Overall Survival at 2 Years with LUMAKRAS® for KRAS G12C Positive Non Small Cell Lung Cancer

SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.

KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

LUMAKRAS® (Sotorasib) is a first-in-class small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that LUMAKRAS® inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors. The CodeBreaK clinical development program for LUMAKRAS® was designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. This program has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100 is a Phase I and II, first-in-human, open-label, single arm, multicenter study, which enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, for their tumor type and stage of disease. The Phase II trial enrolled 126 patients with NSCLC, who had locally advanced or metastatic NSCLC with a KRAS G12C mutation, and had progressed on an immune checkpoint inhibitor and/or platinum-based chemotherapy. Patients with active brain metastases were excluded. Patient received LUMAKRAS® 960 mg orally once daily, until disease progression or unacceptable toxicity. The median age was 64 years, 52% were male, over 90% of patients had a smoking history, median number of prior lines of therapy was two, 92% had prior platinum-based chemotherapy and 90% had prior anti–PD-L1 therapy, 83% had both prior platinum-based chemotherapy and immunotherapy. The Primary end point of the trial was Overall Response Rate (ORR) as assessed by blinded Independent Central Review. Secondary end points included Duration of Response (DOR), Disease Control Rate (DCR), time to recovery, Progression Free Survival (PFS), Overall Survival (OS), and Safety. The examination of biomarkers served as an exploratory end point.

At the time of Primary analysis, at a median follow up of 12.2 months, the ORR was 37.1% and the median Duration of Response was 10 months. Based on the data from the primary analysis, the FDA in 2021 granted accelerated approval to LUMAKRAS®, for the treatment of patients with locally advanced or metastatic NSCLC, whose tumors harbor the KRAS G12C mutation, and who have received prior therapies.

For this updated analysis, the median follow up time for OS was 24.9 months, and the researchers included 174 patients enrolled in Phase I (N=48) and Phase II (N=126) portions of the CodeBreaK 100 trial, who were treated with LUMAKRAS®. The Overall Response Rate was 40.7% and the Disease Control Rate (DCR) was 83.7%. The median time to response was 6 weeks, the median Duration of Response was 12.3 month and 50.6% of responders remained in response for 12 months or more. The median PFS was 6.3 months and the median OS showed no change in the updated analysis, and was 12.5 months. At 1-year, the OS rate was 50.8% and the 2-year Overall Survival was 32.5%. The researchers performed additional analyses on both tumor and blood samples to identify biomarker profiles associated with durable clinical benefit and these showed that prolonged clinical benefit was observed regardless of Tumor Mutation Burden, PDL1 expression, and STK11 co-mutation status. Grade 3 or 4 treatment-related Adverse Events occurred in 21% of patients. Most adverse events were Grade 1 or 2, and treatment-related adverse events occurring in more than 10% of patients included diarrhea, elevated liver enzymes, nausea and fatigue.

It was concluded from this updated analysis that this is the longest follow up of patients on any KRAS G12C inhibitor, and LUMAKRAS® demonstrated meaningful and durable efficacy in patients with KRAS mutated NSCLC for whom treatment options are limited, following progression on first line treatment, and historically have had poor outcomes. Patients on LUMAKRAS® benefitted regardless of Tumor Mutation Burden, PDL1 expression, and STK11 co-mutation status. A global Phase III study (CodeBreaK 200) is underway, comparing LUMAKRAS® to Docetaxel in patients with KRAS G12C-mutated NSCLC.

Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Dy GK, Govindan R, Velcheti V, et al. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022, New Orleans, LA. Abstract CT008.

Genetically Adjusted PSA Values May Improve the Accuracy of Prostate Cancer Detection

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease.

PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy.

The researchers in this study hypothesized that the accuracy of PSA screening for prostate cancer could be improved by accounting for genetic factors that cause changes in PSA levels not associated with prostate cancer. The aim of this study was to characterize genetic determinants of PSA levels in cancer-free men, in order to personalize prostate cancer screening.

The researchers conducted a large Genome Wide Association Study of PSA, to improve Prostate cancer screening, by accounting for genetic factors that cause noncancer-related variations in PSA levels, thereby personalizing prostate cancer screening. This study involved 95,768 men without a diagnosis prostate cancer from the US, UK and Sweden. The researchers identified 128 PSA-related variants across the genome, including 82 novel variants that were not previously recognized, and created a polygenic score for PSA levels. This polygenic score provided a cumulative measure of each individual’s genetic predisposition to high PSA levels.

