment by inhibiting FGFR and PDGFR beta.

AFINITOR® (Everolimus) does not inhibit tyrosine kinases, but is a specific inhibitor of mTOR (Mammalian Target of Rapamycin), which is a serine/threonine kinase, normally activated further downstream in the signaling cascade. With the inhibition of mTOR, protein synthesis is inhibited resulting in decreased angiogenesis, cell proliferation and survival as well as decreased levels of HIF-1 alpha.
A combination of LENVIMA® plus AFINITOR® was shown to be associated with longer Progression Free Survival than AFINITOR® alone as second-line treatment in advanced RCC (Lancet Oncol 2015;16:1473-1482). LENVIMA® plus KEYTRUDA® was shown to have promising antitumor activity in previously treated patients with RCC in a Phase IB-II trial (J Clin Oncol 2020;38:1154-1163). Based on this data, the authors conducted a multicenter, randomized, open-label, Phase III trial to compare the efficacy and safety of LENVIMA® in combination with KEYTRUDA® or AFINITOR® versus SUTENT® alone, in first line treatment of patients with advanced RCC.

The researchers randomly assigned 1069 patients with advanced RCC and no previous systemic therapy in a 1:1:1 ratio to receive LENVIMA® 20 mg orally once daily plus KEYTRUDA® 200 mg IV once every 3 weeks (N=355), LENVIMA® 18 mg orally once daily plus AFINITOR® 5 mg orally once daily (N=357) or SUTENT® 50 mg orally once daily, alternating 4 weeks on and 2 weeks off (N=357). The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up for OS was 26.6 months.

The median PFS was significantly longer with LENVIMA® plus KEYTRUDA® combination, compared to single agent SUTENT® (23.9 months versus 9.2 months, HR=0.39; P<0.001). The median PFS with the LENVIMA® plus AFINITOR® combination was also significantly longer, compared to single agent SUTENT® (14.7 months versus 9.2 months, HR=0.65; P<0.001). The PFS benefit favored the two LENVIMA® combination regimens over single agent SUTENT® across all evaluated subgroups, including those based on MSKCC prognostic risk group and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group. At interim analysis, the OS was significantly longer with LENVIMA® plus KEYTRUDA® than with SUTENT® (HR for death=0.66; P=0.005). This benefit was noted in most subgroups, including patients with PD-L1 positive or negative tumors, with an exception of patients with favorable risk disease as defined by IMDC criteria. Overall Survival with LENVIMA® plus AFINITOR® was however not significantly longer compared with SUTENT® (HR=1.15; P=0.30).

The confirmed ORR was 71% with LENVIMA® plus KEYTRUDA®, 53.5% with LENVIMA® plus AFINITOR®, and 36.1% with single agent SUTENT®. The Complete Response rate was 16.1% in the LENVIMA® plus KEYTRUDA® group, 9.8% in the LENVIMA® plus AFINITOR® group, and 4.2% in the SUTENT® group. The median Duration of Response in patients who had a confirmed response was 25.8 months in the LENVIMA® plus KEYTRUDA® group, 16.6 months in the LENVIMA® plus AFINITOR® group, and 14.6 months in the SUTENT® group. Grade 3 or higher Adverse Events occurred in 82.4% of the patients who received LENVIMA® plus KEYTRUDA® group, in 83.1% of the patients who received LENVIMA® plus AFINITOR®, and in 71.8% of the patients who received SUTENT®.

It was concluded that a combination of LENVIMA® plus KEYTRUDA® provided superior Progression Free Survival and Overall Survival compared to SUTENT®, in the first line treatment of patients with advanced Renal Cell Carcinoma.

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Motzer R, Alekseev B, Rha S-Y, et al. for the CLEAR Trial Investigators. N Engl J Med 2021; 384:1289-1300

FDA Approves LIBTAYO® for Non Small Cell Lung Cancer with High PD-L1 Expression

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SUMMARY: The FDA on February 22, 2021, approved LIBTAYO® (Cemiplimab-rwlc) for the first line treatment of patients with advanced Non Small Cell Lung Cancer (NSCLC) (locally advanced who are not candidates for surgical resection or definitive chemoradiation or metastatic), whose tumors have high PD-L1 expression (Tumor Proportion Score [TPS] 50% or more), as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations.

The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types.

Available Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

LIBTAYO® is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to PD-1 and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. LIBTAYO® is indicated for the treatment of subsets of patients with advanced Basal Cell Carcinoma and advanced cutaneous Squamous Cell Carcinoma.

The present FDA approval of LIBTAYO® is based on EMPOWER-Lung 1, which is a multicentre, open-label, global, Phase III trial, which examined the benefit of LIBTAYO® in the first-line treatment of advanced NSCLC with PD-L1 expression of at least 50%. In this study, 710 (N=710) patients (intent-to-treat) with Squamous or non-Squamous, locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation, or with metastatic NSCLC were randomized (1:1) to receive LIBTAYO® 350 mg IV every 3 weeks for up to 108 weeks (N=356) or 4-6 cycles of investigator’s choice of platinum doublet chemotherapy (N=354). The most common chemotherapy regimens selected were Carboplatin plus Paclitaxel, Carboplatin plus Pemetrexed, and Carboplatin plus Gemcitabine. Crossover from chemotherapy to LIBTAYO® was allowed following disease progression, and never-smokers were not eligible for the trial. The co-Primary end points of the study were Overall Survival (OS) and Progression Free Survival (PFS), per the Blinded Independent Review Committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified population of patients with PD-L1 of at least 50%. Secondary end points included Overall Response Rate (ORR), Duration of Response (DOR), Health-Related Quality of Life (HRQoL), and Safety.

