Category: Hem/Onc Updates

Mutations of STK11/KRAS Genes and Efficacy of Immunotherapy in NSCLC

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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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMpower150 is a multicenter, open-label, randomized, Phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with Stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (ACP-Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (ABCP-Group B), or AVASTIN® plus Carboplatin and Paclitaxel (BCP-Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Among randomized patients with tumors demonstrating no ALK and EGFR mutations, ABCP was associated with significant improvements in Progression Free Survival (PFS) and Overall Survival (OS), compared with BCP, in an updated OS analysis. ABCP also prolonged OS and PFS compared with BCP in an exploratory subgroup analysis of patients with EGFR-sensitizing mutations.

The Serine‐Threonine Kinase 11 (STK11) gene is located on the short arm of chromosome 19 and germline STK11 mutations are often detected in Peutz‐Jeghers syndrome, an Autosomal Dominant disorder resulting in mucocutaneous hyperpigmentation, hamartomas throughout the gastrointestinal tract, and a predisposition for breast, lung, pancreas, and gastrointestinal malignancies including cancers of the colon and small bowel. Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of NSCLC (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. Although immune checkpoint inhibitors with or without chemotherapy have demonstrated survival benefit in patients with KRAS mutated tumors, it remains unclear how co-occurring STK11, KEAP1, and TP53 mutations affect outcomes following immune checkpoint blockade.

The authors in this publication conducted a retrospective exploratory analysis of the efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel), in patients with KRAS mutations and co-occuring STK11, KEAP1, or TP53 mutations, from the IMpower150 nonsquamous NSCLC patient population. Mutation status was determined by circulating tumor DNA Next-Generation Sequencing.

Among the KRAS mutated population, there was numerical improvement in median OS with ABCP compared to BCP (19.8 vs 9.9 months; HR=0.50), as well as PFS (8.1 vs 5.8 months; HR=0.42) respectively. The median OS with ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was 11.7 vs 9.9 months (HR=0.63), and PFS was 4.8 vs 5.8 months (HR=0.80), when compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel). When compared to BCP, the ABCP group showed numerically greater survival than the ACP group among KRAS mutated patients. These results were consistent with reported survival improvements with immune checkpoint inhibitors in KRAS-mutant NSCLC.

In KRAS mutant patients across PD-L1 subgroups, OS and PFS were longer with ABCP when compared with BCP, but in PD-L1-low and PD-L1-negative subgroups, OS with ACP was similar to BCP. Conversely, in KRAS wild type patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups.

KRAS was frequently comutated with STK11, KEAP1, and TP53 and these subgroups conferred different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-wild type and/or KEAP1wild type. In KRAS mutated patients with co-occurring STK11 and/or KEAP1 mutations (44.9%) or TP53 mutations (49.3%), survival was longer with ABCP than with ACP or BCP.

It was concluded that this analysis supported previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. Even though the clinical efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel) and ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was favorable compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel) in these mutational subgroups, survival benefits were greater in the KRAS mutated and KEAP1 and STK11 wild type population versus KRAS mutated and KEAP1 and STK11 mutated population, suggesting both prognostic and predictive value of mutational analysis. The researchers added that these results suggest that TECENTRIQ® in combination with AVASTIN® and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. West JH, McCleland M, Cappuzzo, F, et al. J Immunother Cancer. 2022 Feb;10(2):e003027. doi: 10.1136/jitc-2021-003027.

IMFINZI® Plus Tremelimumab Significantly Improves Overall Survival in Advanced Hepatocellular Carcinoma

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SUMMARY: The American Cancer Society estimates that for 2022, about 41,260 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US and 30,520 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis and only 7% of patients with advanced disease survive five years. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. Tremelimumab is a human monoclonal antibody that targets and blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In a Phase II study, a single priming dose of Tremelimumab added to IMFINZI® (STRIDE regimen), showed encouraging clinical activity and limited toxicity in patients with unresectable HepatoCellular Carcinoma (HCC), suggesting that a single exposure to Tremelimumab may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicentre, global, Phase III study conducted in 190 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. In this study, 1,171 patients with Stage III or IV unresectable hepatocellular carcinoma who had received no prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue), were randomly assigned to receive either the STRIDE regimen which consisted of a single priming dose of Tremelimumab 300 mg IV added to IMFINZI® (Durvalumab) 1500 mg IV, followed IMFINZI® 1500 mg IV by every 4 weeks (N= 393), IMFINZI® monotherapy given at the same dose and schedule (N = 389) or NEXAVAR® (Sorafenib) 400 mg orally BID (N=389). Enrolled patients had ECOG performance status of 0 or 1 and Child-Pugh A disease and could not have main portal vein thrombosis. Patients were stratified based on macrovascular invasion (Yes versus No), etiology of liver disease (Hepatitis B virus versus Hepatitis C virus versus others), and ECOG Performance Status (0 versus 1). The Primary endpoint was Overall Survival (OS) for STRIDE regimen versus NEXAVAR® and key Secondary endpoints included OS for IMFINZI® monotherapy versus NEXAVAR®, Objective Response Rate and Progression Free Survival (PFS) for STRIDE and IMFINZI® monotherapy.

