Author: RR

Late Breaking Abstract – ASCO 2023: Adjuvant Treatment with Ribociclib in Early Breast Cancer

RR

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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant Endocrine Therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

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

Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.

NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Safety, Quality of Life, and Overall Survival.

At a median follow up of 34 months, as of data cutoff, 74.7% of patients remained on study treatment, with 1,984 patients on Ribociclib and 1,826 patients on Endocrine Therapy alone. The addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%. The 3-year invasive DFS rates were 90.4% in the Ribociclib group, compared with 87.1% in the Endocrine Therapy alone. This invasive DFS benefit was generally consistent across stratification factors and other subgroups. There was a trend towards improvement in Overall Survival with the addition of Ribociclib, although further follow up is needed. This regimen had a favorable safety profile with no new safety signals.

It was concluded from this study that the addition of Ribociclib to Endocrine Therapy demonstrated a statistically significant, clinically meaningful improvement in invasive Disease Free Survival, with a well-tolerated safety profile. The authors added that this study results support the addition of Ribociclib to Endocrine Therapy as the treatment of choice in a broad group of patients with Stage II or III HR+/HER2-negative early breast cancer, including those with high risk node negative disease. The lower dose of Ribociclib chosen in this study and given over an extended 3-year period may be important to prolong cell cycle arrest and drive more tumor cells into senescence or death.

Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. DOI: 10.1200/JCO.2023.41.17_suppl.LBA500 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA500-LBA500.

FDA Approves Glofitamab for Relapsed or Refractory Large B-Cell Lymphomas

RR

SUMMARY: The FDA on June 15, 2023, granted accelerated approval to Glofitamab-gxbm (COLUMVI®) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified (DLBCL, NOS) or Large B-Cell Lymphoma (LBCL) arising from Follicular Lymphoma, after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas 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 5-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, CAR T-cell therapy, 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. There is a critical unmet need for this patient group.

Glofitamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Glofitamab differs from other CD20-directed CD3 T-cell engager bispecific antibodies in that it has two anti-CD20 binding domains. It is therefore bivalent for the tumor antigen and monovalent for the T-cell CD3 protein. Further, it is a time-limited therapy.

The present FDA approval was based on positive data from the NP30179 study, which is a Phase I/II, multicenter, open-label, dose-escalation and expansion study, evaluating the safety, efficacy and pharmacokinetics of Glofitamab in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). Once the recommended Phase II dose of Glofitamab was established, patients with DLBCL who had previously received at least two lines of therapy were enrolled in the expansion cohorts. This expansion cohort included 154 patients (N=154), who had Relapsed or Refractory disease, and had received at least two previous lines of therapy including at least one anti-CD20 antibody-containing regimen and at least one anthracycline-containing regimen.

Eighty percent of patients had Relapsed or Refractory DLBCL, and 20% had LBCL arising from Follicular Lymphoma. Approximately 85% of patients were refractory to their most recent therapy and 33% had received prior CAR T-cell therapy. This study excluded patients with active or previous Central Nervous System lymphoma or disease. Treatment consisted of a single dose of Obinutuzumab 1,000 mg IV on Cycle 1 Day 1, to deplete circulating and lymphoid tissue B cells and to mitigate Cytokine Release Syndrome, followed by fixed-duration Glofitamab monotherapy administered by IV infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length was 21 days. Patients were hospitalized for the first dose of Glofitamab and subsequent doses were administered in the outpatient setting unless Cytokine Release Syndrome of Grade 2 or higher was reported after the first dose. The Primary end point was Complete Response (CR) rate according to assessment by an Independent Review Committee. Key Secondary end points included Duration of Response, Progression Free Survival, and Safety. The efficacy analysis included 132 patients.

The Overall Response Rate (ORR) was 56% with a Complete Response rate of 43%. With an estimated median follow up of 11.6 months among responders, the estimated median Duration of Response was 18.4 months. Further, 68.5% of patients who achieved a response continued to respond for 9 months or longer. The median Time to Response was 42 days. The most common adverse reactions, excluding laboratory abnormalities were Cytokine Release Syndrome (CRS), musculoskeletal pain, rash, and fatigue. CRS occurred in 70% (with 4.1% Grade 3 or higher CRS), Immune Effector Cell-Associated Neurotoxicity (ICANS) in 4.8%, serious infections in 16%, and tumor flare in 12%. The most common Grade 3 to 4 laboratory abnormalities were lymphopenia and neutropenia, decrease in serum phosphate and fibrinogen levels, and increase in serum uric acid.