The authors validated the polygenic score by applying the score to PSA values of 5,725 individuals enrolled in the Prostate Cancer Prevention Trial (PCPT) and the 25,917 individuals enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The analysis showed that the score explained 7.3% of variation in baseline PSA values in PCPT trial and 8.8% of variation in baseline PSA values in the SELECT cohort, and the polygenic score was not associated with prostate cancer in both the prevention trials, confirming that the score reflected benign PSA variation.

The researchers next tested the ability of the polygenic score’s ability to improve detection of clinically significant prostate cancer and reduce over diagnosis among a real-world cohort at Kaiser Permanente. They adjusted each individual’s PSA values based on his unique polygenic score and estimated the impact of this adjustment on the PSA thresholds that trigger biopsy referrals. The authors estimated that by substituting the patient’s polygenic score for measured PSA values, 19.6% of negative biopsies in men without prostate cancer potentially could have been avoided, and 15.7% of biopsies could have been avoided in men who had indolent, low-grade prostate cancer (Gleason score <7), which represented 71% of all men.

The researchers then evaluated whether genetically adjusted polygenic score would better detect aggressive prostate cancer (Gleason score 7, PSA 10 ng/mL, T3-T4 stage and/or distant nodal metastases). It was noted that in both the PCPT and the SELECT cohorts, polygenic score was more strongly associated with aggressive prostate cancer than measured unadjusted PSA values. The polygenic score also exceeded the performance of the 269-variant genetic risk score.

The authors from this study concluded that genetically adjusted PSA (polygenic score) could reduce unnecessary testing and overdiagnosis of low-risk prostate cancer, and increase detection of aggressive tumors and thus make PSA a more useful and accurate screening biomarker. The researchers pointed out that the population studied, were primarily European descent, and the polygenic score will need to be validated in more diverse populations.

Genetic determinants of PSA levels improve prostate cancer screening. Kachuri L, Graff RE, Berndt SI, et al. Presented at: AACR Annual Meeting 2022; April 8-13; New Orleans, Louisiana. Abstract 1441/8.

PET Response-Based Radiotherapy De-Escalation in p16 Positive Oropharyngeal Cancer

SUMMARY: The American Cancer Society estimates that about 54,000 new cases of oral cavity or Oropharyngeal Cancer will be diagnosed in the US in 2022 and about 11,230 patients will die of the disease. According to the CDC, based on data from 2014 to 2018, about 46,143 HPV-associated cancers occur in the United States each year (25,719 among women, and 20,424 among men). Cervical cancer is the most common HPV-associated cancer among women, and Oropharyngeal cancers are the most common among men. There has been a significant increase in the incidence during the past several decades, due to changes in sexual practices.

HPV-positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) is an entirely distinct disease entity from HPV-negative Oropharyngeal Squamous Cell Carcinoma. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV (HR-HPV). The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC), when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in head and neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with head and neck cancer and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.

HPV-positive Oropharyngeal Squamous Cell Carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative Oropharyngeal Squamous Cell Carcinoma, which translates to a much better prognosis and survival, when treated with a combination of Cisplatin chemotherapy and Radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste.Oropharynx

To address these toxicities, the authors conducted a prospective Phase II de-escalation study utilizing FDG-PET response criteria to select patients eligible for de-escalated radiotherapy. The researchers hypothesized that early swallow function and quality of life will improve with lower dose radiation. This study enrolled 59 patients (N=59) with Stage I-II (AJCC) p16-positive Oropharyngeal cancer, with FDG-avid disease and any smoking history. Patients with matted lymph nodes or history of head and neck surgery were excluded.

All enrolled patients had a pre-treatment FDG-PET/CT imaging and received weekly Carboplatin and Paclitaxel concurrently with planned radiotherapy at 70 Gy in 35 fractions. FDG-PET was repeated midway through treatment after 2 weeks at fraction 10. Patients who had tumors with lower metabolic activity before treatment and more than 50% reduction in Metabolic Tumor Volume after 2 weeks of treatment were de-escalated from the standard radiotherapy total dose of 70 Gy in 35 fractions, to a total dose of 54 Gy in 27 fractions. The median patient age was 60 years and baseline characteristics showed that both standard and de-escalated cohorts had similar patient demographics and pathology. At the planned interim analysis, early toxicity and Patient Reported Outcomes (PROs) were examined.