The Primary objective of this study was met at the time of data cutoff. At a median follow up of 16.1 months of treatment with the STRIDE regimen, there was a 22% reduction in the risk of death for patients who received the STRIDE regimen compared to NEXAVAR® alone (HR=0.78; P=0.0035). The median OS with the STRIDE regimen was 16.4 months, compared with 13.8 months with NEXAVAR®, and the 3 year OS rate was 30.7% versus 20.2 % respectively. The Overall Response Rate for the combination STRIDE regimen was 20.1% compared to 5.1% for NEXAVAR®

IMFINZI® monotherapy met the objective of OS non-Inferiority to NEXAVAR® (HR=0.86; 96% CI, 0.73–1.03) and the median OS after 16.5 months of median follow up was 16.6 months with IMFINZI® monotherapy versus 13.8 months with NEXAVAR®, and the 3 year OS rate was 24.7% versus 20.2 % respectively. The Overall Response Rate with IMFINZI® monotherapy was 17% compared to 5.1% for NEXAVAR®. The Secondary endpoint of PFS was not superior in either investigational study group relative to the NEXAVAR® control arm.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody Tremelimumab, to another checkpoint inhibitor, IMFINZI®. This combination regimen (STRIDE) demonstrated superior efficacy and a favorable benefit-risk profile when compared with NEXAVAR® and should be considered a novel , first-line standard of care systemic therapy, for patients with unresectable Hepatocellular Carcinoma.

Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Abou-Alfa GK, Chan SL, Kudo M, et al. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379

Factors Associated with Mortality among Cancer Patients with COVID-19 Infection Compared with Those without Cancer

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SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the numbers of infected cases continue to increase worldwide. As of May 15, 2022, over ONE million individuals have died from COVID-19 in the USA. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with cancer are immunocompromised from either the underlying disease or therapy and are susceptible to infections with respiratory viruses. This is even more relevant with the emergence of the COVID-19 pandemic, and numerous studies have been conducted to understand the impact of infection with COVID-19 and outcomes in patients with cancer, infected with COVID-19, with discordant results. The understanding of possible risks, complications and outcomes of COVID-19 infection among cancer patients is important for patients and families, as well as health care systems.

The researchers conducted this study to assess the differences in clinical outcomes between cancer patients with SARS-CoV-2 infection and patients without cancer but with SARS-CoV-2 infection, and also to identify cancer patients at a high risk for poor outcomes. This systematic review and meta-analysis included 81 studies involving 61, 532 patients with cancer. Among 58 849 patients with available data, 52% were male median age ranged from 35- 74 years. Data was extracted from the PubMed, Web of Science, and Scopus databases until June 14, 2021. The main outcomes and measures were the difference in mortality between cancer patients with SARS-CoV-2 infection and control patients, as well as the difference in outcomes for various tumor types and cancer treatments. Majority of patients represented were from the US, UK, Italy, France and China.

In age and sex-matched analysis, the Relative Risk (RR) of mortality from COVID-19 among cancer patients compared to those without cancer was 1.69 (P<0.001). The risk of mortality among cancer patients versus those without cancer decreased with increasing age (Odds Ratio = 0.96; P=0.03). The researchers hypothesized that the reasons for this finding were likely associated with the type of cancer, the intensity of treatments, or behavioral factors such as increased social mixing among patients younger than 50 years, compared to that of an older population.