It was concluded that a fixed duration treatment of off-the-shelf therapy with Glofitamab induced durable Complete Responses, among patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Dickinson MJ, Carlo-Stella C, Morschauser F, et al. N Eng J Med. 2022;387:2220-2231.

Capivasertib in Advanced Hormone Receptor Positive Breast Cancer

RR

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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is 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 HR-positive, HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. A therapy overcoming endocrine resistance is an area of active research in the breast cancer space.

The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is overactivated. Inhibition of the PI3K/Akt signaling pathway leads to inhibition of cell proliferation and induction of apoptosis in tumor cells. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. Overactivation of the PI3K-AKT-PTEN signaling pathway occurs in approximately 50% of HR-positive, HER2-negative breast cancers by means of activating mutations in PIK3CA and AKT1 and inactivating alterations in PTEN. These alterations may be present at the time of cancer recurrence, and can also be acquired following previous treatment including with CDK4/6 inhibitors. Further, AKT signaling may also be activated in the absence of genetic alterations in patients with endocrine resistance.

Capivasertib is a novel, first-in-class, orally bioavailable small molecule inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy, for a variety of human cancers. In the Phase II FAKTION trial, Capivasertib in combination with Fulvestrant significantly improved Progression Free and Overall Survival as compared with Fulvestrant alone, among postmenopausal women with HR-positive advanced breast cancer, who had previously received endocrine therapy. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor and CDK4/6 inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease, and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant, and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or have become resistant to endocrine therapies and CDK4/6 inhibitors.

Capivasertib in Hormone Receptor–Positive Advanced Breast Cancer. Turner N, Oliveria M, Howell SJ, et al., for the CAPItello-291 Study Group. N Engl J Med 2023; 388:2058-2070.

Platelet Transfusion before Central Venous Catheter Placement in Patients with Thrombocytopenia

RR

SUMMARY: Thrombocytopenia is a frequent finding in hospitalized patients and is one of the most common reasons for inpatient hematology consultations. Thrombocytopenia is usually defined as a platelet count of less than 150,000 per cubic millimeter, whereas severe thrombocytopenia is considered as platelet counts less than 50,000 per cubic millimeter. It is estimated that the prevalence of thrombocytopenia at admission to ICU is around 20-30% of patients, and a similar number of patients develop thrombocytopenia (from a normal platelet count) while being treated in the ICU.

Approximately 18% of hospitalized patients undergo Central Venous Catheter (CVC) placement, an invasive procedure, during admission. Central Venous Catheter facilitates simultaneous infusion of multiple medications, administration of vasoactive drugs, irritating or hypertonic solutions such as TPN, as well as hemodialysis and hemodynamic monitoring. The routine use of ultrasound guided CVC placement has greatly reduced the risk of bleeding complication. In clinical practice, platelet-transfusion thresholds range from 20,000 to 50,000 per cubic millimeter, as there is lack of good-quality evidence. It is however unclear whether the use of prophylactically transfused platelet concentrates is necessary to prevent CVC-related bleeding complications, in patients with severe thrombocytopenia.

The PACER trial is a multicenter, randomized, controlled, noninferiority study of Prophylactic Platelet Transfusion Prior to Central Venous Catheter Placement in Patients with Thrombocytopenia. This trial was conducted on hematology wards and in ICUs at 10 hospitals in the Netherlands, to evaluate whether the omission of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter increased the risk of catheter-related bleeding. This study included 373 patients (N=373) randomized in a 1:1 ratio to receive either one unit of platelet concentrate (N=188) or no platelet transfusion (N=185) before CVC placement. CVC placement was ultrasound guided, performed by an experienced operator, could be of any diameter, could be either tunneled or nontunneled, and could be placed in the internal jugular vein, subclavian vein, or femoral vein. Randomization was stratified according to the trial center and catheter type (large-bore dialysis catheter or regular catheter). Patient characteristics at the time of CVC placement were well balanced between the two trial groups. Exclusion criteria included therapeutically administered anticoagulant, a history of congenital or acquired coagulation factor deficiency or bleeding risk, or a spontaneously prolonged INR of 1.5 or more.

The Primary outcome was the occurrence of catheter-related bleeding of Grade 2-4 within 24 hours after CVC placement. Bleeding was assessed according to the Common Terminology Criteria for Adverse Events. The occurrence of bleeding and any related treatments were recorded by trained staff members at each site immediately after CVC placement, and at 1 hour and 24 hours thereafter. A key Secondary outcome was major bleeding (Grade 3-4).