Fifty percent (50%) of the patients met de-escalation criteria and received the lower radiation dose, leading to 20-30% reductions in radiation exposure to sensitive structures in the head and neck prone to toxicities such as larynx, constrictors, oral cavity and salivary glands. De-escalation from the standard radiotherapy resulted in significantly less acute toxicity, and at one month after treatment, patients who received de-escalated therapy lost less weight as a percentage of baseline, compared to standard treatment group (6% versus 11%; P<0.001) and had improved videofluoroscopic swallowing function following treatment, and fewer patients required feeding tube placement during treatment.

The authors concluded that although the trial remains ongoing, mid-treatment FDG-PET response adaptation allows for approximately 50% of early stage p16 positive Oropharyngeal cancer patients to be de-escalated to a total dose of 54 Gy. This in turn can result in approximately 25% reduction in dose delivered to organs known to affect toxicity and quality of life, with significantly better objective measures of toxicity and numerically improved Patient Related Outcomes.

Early Toxicity and Patient Reported Outcomes From a Phase 2 Trial of FDG-PET Response-Based De-Escalated Definitive Radiotherapy for p16+ Oropharynx Cancer. Allen SG, Rosen BS, Aryal MP, et al. 2022 Multidisciplinary Head and Neck Symposium; February 24-26, 2022; Phoenix, AZ. Abstract 1.

NUBEQA® Combination Improves Overall Survival in Metastatic Hormone Sensitive Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 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.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists.

NUBEQA® (Darolutamide) is a potent second-generation Androgen Receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. NUBEQA® does not cross the blood-brain barrier and for this reason has a favorable safety and tolerability profile in prespecified adverse events such as seizures, when compared with other second-generation AR inhibitors such as ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide). It has been associated with increased Overall Survival (OS) among patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC) and has been approved by the FDA for this indication. Whether a combination of NUBEQA®, in combination with Androgen Deprivation Therapy (ADT), and Docetaxel would increase survival among patients with metastatic Hormone-Sensitive Prostate Cancer, is unknown.

ARASENS is an international, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated the efficacy and safety of NUBEQA® (Darolutamide) added to Androgen Deprivation Therapy (ADT) and Docetaxel in patients with metastatic Hormone Sensitive Prostate Cancer. In this study, a total of 1306 patients were randomly assigned 1:1 to receive NUBEQA® (N=651) or placebo (N=655), both in combination with ADT and Docetaxel. All the patients received ADT (either a Luteinizing Hormone Releasing Hormone (LHRH} agonist or antagonist) or underwent Orchiectomy within 12 weeks before randomization and received six cycles of Docetaxel 75 mg/m2 IV given on Day 1 every 21 days, with Prednisone or Prednisolone. Patients received LHRH agonists along with a first-generation anti-androgen agent for at least 4 weeks before randomization to help prevent a tumor flare, and the anti-androgen agent was discontinued before randomization. Patients were then randomly assigned to receive either NUBEQA® 600 mg orally twice daily or matched placebo, and treatment was continued until disease progression or unacceptable toxicities.

Eligible patients had biopsy proven prostate cancer with bone metastases and had to be candidates for ADT and Docetaxel. Patients with regional lymph node involvement only (N1, below the aortic bifurcation) or if they had received ADT more than 12 weeks before randomization, second-generation Androgen Receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer before randomization, or radiotherapy within 2 weeks before randomization, were excluded. The median age was 67 years and both treatment groups were well balanced. All patients had metastatic disease at baseline, 78% of the patients had a Gleason score of 8 or greater, about 80% had bone metastases (Stage M1b) and 18% had visceral metastases (Stage M1c). The Primary end point was Overall Survival (OS) and Secondary end points included were time to Castration-Resistant Prostate Cancer, time to pain progression, symptomatic Skeletal Event-Free Survival and time to initiation of subsequent systemic antineoplastic therapy, as well as Safety. The median follow up for Overall Survival was 43 months.