When mortality and Case Fatality Rate were analyzed by cancer type, the pooled Case Fatality Rate for patients with lung cancer and SARS-CoV-2 infection was 30% and the Relative Risk of mortality in those patients with lung cancer compared with other cancer types was significantly higher at 1.68 (P<0.001). This was followed by hematologic cancer with a pooled Case Fatality Rate for patients with hematologic cancer and SARS-CoV-2 infection of 32%, and the Relative Risk of mortality in patients with hematologic cancer and SARS-CoV-2 infection compared with those with solid malignant neoplasms was 1.42 (P<0.001). Breast cancer (RR, 0.51; P<0.001) and gynecological cancer (RR, 0.76; P=0 .009) were associated with a significantly lower risk of death.

When Case Fatality Rate was analyzed by treatment type, chemotherapy was associated with the highest overall pooled Case Fatality Rate of 30%, and endocrine therapy was associated with the lowest at 11%. Radiotherapy was associated with a Case Fatality Rate of 23%, Immunotherapy, as well as surgery within 3 months of a COVID-19 diagnosis in patients with cancer was associated with a Case Fatality Rate of 19% and targeted therapy was associated with a rate of 18%.

The authors from this analysis concluded that patients with cancer and SARS-CoV-2 infection had a higher risk of death, than patients without cancer. Risk factors associated with poor outcomes from COVID-19 included younger age, lung cancer, and hematologic malignancies.

Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV-2 Infection and Cancer Compared With Those Without CancerA Systematic Review and Meta-analysis. Khoury E, Nevitt S, Madsen WR, et al. JAMA Netw Open. 2022;5(5):e2210880. doi:10.1001/jamanetworkopen.2022.10880

Long Term Disease Free Survival Benefits with Adjuvant OPDIVO® in Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analyses have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

OPDIVO®(Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group, as well as adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.

CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. The mean age was 65.3 years and both treatment groups were well balanced. Approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant Cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS), Overall Survival and Safety.

The authors in this publication reported the DFS outcomes, with 5 additional months of follow up, in all randomized patients. Patients with high-risk, muscle-invasive urothelial carcinoma continued to experience clinically meaningful improvements in Disease Free Survival (DFS), with a median DFS of 22.0 months among those receiving OPDIVO® (95% CI, 17.7-36.9) compared with 10.9 months (95% CI, 8.3-14.0) among those receiving placebo (HR=0.70; 95% CI, 0.57-0.85). The DFS probability at 12 months was 63.5% with OPDIVO® versus 46.9% with placebo. The DFS benefit was even more significant in patients with PD-L1 expression of 1% or more and was Not Reached in the OPDIVO® group versus 8.4 months in the placebo group (HR, 0.53; 95% CI, 0.38-0.75). The DFS probability at 12 months was 67.6% with OPDIVO® versus 46.3% with placebo. The DFS benefits was observed with OPDIVO® among most subgroups analyzed, including age, sex, ECOG PS, nodal status and use of prior Cisplatin-based chemotherapy.

NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS) were also improved with OPDIVO® when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more.

It was concluded that with longer follow up, OPDIVO® continued to show clinically meaningful improvement in Disease Free Survival among patients with high-risk muscle-invasive urothelial carcinoma, when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more. OPDIVO® also improved NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival when compared to Placebo. The authors added that these results support adjuvant OPDIVO® as a Standard of Care for high risk muscle-invasive urothelial carcinoma patients after radical surgery.

Galsky M, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the CheckMate 274 trial of adjuvant nivolumab in patients after surgery for high-risk muscle-invasive urothelial carcinoma. J Urol. 2022;207(suppl 5):e183. doi:10.1097/JU.0000000000002536.01

Expansion of Cancer Risk Profile beyond Breast and Ovarian Cancer for BRCA1 and BRCA2 Pathogenic Variants

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SUMMARY: DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

Pathogenic Variants (PVs) in BRCA1 and BRCA2 (BRCA1/2) are well known to be associated with increased lifetime risk for breast and ovarian cancer in women, and reliable risk estimates are also available and can be as high as 85% and 40% respectively. However, the association of BRCA1 and BRCA2 Pathogenic Variants with cancers other than female breast and ovarian cancers remain uncertain, and these associations have been based on studies with relatively small sample sizes, resulting in imprecise cancer risk estimates. It is therefore important that precise risk estimates are available, in order to optimize clinical management strategies and guidelines for cancer risk management in female and male BRCA1/2 carriers. The NCCN and other guidelines recommend breast and ovarian cancer screening for BRCA1/2 carriers, prostate cancer screening for BRCA2 carriers. Screening is also recommended for pancreatic cancer in BRCA1/2 carriers, but only in the presence of a positive family history of the disease.