Grade 2-4 catheter-related bleeding occurred in 4.8% of patients in the platelet transfusion group and in 11.9% of patients in the no-transfusion group. The absolute risk difference was 7.1%, Relative Risk was 2.45, and noninferiority of withholding platelet transfusion was not shown. The risk of Grade 3 or 4 catheter-related bleeding was lower in the platelet transfusion group compared to the no-transfusion group (2.1% versus 4.9%), with Relative Risks consistent with the Primary outcome.

The bleeding risk in the prespecified exploratory subgroup analysis, were similar to the findings of the Primary analysis. The bleeding risk among the patients being treated on the hematology ward was higher than that among patients in the ICU, and the same was true with the use of tunneled catheters as compared with nontunneled catheters. The differences in CVC-related bleeding risk was attributed to patients in the ICU more often having consumptive thrombocytopenia, whereas patients with hematologic problems in the hematology ward more often have hypoproliferative thrombocytopenia.

It was concluded from this study that in patients with severe thrombocytopenia, withholding prophylactic platelet transfusion before Central Venous Catheter placement in those with a platelet count of 10,000 to 50,000 per cubic millimeter resulted in more catheter-related bleeding events, and prophylactic platelet transfusion was associated with a lower risk of bleeding.

Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia. van Baarle FLF, van de Weerdt EK, van der Velden WJFM, et al. N Engl J Med 2023; 388:1956-1965.

Association between Duration of Immunotherapy and Overall Survival in Advanced Non Small Cell Lung Cancer

RR

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

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. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response.

The optimal duration of treatment with ICIs across tumor types is currently unknown and finding the balance between efficacy, toxicity and cost of therapy remains an ongoing challenge. There are presently no adequately powered, prospective, ICI trials, comparing different treatment durations. Even though patients were treated with first line ICI therapy for up to 2 years in key pivotal trials, a significant number of clinicians are hesitant to discontinue ICI therapy and many patients continue therapy beyond 2 years.
The present study was conducted to assess practice patterns surrounding ICI treatment discontinuation at 2 years and to evaluate the association of duration of therapy with Overall Survival, in patients who received Fixed-Duration ICI therapy for 2 years versus those who continued therapy beyond 2 years.

The researchers in this retrospective, population-based cohort study used the longitudinal Flatiron Health database derived from the Electronic Health Record, which included deidentified data of patients originating from approximately 280 cancer clinics (approximately 800 sites of care) throughout the US. The present study cohort included 1091 adult patients (aged at least 18 years) with a new diagnosis of advanced or metastatic NSCLC between 2016 and 2021, who received frontline treatment with Immune Checkpoint Inhibitor (ICI) either alone or in combination with chemotherapy, who were still on ICI treatment at 2 years, and whose cancer had not progressed. Patients with driver mutations in EGFR, ALK, or ROS1 were excluded. Of these patients who initiated treatment with first-line immunotherapy, the researchers focused on 706 patients who completed 2 years of therapy with ICI, of whom 113 patients stopped ICI therapy at 2 years (Fixed-Duration Therapy group) and 593 patients continued ICI therapy beyond 2 years (Indefinite-Duration Therapy group). The median age was 69 years in both treatment groups Patients in the Fixed-Duration group versus the Indefinite-Duration group were more likely to have a history of smoking, respectively and be treated in an academic center. Approximately 50% of patients in both groups were treated initially with immunotherapy alone versus chemoimmunotherapy. The researchers compared the survival between long-term ICI responders whose therapy was discontinued at 2 years in the absence of death or progression (Fixed-Duration group) and those who continued ICI beyond 2 years (Indefinite-Duration group).

With a median follow up of 14.0 months starting 760 days after treatment initiation, there was no statistically significant difference in Overall Survival between patients treated with Fixed-Duration and Indefinite-Duration ICI therapy on either unadjusted or adjusted analysis, and was 79% and 81% respectively. The researchers noted that among patients still on ICI treatment at 2 years, 4 out of 5 patients continued to receive immunotherapy rather than discontinuing it, suggesting that there was a strong bias toward potential overtreatment versus possible undertreatment.

A small cohort of patients in the Fixed-Duration therapy group had disease progression, and was rechallenged with ICI after at least 30 days without treatment. The median time from cessation of frontline treatment to initiation of second-line therapy was 7.4 months. After ICI rechallenge, median Progression Free Survival 2 (PFS2) was 8.1 months.