The median Overall Survival was not estimable in the NUBEQA® group versus 48.9 months in the placebo group. The addition of NUBEQA® to the combination with ADT and Docetaxel reduced the risk of death by 32%, compared to the placebo group (HR=0.68; P<0.001). This OS benefit was noted across most subgroups. Further, the significant OS benefit with the addition of NUBEQA® was observed, despite receipt of subsequent life-prolonging systemic therapies such as different Androgen-Receptor pathway inhibitors by 75.6% of patients in the placebo control group. The OS at 4 years was 62.7% in the NUBEQA® group and 50.4% in the placebo group.

With regard to Secondary endpoints, the addition of NUBEQA® to ADT and Docetaxel demonstrated consistent benefits. The time to development of Castration-Resistant Prostate Cancer was significantly longer in the NUBEQA® group (HR=0.36; P<0.001), the time to pain progression was also significantly longer in the NUBEQA® group (HR=0.79; P=0.01), as well as symptomatic Skeletal Event-Free Survival (HR=0.61; P<0.001). Further, the time to the initiation of subsequent systemic antineoplastic therapy was also significantly longer in the NUBEQA® group (HR=0.39; P<0.001). Adverse events were similar in the two groups.

The authors concluded that among patients with metastatic Hormone Sensitive Prostate Cancer, the addition of NUBEQA® to Androgen Deprivation Therapy and Docetaxel resulted in significantly longer Overall Survival, as well as improvement in key Secondary end points, with no increase in adverse events.

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith MR, Hussain Saad F, et al. for the ARASENS Trial Investigators. NEJM. February 17, 2022. DOI: 10.1056/NEJMoa2119115.

Elacestrant in Metastatic Breast Cancer Progressing on CDK4/6 Therapy and ESR1-Mutant Subtype

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 express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of ER+/HER2- metastatic breast cancer as first-line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER+ breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).

Fulvestrant is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is the only SERD approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer. However, acquired ESR1 mutations can also occur following Fulvestrant treatment, possibly because of poor bioavailability and incomplete ER blockade when administered intramuscularly. There is therefore an urgent unmet need for an alternate SERD that has activity in tumors harboring ESR1 mutations, and has improved bioavailability allowing oral administration.

Elacestrant is an oral, nonsteroidal, Selective Estrogen Receptor Degrader (SERD) that degrades the Estrogen Receptor (ER) in a dose-dependent manner and inhibits estradiol-dependent functions of ER target gene transcription induction and breast cancer cell proliferation. Estradiol-stimulated tumor growth was diminished by Elacestrant in the ER+ xenograft models derived from heavily pretreated patients, including models resistant to CDK 4/6 inhibitors, Fulvestrant and those harboring ESR1 mutations Y537S and D538G. In an early Phase I trial, Elacestrant was noted to have an acceptable safety profile, and demonstrated single-agent activity with confirmed Partial Responses in heavily pretreated patients with ER+ metastatic breast cancer.

EMERALD trial is a multicenter, International, randomized, open-label, Phase III study designed to evaluate the benefit of Elacestrant in patients with ER+ HER2- advanced or metastatic breast cancer. In this study, 477 postmenopausal women with ER+/HER2- metastatic breast cancer were randomly assigned 1:1 to receive either Elacestrant 400 mg orally daily (N=239) or the Standard of Care which included investigator’s choice of Fulvestrant or an Aromatase Inhibitor including Anastrozole, Letrozole, or Exemestane (N=238). Treatment was given until disease progression. Both treatment groups were well balanced. The median patient age was 63 years, and patients must have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6 inhibitor, had 1 or fewer lines of chemotherapy for advanced disease, and had an ECOG performance status of 0 or 1. In the study, 48% had tumors with mutated ESR1 and these patients were evenly distributed in both treatment groups. Patients were stratified by ESR1-mutation status, prior treatment with Fulvestrant, and visceral metastases. The co-Primary end points were Progression Free Survival (PFS) in the overall population, and in those with ESR1 mutations. Overall Survival (OS) was a Secondary end point.

Treatment with Elacestrant resulted in a statistically significant and clinically meaningful improvement in PFS, compared with Standard of Care. There was a 31% reduction in the risk of progression or death in the Elacestrant group for all patients (HR=0.69; P=0.0018) and a 45% reduction in the risk of progression or death among those with ESR1 mutations (HR=0.55; P=0.0005).