The researchers conducted this study to evaluate the association of BRCA1 and BRCA2 pathogenic variants, with additional cancer types and their clinical characteristics associated with pathogenic variant carrier status. For this study, a large-scale registry based sequencing study was performed across 14 common cancer types in 63, 828 patients and 37, 086 controls, whose data were drawn from a Japanese nationwide multi-institutional hospital-based biobank, between 2003 and 2018. In the study group, the median age was 64 years and 42% were female, whereas the median age was 62 years and 47% were female in the control group. Germline pathogenic variants were identified in the BRCA1 and BRCA2 genes by a multiplex Polymerase Chain Reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Compared with the researchers previous publications for breast, colorectal, pancreatic, and prostate cancers, this study included 14,448 additional controls and 8247 additional cancer cases. These data thus provided a broad view of cancer risks associated with pathogenic variants in BRCA1 and BRCA2 genes.

Pathogenic variants in BRCA1 were significantly associated with increased risk for three other types of cancer types, Biliary tract (Odds Ratio–OR=17.4), Gastric (OR=5.2), and Pancreatic cancer (OR=12.6), in addition to female Breast (OR=16.1) and Ovarian cancer (OR=75.6). Pathogenic variants in BRCA2 increased risk for seven cancer types which included female Breast (OR=10.9), male Breast (OR=67.9), Gastric (OR=4.7), Ovarian (OR=11.3), Pancreatic (OR=10.7), Prostate (OR=4.0), and Esophageal cancer (OR=5.6). Further, Biliary tract, female Breast, Ovarian, and Prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives.

The results of this large study suggested that pathogenic variants in BRCA1 and/or BRCA2 are associated with increased risk of biliary tract, gastric, and esophageal cancers, higher than for European populations, granted that these cancers are known to have a higher incidence rate in East Asian countries. Conversely in this study, the cumulative risk of prostate cancer for BRCA2 carriers was lower than that estimated in the UK and Ireland, suggesting that the cumulative risk for each cancer type may be associated with the different incidence rate in each country.

The authors concluded that this study suggested that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types and is likely broader than that determined from previous analysis of largely European ancestry cohorts. It would therefore be useful to expand indications for genetic testing of individuals with family history of these cancer types.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants. Momozawa Y, Sasai R, Usui Y, et al. JAMA Oncol. 2022 Apr 14: e220476. doi: 10.1001/jamaoncol.2022.0476 [Epub ahead of print]

Segmentectomy versus Lobectomy in Small-Sized Peripheral Non-Small Cell Lung Cancer

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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 and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Lobectomy is the standard of care for early-stage resectable Non-Small Cell Lung Cancer (NSCLC). Pneumonectomy is rarely performed due to unacceptably high mortality rate. Sublobar resection (Wedge resection or Segmentectomy) is considered a “compromise operation” in selected high risk patients with early stage lung cancer. With the approval of lung cancer screening in high risk individuals and subsequent detection of small tumors, Sublobar resections have been on the rise, even in good-risk patients in many institutions. Sublobar resection includes wedge resection and segmentectomy. In wedge resection, the lung tumor is removed with a surrounding margin of normal lung tissue, and is not an anatomical resection. Segmentectomy, unlike wedge resection, is an anatomical resection that usually includes one or more pulmonary parenchymal segments with the dissection of intraparenchymal and hilar lymph nodes. Wedge resection is inferior to anatomic segmentectomy and is associated with an increased risk of local recurrence and decreased survival in patients with Stage I NSCLC.

The clinical benefits and survival outcomes of segmentectomy have not been investigated in a randomized trial setting. The aim of this study was to investigate if segmentectomy was non-inferior to lobectomy in patients with small-sized peripheral NSCLC. In this randomized, controlled, multicenter, non-inferiority trial, 1106 patients (intention-to-treat population) were enrolled in Japan between Aug, 2009 and Oct 2014, and were randomly assigned 1:1 to receive either lobectomy (N=554) or segmentectomy (N=552). Enrolled patients had clinical Stage IA NSCLC based on contrast-enhanced CT scan and had a single tumor 2 cm or less in diameter, not located in the middle lobe, the center of which was in the outer third of the lung field, with no evidence of lymph node metastasis. Patient baseline clinicopathological factors were well balanced between the two treatment groups. The Primary endpoint was Overall Survival and Secondary endpoints included postoperative respiratory function at 6 months and 12 months, Relapse-Free Survival, proportion of local relapse and adverse events.