This trial demonstrated statistically significant improvements in OS and PFS for patients receiving LIBTAYO® compared to those treated with platinum-based chemotherapy, despite a high crossover rate (74%). The median OS was 22.1 months with LIBTAYO® versus 14.3 months with chemotherapy (HR=0.68; P=0.0022), demonstrating that LIBTAYO® reduced the risk of death by 32% compared to chemotherapy. An additional analysis of 563 patients with proven PD-L1 expression of 50% or higher found that the median OS was Not Reached with LIBTAYO® (N=283) versus 14.2 months with chemotherapy (N=280). LIBTAYO® reduced the risk of death by 43% compared to chemotherapy HR=0.57; P=0.0002). The median PFS was 6.2 months in the LIBTAYO® group and 5.6 months in the chemotherapy group (HR= 0.59; P<0.0001). Among those with PD-L1 expression of 50% or higher, the median PFS was 8.2 months with LIBTAYO® versus 5•7 months with chemotherapy (HR=0•54; P<0•0001). The confirmed ORR was 37% and 21% in the LIBTAYO® and chemotherapy arms respectively, and the median DOR was 21.0 months in the LIBTAYO® arm versus 6.0 months in the chemotherapy arm.

The authors concluded that LIBTAYO® monotherapy significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non Small Cell Lung Cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population.

Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Sezer A, Kilickap S, Gümüş M, et al. Lancet. 2021;397:592-604. doi: 10.1016/S0140-6736(21)00228-2.

FDA Approves Antibody Drug Conjugate ZYNLONTA® for Large B-Cell Lymphoma

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SUMMARY: The FDA on April 23, 2021 granted accelerated approval to ZYNLONTA® (Loncastuximab tesirine-lpyl ), a CD19-directed antibody and alkylating agent conjugate, for adult patients with Relapsed or Refractory Large B-Cell Lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, DLBCL arising from Low Grade Lymphoma, and High Grade B-Cell Lymphoma.

The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-Cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. For patients who fail first line therapy, outcomes are poor, worsening with each line of therapy, and the chance for cure or long term disease-free survival diminishes. There is a significant unmet need for patients with Relapsed/Refractory DLBCL.

ZYNLONTA® is a CD19-directed Antibody Drug Conjugate comprised of a humanized anti-CD19 antibody, conjugated through a linker to a potent pyrrolobenzodiazepine (PBD) dimer toxin. Once bound to a CD19-expressing cell, ZYNLONTA® is internalized by the cell following which the toxic payload is released. The potent toxin then binds irreversibly to DNA to create highly potent interstrand cross-links that block DNA strand separation, thereby disrupting essential DNA metabolic processes such as replication and ultimately resulting in cell death. CD19 is a clinically validated target for the treatment of B-cell malignancies.

The present FDA approval of ZYNLONTA® was based on LOTIS-2, which is an open-label, single arm trial in which 145 adult patients who had Relapsed or Refractory DLBCL or High Grade B-Cell Lymphoma were included. This study included transplant eligible and ineligible patients, patients with double or triplet-hit lymphoma, and patients who previously received stem cell transplant or CD 19-targeted CAR-T cell therapy. Patients received ZYNLONTA® 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles. Treatment was continued until progressive disease or unacceptable toxicity. Enrolled patients had at least two prior systemic regimens. The main efficacy outcome measure was Overall Response Rate (ORR). Pre-specified analyses of ORR and Duration of Response (DoR) by demographic and clinical characteristics were performed, and ORR was assessed by independent reviewer according to the Lugano response criteria.

The ORR was 48.3% with a Complete Response Rate of 24.1%. The Partial Response (PR) rate was 24.1%. Patients had a median time to response of 1.3 months and the median Duration of Response for the 70 responders was 10.3 months (inclusive of patients who were censored). The most common Grade 3 or higher treatment-related adverse events included neutropenia with a low incidence of febrile neutropenia, thrombocytopenia, Gamma-Glutamyl Transferase increase, and anemia.

The authors concluded that ZYNLONTA® had substantial single-agent antitumor activity in patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma, with encouraging and durable responses noted in patients with high-risk characteristics.

Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Caimi PF, Ai WZ, Alderuccio JP, et al. Presented at the 62nd ASH Annual Meeting and Exposition, December 5-8,2020. Abstract#1183

Role of Chemotherapy in Postmenopausal Women with Node Positive Early 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 (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. For women 50 years old or younger who received chemotherapy and had a Recurrence Score of 16 to 25, there was a lower rate of distant recurrence and the risk of recurrence and benefit of chemotherapy was further influenced by the tumor size and grade. 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.