The PFS at 12 months with Elacestrant was 22.3% in all patients compared with 9.4% for those receiving the Standard of Care treatment. Among the ESR1 mutation group, the 12 month PFS rate was more pronounced and was 26.8% with Elacestrant, compared to 8.2% with Standard of Care. The benefits with Elacestrant compared with Standard of Care, was consistent across multiple prespecified subgroups including patients who had received prior Fulvestrant. There also was a trend toward improved Overall Survival in patients who received Elacestrant, compared with Standard of Care. The final OS results however are not expected until late 2022. Elacestrant was well tolerated and treatment discontinuation rate was not significantly different between the two treatment groups.

It was concluded that Elacestrant is the first oral Selective Estrogen Receptor Degrader that demonstrated significant and clinically meaningful improvement in PFS compared with Standard of Care endocrine therapy in patients with ER+/ HER2- metastatic breast cancer in the second/third line after treatment with a CDK4/6 inhibitor, and has the potential to become the new standard of care in the study population.

Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of the EMERALD phase 3 trial. Bardia A, Neven P, Streich G, et al. Presented at 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-02.

Defining Patient Groups With Triple Negative Breast Cancer Who Derive Benefit From KEYTRUDA® plus Chemotherapy

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. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition, and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

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. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first line treatment of advanced TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-Paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS-Combined Positive Score of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety.

In the primary analysis of the KEYNOTE-355 trial, the Overall Survival results after a median follow up of 44.1 months in the subgroup of patients with PD-L1 CPS (Combined Positive Score) of 10 or more was significantly better with first line KEYTRUDA® plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively; HR=0.73; P=0.0093). This represented a 27% reduction in the risk of death with the KEYTRUDA® combination. KEYTRUDA® in combination with chemotherapy, also significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. However, among patients with CPS of 1 or greater, the median PFS was not considered statistically significant, based on prespecified statistical criteria.

The researchers here in presented the results of a subgroup analysis, stratified by levels of PD-L1 expression, as assessed by CPS score. In the subgroups with CPS scores of less than 1 and 1-9, Overall Survival was similar for KEYTRUDA® plus chemotherapy and placebo plus chemotherapy. However, in subgroups with CPS 10-19 and CPS 20 or more, there was sustained separation of the Overall survival curves starting at approximately 10 months and the survival was improved by about 28%.

The authors noted that the general trend for PFS was consistent with that observed for Overall Survival, with improving PFS trend among those subgroups with PD-L1 enriched CPS of 10 or more. In the subgroup of patients with a CPS of 10-19 and CPS of 20 or more, the addition of KEYTRUDA® to chemotherapy resulted in a more sustained separation of PFS curves, beginning at approximately 4 months, compared with placebo plus chemotherapy. The Hazard Ratios for these two groups were 0.70 and 0.62, respectively. Toxicities of any grade were reported in 96% of the experimental group and 95% of the placebo plus chemotherapy group. The rate of Grades 3-5 treatment-related adverse events was 68.1% and 66.9%, respectively and the majority of treatment discontinuations in this study were for progressive disease.

The researchers based on this subgroup analyses concluded that a CPS of 10 or more is a reasonable cutoff to define the population of women with metastatic Triple Negative Breast Cancer, expected to derive treatment benefit from KEYTRUDA® plus chemotherapy, lending further support to KEYTRUDA® plus chemotherapy as a standard of care treatment regimen for this group of patients.

Final results of KEYNOTE-355: randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Cortés J, Cescon DW, Rugo HS, et al. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-02.

Elevated White Cell Count and Risk of Thrombotic Events in Polycythemia Vera

SUMMARY: Polycythemia Vera (P. Vera) is a clonal myeloproliferative neoplasm characterized by isolated erythrocytosis in a majority of the patients, with the remaining demonstrating leukocytosis and/or thrombocytosis along with erythrocytosis. Patients usually present with this disorder in their sixth decade and are often asymptomatic, with the diagnosis made incidentally on routine laboratory evaluation. About 30% of the patients however, may initially present with a thrombotic episode, whereas a small percentage of patients may present with disease related symptoms such as pruritus and fatigue. The conventional risk factors for thrombotic events in MyeloProliferative Neoplasms (MPN) are age more than 60 years and prior thrombosis, and the presence of both these risk factors is associated with a 7-fold increased risk of thrombosis.