At a median follow up of 7.3 years, the 5-year Overall Survival was 94.3% for segmentectomy and 91.1% for lobectomy. Both superiority and non-inferiority in Overall Survival were confirmed using a stratified Cox regression model (HR=0.663; one-sided P<0.0001 for non-inferiority and P=0.0082 for superiority). This improved Overall Survival benefit was observed consistently across all predefined subgroups in the segmentectomy group. At 1 year follow-up, the significant difference in the reduction of median FEV1 between the two treatment groups was 3.5% (P<0.0001), but this however did not reach the predefined threshold for clinical significance of 10%. The 5-year Relapse-Free Survival was 88% for segmentectomy and 87.9% for lobectomy and was not statistically significant. The probability of local recurrence was approximately doubled and was 10.5% for segmentectomy and 5.4% for lobectomy (P=0.0018). Postoperative complications of grade 2 or worse occurred at similar frequencies in both treatment groups.

The authors concluded that this study is the first Phase III trial to show Overall Survival benefit with segmentectomy, compared to lobectomy, in patients with small-peripheral NSCLC. They added that segmentectomy should be the standard surgical procedure for this population of patients.

Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. Saji H, Okada M, Tsuboi M, et al. The Lancet 2022;399:1607-1617.

FDA Grants Regular Approval to ENHERTU® for Breast Cancer

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SUMMARY: The FDA on May 4, 2022, approved ENHERTU® (Trastuzumab Deruxtecan) for adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. In 2019, ENHERTU® received accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The following trial was the confirmatory trial for the accelerated approval. 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA® given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a taxane. There is however no standard treatment option for this patient population following progression on KADCYLA®.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA®, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure. In the DESTINY-Breast 01 Phase II registration trial involving patients with HER2-positive metastatic breast cancer, who had received two or more prior HER2 targeted therapies including KADCYLA®, the Objective Response Rate (ORR) was 60.9%, with 6% Complete Responses and 54.9% Partial Response, with a median response duration of 14.8 months. The median PFS was 16.4 months. This benefit was consistent across all key subgroups, including patients who had previously received PERJETA® therapy.

The present FDA approval was based on DESTINY-Breast 03, which is a global, multicenter, open-label, randomized Phase III study, in which the efficacy and safety of ENHERTU® was compared with KADCYLA®, in patients with HER2-positive metastatic breast cancer previously treated with Trastuzumab and a Taxane or developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. In this study, 524 pts were randomized 1:1 to receive ENHERTU® 5.4 mg/kg (N=261) or KADCYLA® 3.6 mg/kg (N=263) once every 3 weeks. Randomization was stratified by hormone receptor status, prior treatment with Pertuzumab, and history of visceral disease. The median patient age was 54 years and patients in both treatment groups were comparable in terms of baseline characteristics including age, HER2-positivity status, ECOG Performance Status, prior treatment for breast cancer, brain metastases, and prior cancer therapy with agents including Trastuzumab. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Secondary endpoints include Overall Survival (OS), Objective Response Rate (ORR), Duration of Response, PFS by investigator, and Safety.

At the time of the prespecified interim analysis of this study, the median follow up was approximately 16 months and the median PFS by BICR review was Not Reached with ENHERTU® and was 6.8 months with KADCYLA® (HR=0.28; P= <0.0001). This represented a very statistically significant 72% reduction in the risk for progression or death with ENHERTU® compared to KADCYLA®. The investigator-assessed PFS was similar (25.1 versus 7.2 months, HR=0.26, P<0.0001). This PFS benefit was observed as early as 4 weeks and remained consistent throughout the follow up period. PFS was significantly higher with ENHERTU® in all prespecified key subgroups, including Hormone Receptor status, prior treatment with PERJETA®, visceral disease, number of prior lines of therapy, and the presence or absence of brain metastases. Majority of patients in the ENHERTU® group experienced a reduction in tumor size, and the ORR was significantly higher among patients in the ENHERTU® compared to those who received KADCYLA® (82.7% versus 36.1%; P<0.0001), with a near doubling of the Complete Response rate in the ENHERTU® group, at 16.1% compared to 8.7% in the KADCYLA® group. The estimated 12-month Overall Survival rate was 94.1% versus 85.9% respectively (HR=0.56; P=0.007), but was not considered significant as it did not cross the prespecified boundary for significance, likely due to the immaturity of the dataset.