The authors from this study findings concluded that for patients who are progression-free on Immune Checkpoint Inhibitor therapy for NSCLC, it is a reasonable strategy to stop ICI therapy at 2 years, rather than continuing therapy indefinitely, as there was no statistically significant difference in Overall Survival by Fixed-Duration (2 years) versus Indefinite-Duration (more than 2 years) of ICI therapy.

Association Between Duration of Immunotherapy and Overall Survival in Advanced Non–Small Cell Lung Cancer. Sun L, Bleiberg B, Hwang W-T, et al. JAMA Oncol. Published online June 4, 2023. doi:10.1001/jamaoncol.2023.1891

Overall Survival with DARZALEX®, REVLIMID®, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX)

RR

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730 new cases will be diagnosed in 2023 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed or Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Previously published Phase I and II studies involving patients with Relapsed or Refractory multiple myeloma demonstrated promising efficacy of DARZALEX® when given as a single agent, as well as when given along with Lenalidomide (REVLIMID®) and Dexamethasone.

POLLUX is a multicenter, randomized, open-label, active-controlled, Phase III trial in patients with Relapsed or Refractory multiple myeloma. In this study, 569 patients who had Relapsed or Refractory multiple myeloma were assigned in a 1:1 ratio to receive either DARZALEX®, REVLIMID® and Dexamethasone (D-Rd group, N=286) or REVLIMID® and Dexamethasone (Rd group, N=283). Patients refractory to REVLIMID® were excluded. Patients in the DARZALEX® group received DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter. Both treatment groups received REVLIMID® 25 mg PO on days 1-21 of each cycle and Dexamethasone 40 mg PO weekly. The Primary end point was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), Time to disease progression, Response Rate, Time to response, Duration of Response, and percentage of patients with results below the threshold for Minimal Residual Disease (MRD). Minimal Residual Disease status was evaluated for patients who had a Complete Response by Next-Generation sequencing assay of bone marrow.

At a median follow-up of 13.5 months, the PFS at 12 months was 83.2% in the DARZALEX® group compared to 60.1% in the control group (HR=0.37; P<0.001). The Overall Response Rate was significantly higher in the DARZALEX® group than in the control group (92.9% versus 76.4%, P<0.001) and further, there was a higher rate of Complete Response or better (43.1% vs. 19.2%, P<0.001). In the DARZALEX® group, 22.4% of the patients had results below the threshold for MRD (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001).

The authors in this publication reported updated efficacy and safety results at the time of final Overall Survival (OS) analysis of POLLUX, after a follow-up of more than 6.5 years. After positive primary analysis and protocol amendment, patients receiving Rd were offered DARZALEX® monotherapy after disease progression. At a median follow-up of 79.7 months, D-Rd significantly prolonged OS, with a 27% reduction in the risk of death compared to Rd alone (median 67.6 versus 51.8 months, respectively; HR=0.73; P=0.0044). Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age 65 years or older and patients with one, two, or three prior lines of therapy, International Staging System Stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a Proteasome Inhibitor. MRD negativity rates in this final analysis were nearly five times higher with D-Rd versus Rd (33.2% versus 6.7%) and regardless of the treatment group, MRD negativity was associated with improved OS, emphasizing the importance of achieving MRD negativity.

The most common Grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia, anemia, pneumonia, thrombocytopenia and diarrhea. Even though the incidence of Grade 3/4 infections was higher with D-Rd versus Rd, the discontinuation rate was similar in both treatment groups. No new safety concerns were observed with longer follow up.

It was concluded that in this updated analysis of the POLLUX study, DARZALEX® in combination with REVLIMID® and Dexamethasone significantly extended Overall Survival compared to REVLIMID® and Dexamethasone, in patients with Relapsed or Refractory multiple myeloma. The authors added that the POLLUX study reported the longest median Overall Survival observed to date in Phase III studies of REVLIMID® and Dexamethasone-based triplets in Relapsed or Refractory multiple myeloma. These results complement and strengthen the Overall Survival data recently reported with DARZALEX® plus VELCADE® (Bortezomib) and Dexamethasone in the Phase III CASTOR study in Relapsed or Refractory multiple myeloma.

Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial. Dimopoulos MA, Oriol A, Nahi H, et al. J Clin Oncol 2023;41;1590-1599

Pathologic Complete Response and Individual Patient Prognosis after Neoadjuvant Chemotherapy Plus Anti-HER2 Therapy in 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 (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.

Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (pCR) following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. In a comprehensive meta analysis by Spring L., et al. (Clin Cancer Res. 2020;26:2838-2848), in the subgroup of HER2-positive patients (N= 5,711), an association between pCR and both EFS and OS could be observed. With the availability of different post-neoadjuvant treatments in the HER2-positive treatment setting, it is important and relevant to define patients with increased risk of relapse, despite the achievement of pCR.

The rationale for this study was to characterize the prognostic role of pCR (pathological Complete Response) in patients with HER2-positive early breast cancer, and whether clinical factors, such as Tumor stage, Nodal involvement, and Hormone Receptor status, had prognostic relevance in patients with HER2-positive early breast cancer, with and without pCR, following neoadjuvant systemic treatment with chemotherapy plus anti-HER2 therapy.

The present analysis included individual data from 3710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive early breast cancer. The following trials were included: CHERLOB, GeparQuattro, GeparQuinto, GeparSixto, HANNAH, LAPATAX, NEOALTTO, NEOSPHERE, NOAH, NSABP B-41, and TRYPHAENA. Each of these trials had 100 or more patients enrolled, and data was available for pCR, Event Free Survival (EFS), and Overall Survival (OS) after a follow up of 3 or more years. The definition of pCR used for the current analysis was the absence of residual invasive cancer in the resected breast specimen and all sampled ipsilateral lymph nodes, but allowing for in situ cancer (ypT0/Tis ypN0). Across trials, median age was 49 years, and 56.7% of patients were diagnosed with Tumor stage cT1-2. Nodal involvement was present at diagnosis in 64.9% of patients, and 54.9% were Hormone Receptor-positive. The median follow up across trials was 61.2 months. The objective of this study was to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy and anti-HER2 therapy.

Across trials, approximately 40.4% of patients had a pCR and 59.6% had residual disease after neoadjuvant therapy. A pCR occurred more often in patients with T1-2 tumors, absence of Nodal metastases, and Hormone Receptor-negative disease. Patients experiencing a pCR were at lower risk of disease recurrence or death regarding EFS (HR=0.39; P<0.001) and had a significantly better OS (HR=0.32; P<0.001).

In patients who had a pCR, clinical T stage (cT1-2 versus cT3-4) and clinical N stage (cN0 versus cN+) status were independent prognostic factors for EFS, but only clinical T stage was significantly prognostic for OS, identifying patients at higher risk of relapse despite pCR . By contrast, in patients without pCR and with residual disease, clinical T stage, clinical N stage and Hormone Receptor status were independent prognostic factors for EFS as well as OS. For patients not having a PCR, risk factors included the presence of T3-4 tumors, clinical Node Positive disease or Hormone Receptor-negative status.

The authors concluded that patients achieving pathological Complete Response have better survival outcomes than patients who do not. Nonetheless, Tumor size and Nodal status remain important poor prognostic features even after a pathologic Complete Response and adjuvant therapy in pathological Complete Response patients should not be attenuated.

Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti–Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer. van Mackelenbergh MT , Loibl S , Untch M, et al., on behalf of the CTNeoBC project. J Clin Oncol 2023; 41:2998-3008

Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update

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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. There is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, 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.

Since the first publication of a VTE guideline by ASCO in 2007, there have been 3 updates, with the last update in 2023. ASCO convened an Expert Panel to review the evidence and revise previous recommendations as needed. The 2019 guideline update included a systematic review of 35 publications on VTE prophylaxis and treatment, and 18 publications on VTE risk assessment published from August 1, 2014, through December 4, 2018. After publication of five potentially practice-changing randomized clinical trials between November 1, 2018, and June 6, 2022, an updated systematic review was performed by the ASCO Expert Panel for two guideline questions: perioperative thromboprophylaxis and treatment of VTE.

The purpose of this guideline update is to provide updated recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. The term direct factor Xa inhibitors is used in this update, rather than the previously used direct oral anticoagulants, for increased specificity.

Guideline Question
How should venous thromboembolism (VTE) be prevented and treated in patients with cancer?