Overactivation of the JAK-STAT signal transduction pathway caused by V617F mutation has been implicated in majority of the patients with P. Vera. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with P. Vera, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines, associated with this abnormal signaling. JAK2 mutations such as JAK2 V617F are seen in approximately 95% of patients with P. Vera.Molecular-Mechanisms-of-MPNs

Studies have shown that JAK2 mutations that result in the overproduction of erythrocytes, leukocytes, and platelets in P. Vera also promote direct activation of leukocytes and platelets. Activated platelets and leukocytes bind to each other and activate endothelial cells, which may in turn contribute to the prothrombotic state. The prospective CYTO-PV trial published in 2011, established that maintaining hematocrit less than 45% through phlebotomies and/or cytoreductive drugs significantly decreased the risk of thrombotic events in P. Vera patients. Even though several retrospective analyses strongly suggest an association between leukocytosis and thrombosis, leukocytosis particularly at the time of the thrombotic event in P. Vera patients, no prospective trial has been conducted to assess the impact of WBC counts on thrombotic risk in P. Vera.

The REVEAL study is a large, real-world, multicenter, prospective, noninterventional, observational study, in which patients with P. Vera from US community practice and academic centers were enrolled , to evaluate the association between elevated blood counts and occurrence of thrombotic events in patients with P. Vera, using data from the REVEAL study.

This study analyzed the data of 2271 eligible patients for this analysis (78% high risk and 22% low risk). The median patient age was 66 years and 54% were male. The median disease duration was 4.1 years, 20% had a history of thrombotic events and majority of patients (53%) were receiving Hydroxyurea. Patient data was collected at diagnosis, at a 6-month period, and during follow up, 3 years from last patient enrollment, between July 2014 and August 2019 and the researchers analyzed the association between blood counts and thrombotic events. Out of 106 patients who had thrombotic events, 30 had arterial thrombotic events, most commonly, Transient Ischemic Attack and 76 had venous thrombotic events, most commonly, Deep Vein Thrombosis.

It was noted that hematocrit greater than 45% versus 45% or less (P=0.0028), WBC more than 11×109/L versus 11×109/L or less (P<0.0001), and Platelet counts more than 400×109/L versus 400×109/L or less (P=0.0170) were each associated with increased risk of thrombotic events. A WBC count of 11×109/L or more was associated with the highest thrombotic event risk compared with WBC count less than 7×109/L (P<0.0001). In all models analyzed, advanced age and history of thrombotic events, were associated with increased thrombotic event risk.

The authors concluded that in this analysis of the largest real-world cohort of P. Vera patients to date, hematocrit more than 45%, as well as WBC more than 11×109/L and Platelet counts more than 400×109/L, were each associated with increased risk of thrombotic events. The authors added that these data support the incorporation of blood count values into risk stratification and treatment strategies for patients with P. Vera in clinical practice, and to move beyond the conventional risk model.

A Real-World Evaluation of the Association between Elevated Blood Counts and Thrombotic Events in Polycythemia Vera (Analysis of Data from the REVEAL Study). Gerds AT, Mesa RA, Burke JM, et al. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 239.

Long Term Survival Benefit with Maintenance ONUREG® in AML Patients

SUMMARY: The American Cancer Society has estimated that in 2021, 20,240 new cases of Acute Myeloid Leukemia (AML) were diagnosed in the United States and 11,400 patients died of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5 year Overall Survival (OS) in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

Cytotoxic chemotherapy for AML often consists of induction therapy to achieve remission, followed by consolidation therapy. However, standard induction chemotherapy achieves Complete Remission in only 40-60% of AML patients older than 60 years of age, and majority of these patients will eventually relapse. This had been attributed to clonal evolution and epigenetic reprogramming, leading to aberrant DNA methylation, and persistence of leukemia-initiating cells.

Longer duration of first remission is associated with better survival outcomes. Postremission maintenance therapies to prevent early AML relapse has been an area of active research with little progress made until now. Patients with AML who are under age 55 with high-risk cytogenetics, in first clinical remission,are considered for allogeneic Hematopoietic Stem Cell Transplantation (HSCT), as this has shown to offer survival advantage over conventional chemotherapy. This therapeutic option however is not feasible for many elderly patients.

Oral Azacitidine (ONUREG®) is a hypomethylating agent that has a distinct pharmacokinetic as well as pharmacodynamic profile from the parenteral Azacitidine preparation, and can be administered in extended dosing schedules (for 14-21 days per 28-day treatment cycle) to sustain therapeutic activity.