Adjudicated treatment related Interstitial Lung Disease/pneumonitis was more common in the ENHERTU® compared with the KADCYLA® treatment arm, at rates of 10.5% and 1.9%, respectively and most of the events were Grade 1 or 2 in severity, and none at Grade 4 or 5 in either treatment group. Interstitial Lung Disease profile was of less concern, than was seen in previous trials of ENHERTU® in more heavily pretreated patients. All Left Ventricular Ejection Fraction decreases were Grade 1 or 2 and were seen in 2.7% of the ENHERTU® group and in 0.4% of KADCYLA® group. Other serious adverse reactions in patients who received ENHERTU® included, vomiting, pyrexia, and urinary tract infection.

The researchers concluded that ENHERTU® demonstrated a highly statistically significant and clinically meaningful improvement in Progression Free Survival, when compared to KADCYLA®, in patients previously treated with Trastuzumab and Taxane for HER2-positive metastatic Breast cancer, with manageable toxicities.

Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (Pts) with HER2+ metastatic breast cancer (mBC): Results of the randomized phase III DESTINY-Breast03 study. Cortés J, Kim SB, Chung WP, et al. Presented at: European Society for Medical Oncology 2021 Virtual Congress. September 16-21, 2021; virtual. Abstract LBA1.

Lower Gastrointestinal Endoscopy before Age 50 Years Reduces Risk for Colorectal Cancer among Women

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

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than 50 years of age, according to data in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. The increase in the incidence of CRC in young adults has been attributed to western style, high carbohydrate, high fat, low fiber diet, which can initiate inflammation and proliferation in the colonic mucosa within two weeks. Other lifestyle factors associated with CRC include obesity, high consumption of processed meat and alcohol, low levels of physical activity and cigarette smoking.

Based on benefits versus burden estimated by comparative modeling approaches using microsimulation models of CRC screening in a hypothetical cohort of 40-year-old US individuals, the American Cancer Society and the US Preventive Services Task Force within the past 4 years recommended lowering the age for screening initiation to 45 years for individuals at average risk. The recommended screening strategies include stool-based tests and endoscopic screening methods. Evidence from randomized clinical trials and prospective cohort studies has shown that endoscopic screening can reduce the incidence of and mortality from CRC, and endoscopic screening has the added advantage of CRC prevention by removal of precancerous lesions that could later become malignant, as well as detection of early-stage cancers that can be more effectively treated. There are however limited data with regards to the effectiveness of endoscopic screening in younger populations.

The authors conducted this prospective cohort study of lower gastrointestinal endoscopy (sigmoidoscopy or colonoscopy) among US female health professionals enrolled in the Nurses’ Health Study II between 1991 and 2017, to evaluate the association between endoscopy initiated at different ages and risk of CRC. The researchers also estimated the absolute risk reduction associated with endoscopy initiated at different ages through age 60 years. This analysis included 111,801 women, the median age was 36 years at the time of enrollment, and data analysis was performed from August 2020 to June 2021. The Primary end point of this study was overall CRC incidence. Secondary outcomes included incidence of younger-onset CRC (CRC diagnosed before 55 years of age) and CRC mortality.

The researchers noted that in the multivariable analysis after adjustment for age, family history, and lifestyle risk factors for CRC, compared with no endoscopy, women who underwent endoscopy had a significantly lower risk for incident colorectal cancer for age at initiation before 45 years (HR=0.37; 95% CI, 0.26-0.53), 45 to 49 years (HR=0.43; 95% CI, 0.29-0.62), 50 to 54 years (HR=0.47; 95% CI, 0.35-0.62), and 55 years or older (HR=0.46; 95% CI, 0.30-0.69).

The authors then estimated the multivariable-adjusted cumulative incidence of CRC and calculated the absolute risk reduction associated with each age group at endoscopy initiation. There was an absolute reduction in the estimated cumulative incidence of CRC through age 60 years, for women who initiated endoscopy between ages 45 to 49 years, compared with 50 to 54 years. Compared with no endoscopy, initiation of endoscopy before 50 years of age was also associated with a reduced risk of CRC diagnosed before 55 years of age (before age 45 years, HR=0.45; 95% CI, 0.29-0.70; 45-49 years, HR= 0.43, 95% CI, 0.24-0.76).

It was concluded that based on this analysis in a large, prospective cohort of women over a 26 year period, initiation of colorectal cancer screening before 50 years of age was associated with a reduced risk of CRC, and earlier initiation of endoscopy was associated with a greater absolute risk reduction of CRC, compared with initiation at later ages.