CLINICAL QUESTION 1.
Should hospitalized patients with cancer receive anticoagulation for VTE prophylaxis?
Recommendation 1.1.
Hospitalized patients who have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications
Recommendation 1.2.
Hospitalized patients who have active malignancy without additional risk factors may be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications
Recommendation 1.3.
Routine pharmacologic thromboprophylaxis should not be offered to patients admitted for the sole purpose of minor procedures or chemotherapy infusion, nor to patients undergoing stem-cell/bone marrow transplantation

CLINICAL QUESTION 2.
Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy?
Recommendation 2.1.
Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer
Recommendation 2.2.
High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or low-molecular-weight heparin (LMWH) provided there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting
Recommendation 2.3.
Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients

CLINICAL QUESTION 3.
Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis?
Recommendation 3.1.
All patients with malignant disease undergoing major surgical intervention should be offered pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or LMWH unless contraindicated because of active bleeding, or high bleeding risk, or other contraindications
Recommendation 3.2.
Prophylaxis should be commenced preoperatively
Recommendation 3.3.
Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk
Recommendation 3.4.
A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients
Recommendation 3.5.
Pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7 to 10 days.
Recommendation 3.6.
Extended prophylaxis with LMWH for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of VTE, or with additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis
Recommendation 3.7. (UPDATED ASCO RECOMMENDATION FROM 2023)
Patients who are candidates for extended pharmacologic thromboprophylaxis after surgery may be offered prophylactic doses of low molecular weight heparin (LMWH). Alternatively, patients may be offered prophylactic doses of rivaroxaban or apixaban after an initial period of LMWH or unfractionated heparin (UFH)
Qualifying statement: Evidence for rivaroxaban and apixaban in this setting remains limited. The two available trials differed with respect to type of cancer, type of surgery, and timing of rivaroxaban or apixaban initiation after surgery.

CLINICAL QUESTION 4.
What is the best method for treatment of patients with cancer with established VTE to prevent recurrence?
Recommendation 4.1. (UPDATED ASCO RECOMMENDATION FROM 2023)
Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance less than 30 mL/min)
Recommendation 4.2. (UPDATED ASCO RECOMMENDATION FROM 2023)
For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists (VKAs). VKAs are inferior but may be used if LMWH or direct oral anticoagulants (DOACs) are not accessible. There is an increase in major bleeding risk with DOACs, particularly observed in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOAC.
Recommendation 4.3.
Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile
Recommendation 4.4.
Based on expert opinion in the absence of randomized trial data, uncertain short-term benefit, and mounting evidence of long-term harm from filters, the insertion of a vena cava filter should not be offered to patients with established or chronic thrombosis (VTE diagnosis more than 4 weeks ago), nor to patients with temporary contraindications to anticoagulant therapy (eg, surgery). There also is no role for filter insertion for primary prevention or prophylaxis of pulmonary embolism (PE) or deep vein thrombosis due to its long-term harm concerns. It may be offered to patients with absolute contraindications to anticoagulant therapy in the acute treatment setting (VTE diagnosis within the past 4 weeks) if the thrombus burden was considered life-threatening. Further research is needed
Recommendation 4.5.
The insertion of a vena cava filter may be offered as an adjunct to anticoagulation in patients with progression of thrombosis (recurrent VTE or extension of existing thrombus) despite optimal anticoagulant therapy. This is based on the panel’s expert opinion given the absence of a survival improvement, a limited short-term benefit, but mounting evidence of the long-term increased risk for VTE
Recommendation 4.6.
For patients with primary or metastatic CNS malignancies and established VTE, anticoagulation as described for other patients with cancer should be offered, although uncertainties remain about choice of agents and selection of patients most likely to benefit
Recommendation 4.7.
Incidental PE and deep vein thrombosis should be treated in the same manner as symptomatic VTE, given their similar clinical outcomes compared with patients with cancer with symptomatic events
Recommendation 4.8.
Treatment of isolated subsegmental PE or splanchnic or visceral vein thrombi diagnosed incidentally should be offered on a case-by-case basis, considering potential benefits and risks of anticoagulation

CLINICAL QUESTION 5.
Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?
Recommendation 5.
Anticoagulant use is not recommended to improve survival in patients with cancer without VTE

CLINICAL DECISION 6.
What is known about risk prediction and awareness of VTE among patients with cancer?
Recommendation 6.1.
There is substantial variation in risk of VTE between individual patients with cancer and cancer settings. Patients with cancer should be assessed for VTE risk initially and periodically thereafter, particularly when starting systemic antineoplastic therapy or at the time of hospitalization. Individual risk factors, including biomarkers or cancer site, do not reliably identify patients with cancer at high risk of VTE. In the ambulatory setting among patients with solid tumors treated with systemic therapy, risk assessment can be conducted based on a validated risk assessment tool (Khorana score)
Recommendation 6.2.
Oncologists and members of the oncology team should educate patients regarding VTE, particularly in settings that increase risk, such as major surgery, hospitalization, and while receiving systemic antineoplastic therapy

Notes regarding off-label use in guideline recommendations: Apixaban, rivaroxaban, and LMWH have not been US FDA–approved for thromboprophylaxis in outpatients with cancer (recommendation 2.2 for apixaban and rivaroxaban; recommendations 2.2 and 2.3 for LMWH). Dalteparin is the only LMWH with US Food and Drug Administration approval for extended therapy to prevent recurrent thrombosis in patients with cancer (recommendation 4.2).

Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer: ASCO Guideline Update.Key NS , Khorana AA , Kuderer NM, et al. J Clin Oncol 2023; 41:3063-3071.

Whole Exome Sequencing Identifies Cancer Predisposition Syndromes Missed by Current Screening Guidelines

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SUMMARY: Hereditary factors play an important role in the risk of developing several cancers. Therefore, identification of a germline predisposition can have important implications for treatment decision making, risk-reducing interventions, cancer screening for early diagnosis, germline testing and targeted surveillance of unaffected relatives. Previously published studies have been biased by estimating the prevalence of germline cancer susceptibility in patients with breast, prostate, and colorectal cancer from registry populations, genetic testing companies, and high-risk cancer clinics.

With the widespread adoption of Next Generation Sequencing (NGS), multiple genes can be tested simultaneously (MultiGene Panel Testing-MGPT), rather than sequential single-gene testing, making MultiGene Panel Testing cheaper, faster and more efficient. Further, single-test multigene multiplexing strategy analyzes numerous cancer susceptibility genes and frequently detects highly penetrant, clinically actionable Pathogenic Germline Variants (PGV) in individuals whose clinical histories fail to fulfill syndrome-specific testing criteria. This is clinically relevant, as it has become increasingly complex to determine which individuals warrant germline testing. Several risk assessment models have been developed to provide probability of an individual carrying a germline mutation. These models provide syndrome-specific risk assessment for Lynch Syndrome, Hereditary Breast and Ovarian Cancer syndrome (HBOC)), etc.

The Genomics and Population Health Action Collaborative was formed in 2015 with the goal of identifying challenges and potential best practices for the widespread integration of evidence-based genomics applications in population health programs. They endorsed 11 genes associated with the three CDC Tier 1 inherited Autosomal Dominant cancer predisposition conditions – Hereditary Breast and Ovarian Cancer syndrome, Lynch syndrome, and Familial Hypercholesterolemia, as being a reasonable starting point for primary genomic screening in the general population.

Tapestry study is collaboration between Mayo Clinic and Helix, a population genomics company. The Tapestry trial included 44,306 patients who received treatment across Mayo Clinic sites in Minnesota, Arizona and Florida. Researchers gathered and evaluated saliva samples for pathogenic mutations in BRCA1 and BRCA2 (denoting Hereditary Breast and Ovarian Cancer), as well as MLH1, MSH2, MSH6, PMS2 and EPCAM (denoting Lynch syndrome). The mean age was 55 years, 63% were women and 90% were Caucasian. The aim of this study was to evaluate whether screening in a multisite tertiary medical center using Whole Exome Sequencing (WES) could efficiently identify carriers of two conditions, Hereditary Breast and Ovarian Cancers and Lynch syndrome, and determine the frequency of incremental carriers identified outside of traditional clinical practice guidelines.

The researchers identified 550 carriers of pathogenic mutations, including 387 individuals with Hereditary Breast and Ovarian Cancer syndrome (HBOC) and 163 with Lynch syndrome. Of these individuals with pathogenic mutations, 52.1% had no knowledge prior to this study that they carried cancer predisposition genes, and 39.2% of CARRIERS did not meet NCCN criteria for genetic testing, including 56.2% of those with Lynch syndrome and 32% of those with HBOC. Among the patients who were NEWLY DIAGNOSED with Lynch syndrome and HBOC syndrome during this study, 60% were ineligible for genetic testing per the current guidelines. They included 78% of those with Lynch syndrome and 51% of those with HBOC syndrome. Some of the reasons for not meeting NCCN criteria included having no personal history of cancer (63.3%), an insufficient number of relatives who had cancer (60.5%) and a cancer type or types not related to a genetic syndrome (58.6%). Among those who met NCCN guidelines for testing, 34.2% reported not knowing their diagnosis prior to the study. The researchers also noted that patients with HBOC or Lynch syndrome from racial and ethnic minority groups were significantly more likely than white patients to not meet NCCN screening criteria (49% versus 32%, respectively).