ONUREG® is the first and only FDA-approved therapy indicated for continued treatment of adult patients with AML who achieved first Complete Remission (CR) or Complete Remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy, and are not able to complete intensive curative therapy.

This FDA approval was based on an International, double-blind, placebo-controlled, Phase III QUAZAR AML-001 trial, in which ONUREG® was evaluated as maintenance therapy in patients with AML, who were in first remission after intensive chemotherapy. Eligible patients were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for Hematopoietic Stem Cell Transplantation. Patients (N=472) were randomly assigned to receive ONUREG® 300 mg orally (N=238) or placebo (N=234), once daily for 14 days of a 28-day cycle. The median age was 68 years. The Primary end point was Overall Survival (OS). Secondary end points included Relapse Free Survival (RFS) and Health-Related Quality of Life.

At the time of the primary analysis in 2019, with a median follow up of 41.2 months, maintenance treatment with ONUREG® significantly prolonged median OS, when compared to placebo (24.7 months versus 14.8 months; P<0.001). The median RFS was also significantly longer with ONUREG® than with placebo (10.2 months versus 4.8 months; P<0.001). These survival benefits were demonstrated in most treatment subgroups. Further, with a median follow up of 51.7 months, the median OS remained unchanged, and the median OS with oral ONUREG® was 24.7 months versus 14.8 months with placebo (HR=0.69; P=0.0008). The 3-year OS rates in the experimental and control arms were 37.4% and 27.9%, respectively and at 5 years were 26.2% and 19.2%, respectively. Overall Quality of life was preserved while on treatment with ONUREG®. The most common adverse reactions associated with ONUREG® treatment were nausea, vomiting, diarrhea, abdominal pain, constipation, fatigue/asthenia, febrile neutropenia and pneumonia.

The authors concluded that maintenance treatment with ONUREG® was associated with significantly longer Overall and Relapse Free Survival when compared to placebo, among elderly patients with AML, who were in remission after chemotherapy. This survival benefit was maintained with one additional year of follow up. The researchers added that these updated data suggests that maintenance therapy with ONUREG® provides a sustained, long term Overall Survival benefit in elderly patients with AML in first remission.

Long-Term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 Trial. Wei AH, Döhner H, Sayar H, et al. Blood. 2021;138(suppl 1):871. doi:10.1182/blood-2021-147501.

Postmenopausal Women with Node Positive Breast Cancer May Not Benefit From Chemotherapy

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 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 adjuvant 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 at least 16, there was a lower rate of distant recurrence, and the absolute benefit increased with increasing recurrence score. Further, 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 (A Clinical Trial RX for Positive Node, Endocrine Responsive Breast Cancer) trial was designed to determine the benefit of chemotherapy, in patients with HR-positive, HER2-negative breast cancer and 1-3 positive axillary lymph nodes (nodal stage N1), 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 (N=2547) or endocrine therapy alone (N=2536). The median patient age was 57.5 years and 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 distant Relapse Free Survival (RFS) and Overall Survival (OS).

At a median follow up of 6.1 years, the chemotherapy benefit with respect to increasing invasive DFS differed according to menopausal status. Among postmenopausal women, in this updated analysis with longer follow up, the invasive DFS at 5 years was 91.9% in the endocrine therapy alone group, and was 91.3% in those treated with chemotherapy plus endocrine therapy (HR=1.02; P=0.89). Postmenopausal women with recurrence scores of 0 to 25 continued to NOT benefit from adjuvant chemotherapy.

Among premenopausal women however, the invasive DFS at 5 years was 89% in the endocrine therapy alone group and 93.9% % in those treated with chemotherapy plus endocrine therapy (HR=0.64; P=0.004). There was a 5-year absolute benefit of 4.9% for invasive DFS with chemotherapy among premenopausal women. There was a similar increase noted in the distant Relapse Free Survival (HR=0.58; P=0.009). The relative chemotherapy benefit did not increase as the Recurrence Score increased.

It was concluded from this practice-changing study 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 benefited from chemotherapy plus endocrine therapy and had a longer invasive Disease Free Survival and distant Relapse Free Survival, than those who received endocrine therapy alone.

21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. Kalinsky K, Barlow WE, Gralow JR, et al. N Engl J Med 2021;385:2336-2347

POLIVY® in Previously Untreated Diffuse Large B-Cell Lymphoma

SUMMARY: 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 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 (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. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor.