Age at Initiation of Lower Gastrointestinal Endoscopy and Colorectal Cancer Risk Among US Women. Ma W, MD, Wang M, Wang K, MD, et al. JAMA Oncol. Published online May 5, 2022. doi:10.1001/jamaoncol.2022.0883

Risk of Coagulopathy Persists for Several Months after COVID-19

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SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the numbers of infected cases continue to increase worldwide. As of May 1, 2022, over 81.4 million total cases have been reported in the US and 993,000 individuals have died from COVID-19. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

One of the most important and significant poor prognostic features in patients with COVID-19 is the development of coagulopathy, which is associated with an increased risk of death. The coagulation changes seen suggest the presence of a hypercoagulable state that can potentially increase the risk of thromboembolic complications. The coagulation abnormalities mimic other systemic coagulopathies associated with severe infections, such as Disseminated Intravascular Coagulation (DIC) or Thrombotic MicroAngiopathy (TMA), but the features are distinct in that, with DIC associated with sepsis, thrombocytopenia is usually more profound, and D-dimer concentrations do not reach the high values as seen among patients with COVID-19. COVID-19 infection related coagulopathy can also be associated with increased Lactate DeHydrogenase (LDH), and in some patient’s strikingly high ferritin levels, reminiscent of findings in TMA.

Severe COVID-19 infection is characterized by high concentrations of proinflammatory cytokines and chemokines such as Tumor Necrosis Factor-α (TNF-α) and interleukins including IL-1 and IL-6. IL-6 can induce tissue factor expression on mononuclear cells, initiating coagulation activation and thrombin generation, whereas TNF-α and IL-1 suppress endogenous anticoagulant pathways. COVID-19 infection also has a direct effect on endothelial cells, resulting in an exaggerated inflammatory response, down regulation of Angiotensin Converting Enzyme 2 receptors, and activation of the coagulation system. The relative incidence of pulmonary embolism is higher with COVID-19 infection and has been attributed to immunothrombosis (thrombosis in the pulmonary vessels from local inflammation). The increased risk of bleeding has been attributed to endothelial dysfunction, coagulopathy, or DIC. Previously published studies on the risk of venous thromboembolism after COVID-19 infection have shown conflicting results.

The researchers conducted this analysis using self-controlled case series and matched cohort study methods, and the objective of this study was to quantify the risk of deep vein thrombosis and pulmonary embolism, as well as bleeding after covid-19. Using Swedish national health databases, the researchers identified 1,057,174 individuals who tested positive for SARS-CoV-2 between February 2020 and May 2021. The incidence of first deep venous thrombosis (DVT), pulmonary embolism (PE), and bleeding during the subsequent 180 days was recorded, regardless of disease severity. A cohort of 4,076,342 individuals who did not have COVID-19 served as matched controls. The mean age was 40.2 years, 49% were males and 51% were females.

After statistical adjustments, the risks for DVT, PE, and bleeding were significantly higher in the 30 days following diagnosis of COVID-19 compared to the matched control group (risk ratios 5, 33 and 2; meaning 5 times, 33 times, 2 times more respectively). These risks remained significantly elevated for three, six, and two months after COVID-19, respectively. Further, there was a higher risk of events in patients with comorbidities, patients with more severe covid-19, and during the first pandemic wave, compared with the second and third waves.

It was concluded that the finding from this study support thromboprophylaxis to avoid thrombotic events, especially for high risk patients, and strengthens the importance of vaccination against covid-19. The authors added that it remains unclear whether the period of thromboprophylaxis after covid-19 should be extended, and additional clinical research would be beneficial.

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study. Katsoularis I, Fonseca-Rodríguez, Farrington P, et al. BMJ 2022; 377 doi: https://doi.org/10.1136/bmj-2021-069590 (Published 06 April 2022)

DARZALEX® plus KYPROLIS® and Dexamethasone in Relapsed or Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients are expected to die of the disease. Multiple Myeloma (MM) in 2022 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile or refractory disease have the worst outcomes. The median survival for patients with Myeloma is over 10 years.