It was concluded that genomic screening in the broad general population for CDC Tier 1 genetic conditions has the potential to identify 50% of at-risk carriers who are otherwise not detected in current medical practice. Early diagnosis and intervention could have a positive impact on public health, and a systemic bias in the current guidelines could potentially be overcome by universal genetic testing. The authors added that the limitation of this study is that the patient population in this study may not reflect the demographics of the general population.

Exome sequencing identifies individuals with cancer predisposition syndromes missed by current screening guidelines (AACR press release). Available at: www.aacr.org/about-the-aacr/newsroom/news-releases/exome-sequencing-identifies-individuals-with-cancer-predisposition-syndromes-missed-by-current-screening-guidelines/. Published April 18, 2023.

FDA Approves BiSpecific Antibody EPKINLY® for Aggressive Non Hodgkin Lymphomas

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SUMMARY: The FDA on May 19, 2023, granted accelerated approval to Epcoritamab-bysp (EPKINLY®) for relapsed or refractory Diffuse Large B-Cell Lymphoma (DLBCL) not otherwise specified, including DLBCL arising from indolent lymphoma, and High-Grade B-Cell Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas 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 5-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, CAR T-cell therapy, 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.

Epcoritamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

EPCORE NHL-1 is an ongoing, open-label, multi-cohort, multicenter, Phase 1/2b, single-arm trial in which the safety, tolerability, pharmacokinetics and preliminary efficacy of Epcoritamab in combination with standard-of-care (SOC) agents are being examined in patients with relapsed, progressive or refractory CD20+ mature B-cell Non-Hodgkin Lymphoma (NHL), including Diffuse Large B-Cell Lymphoma. Phase 1 of the trial consists of a first-in-human, dose-escalation portion, and Phase 2 is the expansion and optimization part.

The Phase 2 expansion cohort included 157 patients with relapsed/refractory Large B-Cell Lymphoma who were previously treated with a median of 3 lines of prior therapy. The median age was 64 years and median time from initial diagnosis was 1.6 yrs. Approximately 39% of patients had received prior CAR T-cell therapy, 20% had prior Autologous Stem Cell Transplantation, 61% had Primary refractory disease and 14% of patients with Diffuse Large B-Cell Lymphoma were confirmed Double Hit/Triple Hit by central FISH. Epcoritamab was administered subcutaneously in 28-day cycles until disease progression or unacceptable toxicity. Mitigation of Cytokine Release Syndrome included step-up dosing and corticosteroid prophylaxis in the first cycle alone. Step-up dosing was 0.16 mg on Day 1, 0.8 mg on Day 8, and 48 mg on Day 15 and Day 22 in Cycle 1, followed by fixed dosing of 48 mg weekly dosing during Cycles 2-3, every other week during Cycle 4-9, and then every four weeks on Day 1 of subsequent cycles. Per protocol, 24-hour hospitalization was required only for the first full dose (48 mg) to ensure close observation of patients. The Primary endpoint was Overall Response Rate (ORR) by Independent Review Committee. Key Secondary endpoints included the Duration of Response (DOR), time to response, Progression Free Survival (PFS), Overall Survival (OS), Complete Response (CR) rate, Safety, and tolerability.

At a median follow-up of 10.7 months, the Overall Response Rate for the total population was 63%, with a Complete Response Rate of 39%. The median Duration of Response was 12.0 months and was Not Reached among complete responders. Overall and Complete Response rates were similar across key prespecified subgroups. The median time to response was 1.4 months. MRD negativity was assessed by a ctDNA NGS assay and 46.4% were MRD negative at any time point on treatment. MRD negativity was reached at a median of 8 weeks for complete responders, and high MRD negativity rates were observed across all prespecified subgroups. MRD-negative responses were durable and correlated with PFS. The most common adverse events were Cytokine Release Syndrome (majority were Grade 1 or 2, with most events occurring after the first full dose), fever and fatigue. Immune effector Cell-Associated Neurotoxicity Syndrome occurred in 6.4% of patients.

It was concluded that subcutaneous single agent Epcoritamab is a convenient, off-the-shelf therapy that resulted in deep and durable responses, including high MRD negativity rates, with manageable safety, in highly refractory patients with Large B-cell lymphoma, including those with prior CAR T-cell exposure.

Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. Thieblemont C, Phillips T, Ghesquieres H, et al. J Clin Oncol. 2023;;41:2238-2247.