CD79b is a B-cell specific surface protein, which is a component of the B-cell receptor and is ubiquitously expressed on the surface of malignant B cells. POLIVY® (Polatuzumab vedotin) is a CD79b-directed Antibody-Drug Conjugate (ADC) with activity against dividing B cells. It consists of three components: 1) the humanized ImmunoGlobulin G1 (IgG1) monoclonal antibody specific for human CD79b; 2) the small molecule anti-mitotic agent MMAE (monomethyl auristatin E) and 3) a protease-cleavable linker that covalently attaches MMAE to the Polatuzumab antibody. Upon binding to CD79b, POLIVY® is internalized, and the linker is cleaved by lysosomal proteases thus enabling intracellular delivery of MMAE. MMAE then binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis. POLIVY® demonstrated efficacy in patients with Relapsed or Refractory DLBCL, resulting in significantly longer Overall Survival when combined with Bendamustine and Rituximab, compared to Bendamustine and Rituximab alone. Based on these finding, the FDA granted accelerated approval to POLIVY® in June 2019.

In a Phase Ib-II study POLIVY® in combination with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) resulted in a 89% Overall Response rate and 77% Complete Responses when given as first line therapy, in patients with DLBCL. In this study, Vincristine was excluded from the regimen owing to the risk of overlapping neurotoxicities with POLIVY®. The present POLARIX trial was conducted to evaluate the efficacy and safety of pola-R-CHP as compared with R-CHOP, in patients with previously untreated DLBCL.

The POLARIX is a randomized, double-blind, placebo-controlled, International Phase III trial in which a total of 879 treatment naïve, CD20-positive, intermediate or high-risk DLBCL patients were randomly assigned in a 1:1 ratio to receive 6 cycles of either pola-R-CHP (N=440) or R-CHOP (N=439). Patients on Day 1 of each 21 day cycle, received POLIVY® 1.8 mg/kg IV and a placebo matching Vincristine IV (pola-R-CHP group) or a placebo matching POLIVY® and intravenous Vincristine at a dose of 1.4 mg/m2 (maximum of 2 mg) (R-CHOP group), along with Rituximab 375 mg/m2 IV, Cyclophosphamide 750 mg/m2 IV and Doxorubicin 50 mg/m2 IV. All the patients also received Prednisone 100 mg orally once daily on Days 1-5 of each of the first six cycles. During cycles 7 and 8, patients in both treatment groups received Rituximab monotherapy at 375 mg/m2 IV. The median patient age was 65 years and stratification was based on IPI score and presence or absence of bulky disease, Subtypes of DLBCL were centrally evaluated and were balanced between the two treatment groups. Patients were eligible regardless of the Cell of Origin or the presence of rearrangements in MYC, BCL2, BCL6, or a combination of these. Patients with known CNS involvement were excluded but CNS prophylaxis with intrathecal chemotherapy was permitted, in accordance with institutional practice guidelines. The use of Granulocyte Colony-Stimulating Factor (G-CSF) was required during the first six cycles of treatment for primary prophylaxis against neutropenia and consolidative radiotherapy to initial sites of bulky disease or extranodal sites was allowed at the discretion of the investigator. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS) and Safety.

At a median follow up of 28.2 months, the PFS was significantly higher in the pola-R-CHP group compared to the R-CHOP group. The PFS at 2 years was 76.7% in the pola-R-CHP group versus 70.2% in the R-CHOP group (stratified HR=0.73; P=0.02). Treatment with pola-R-CHP resulted in a risk of disease progression, relapse, or death that was 27% lower, compared to R-CHOP. Patient subgroups that did not show a clear benefit with pola-R-CHP included patients 60 years of age or younger, patients with the Germinal Center B-cell-like subtype of DLBCL, patients who had bulky disease, and patients who had lower IPI scores. Overall Survival at 2 years did not differ significantly between the treatment groups and the researchers attributed the lack of a significant difference between the two groups in Overall Survival, to the availability of new, effective treatments for relapsed or refractory DLBCL, as well as short duration of follow up at the time of this reporting. The safety profile was similar in the two treatment groups.

The authors concluded that among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. Tilly H, Morschhauser F, Sehn LH, et al. December 14, 2021. DOI: 10.1056/NEJMoa2115304