REVLIMID® (Lenalidomide) in combination with VELCADE® (Bortezomib) and Dexamethasone is the preferred regimen according to the NCCN guidelines, for both transplant and non-transplant candidates with newly diagnosed Multiple Myeloma, and when given continuously or with maintenance therapy, has improved survival outcomes. Nonetheless, a significant number of patients progress while on these agents or discontinue therapy due to toxicities. There is therefore a need for effective and tolerable regimens for patients who are exposed or refractory to REVLIMID® or VELCADE®.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE®, proteasome inhibition with KYPROLIS® is irreversible. DARZALEX® (Daratumumab) 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 Dependent Cytotoxicity (CDC) and direct Apoptosis. Additionally, DARZALEX® may play a role in immunomodulation, by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Both KYPROLIS® and DARZALEX® are approved as single agents, as well as in combination with other drugs, for the treatment of patients with Relapsed/Refractory Multiple Myeloma. In a Phase I study, KYPROLIS® in combination with Dexamethasone and DARZALEX® demonstrated safety and efficacy in patients Relapsed/Refractory Multiple Myeloma.

The efficacy of KYPROLIS® and DARZALEX® along with Dexamethasone was evaluated in two clinical trials, CANDOR and EQUULEUS. CANDOR is a global, multicenter, open-label, randomized Phase III trial, which included Relapsed/Refractory Multiple Myeloma patients with measurable disease who had received 1-3 prior lines of therapy, with Partial Response or better to one or more lines of therapy. A total of 466 patients were randomly assigned 2:1 to receive triplet of KYPROLIS®, Dexamethasone, and DARZALEX® (KdD)- N=312 or KYPROLIS® and Dexamethasone (Kd) alone- N=154. All patients received KYPROLIS® as a 30 minute IV infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). DARZALEX® 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly for the remaining doses of the first 2 cycles, then every 2 weeks for 4 cycles (cycles 3-6), and every 4 weeks thereafter. All patients received Dexamethasone 40 mg oral or IV weekly (20 mg for patients over 75 years of age). Patients were stratified by disease stage, previous Proteasome Inhibitor or anti-CD38 antibody exposure, and number of previous therapies. The median age was 64 years, 42% and 90% received prior REVLIMID® and VELCADE® (Bortezomib) containing regimens respectively, and a third of patients were refractory to REVLIMID®. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Overall Response Rate (ORR), Minimal Residual Disease (MRD)-negative status, Complete Response (CR) rate at 12 months, Overall Survival (OS), Duration of Response, and Safety.

After a median follow up of 17 months, the study met its Primary endpoint and the median PFS was not reached for the KdD arm and was 15.8 months for the Kd arm (HR=0.63; P=0.0027). This represented a 37% reduction in the risk of progression or death in the KdD group. The PFS benefit of KdD was maintained across prespecified subgroups, particularly among REVLIMID®-exposed and REVLIMID®-refractory patients. The ORR was 84.3% in the KdD group versus 74.7% in the Kd group (P=0.004), with a CR rate or better of 28.5% versus 10.4% respectively. The median time to first response was one month in both treatment groups. Patients treated with KdD achieved deeper responses which was nearly 10 times higher, with a MRD-negative Complete Response rate at 12 months of 12.5% for KdD versus 1.3% for Kd (P<0.0001). The median treatment duration was longer in the KdD group compared to the Kd group (70.1 versus 40.3 wks). The median OS was not reached in either groups, at a median follow up time of 17 months. The FDA in August , 2020, approved KYPROLIS® (Carfilzomib) and DARZALEX® (Daratumumab), in combination with Dexamethasone, for adult patients with Relapsed or Refractory multiple myeloma, who have received one to three lines of therapy.

The analysis in the present publication was a preplanned interim analysis for Overall Survival. However the Overall Survival data were not mature at the time of data cutoff. The authors provided updated PFS and safety data, with 11 months of additional follow up. At a median follow up was 27.8 months, the median PFS was 28.6 months in the KdD group and 15.2 months in the Kd group (HR=0.59; P<0.0001), representing a 41% reduction in the risk of progression or death in the KdD group. Treatment-related Adverse Events were consistent with the primary analysis. Grade 3 or more adverse events occurred in 87% patients in the KdD group and 76% in the Kd group and were most commonly thrombocytopenia (25% versus 16%), hypertension (21% versus 15%) and pneumonia (18% versus 9%), respectively.

The authors concluded that with longer follow up, a combination of KYPROLIS® along with Dexamethasone and DARZALEX® provided a clear and durable Progression Free Survival benefit over KYPROLIS® and Dexamethasone alone, making KdD an emerging standard of care for patients with relapsed or refractory multiple myeloma.

Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Usmani SZ, Quach H, Mateos M-V, et al. The Lancet Oncology 2022;23:65-76.