Author: RR

TUKYSA® Combination in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

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. 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), KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). 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®.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 52 years and patient demographics as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and Safety.

At median follow-up of 29.6 months, median OS in all patients with brain metastases at baseline was 9.1 months longer in the TUKYSA® combination group compared to the placebo combination group (21.6 versus 12.5 months, HR=0.60; P<0.001), with a 40% reduction in the risk of death with the TUKYSA® combination. The estimated 1-year OS was 70.0% for the TUKYSA® combination group and 50.6% for the placebo combination group and the estimated 2-year OS was 48.5% and 25.1% respectively.

The researchers in this exploratory subgroup analyses reported efficacy outcomes for patients with brain metastases, as well as time to new brain lesion(s) as the site of first progression or death, in all patients enrolled in HER2CLIMB trial, at a median follow up of 29.6 months.

There was greater CNS Progression Free Survival in the TUKYSA® combination group compared with the placebo combination group and was 5.7 months longer (9.9 versus 4.2 months, HR=0.39; P<0.001), with a 61% reduction in the risk of CNS progression with the TUKYSA® combination. The estimated 1 and 2-year CNS Progression Free Survivals were 38.4% versus 7.9% and 19.3% versus 0%, respectively.

Among those with active brain metastases and measurable disease at baseline, the intracranial Objective Response Rates for the TUKYSA® combination group were 47.3% versus 20.0% for the placebo combination group, with a median duration of intra cranial response of 8.6 versus 3.0 months, respectively.

The risk of developing new brain lesions as the site of first progression or death was reduced by 45% in the TUKYSA® combination group versus the placebo-combination group (HR=0.55; P =0.006).

The authors concluded that in this exploratory subgroup analysis, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, while reducing the risk of developing new brain lesions. The authors added that HER2CLIMB is currently the only double-blind, randomized, controlled clinical trial for patients with HER2-positive metastatic breast cancer, that prospectively included patients with both active and stable brain metastases.

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. Lin NU, Murthy RK, Abramson V, et al. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610

FDA Grants Accelerated Approval to KRAZATI® for KRAS G12C-mutated NSCLC

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SUMMARY: The FDA on December 12, 2022, granted accelerated approval to KRAZATI® (Adagrasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics for KRAZATI®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

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

KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 25% of Non-Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

KRAZATI® (Adagrasib) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike LUMAKRAS® (Sotorasib), which is also a selective covalent inhibitor of KRAS G12C, KRAZATI® has a longer drug half-life of 23 hours, as compared to 5 hours for LUMAKRAS®, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. KRYSTAL-1 is a Phase I/II multiple expansion cohort trial involving patients with advanced solid tumors harboring a KRAS G12C mutation. KRAZATI® demonstrated clinical activity in patients with KRAS G12C-mutated solid tumors, including colorectal, pancreatic, and biliary tract cancers. Further, preliminary data from two patients with untreated CNS metastases from a Phase 1b cohort showed antitumor activity against CNS metastases, with satisfactory concentrations of KRAZATI® in the CSF.

The present FDA approval was based on the results from Cohort A, a Phase 2 cohort of the KRYSTAL-1 study in which KRAZATI® at a dose of 600 mg orally twice daily was evaluated in patients with KRAS G12C-mutated NSCLC, previously treated with chemotherapy and anti-Programmed Death 1 (PD-1) or Programmed Death Ligand 1 (PD-L1) therapy. This registration study included a total of 116 unresectable or metastatic NSCLC patients, with histologically confirmed diagnosis, with KRAS G12C mutation (detected in tumor tissue at a local or central laboratory), who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy (in sequence or concurrently), and who had measurable tumor lesions. Enrolled patients received KRAZATI® 600 mg capsule twice daily, and treatment was continued until disease progression or unacceptable toxicities. The median patient age was 64 years, 97% had adenocarcinoma histology, 98% had both platinum-based therapy and checkpoint inhibitor therapy, and 21% of patients had CNS metastases. Key exclusion criteria included active CNS metastases (patients were eligible if CNS metastases were adequately treated and neurologically stable), carcinomatous meningitis, and previous treatment with a KRAS G12C inhibitor. Exploratory Biomarker Analyses included candidate biomarkers (PD-L1 Tumor Proportion Score and mutational status of STK11, KEAP1, TP53, and CDKN2A on tumor-tissue specimens, blood specimens, or both, for their association with tumor response. The Primary end point was Objective Response Rate as assessed by blinded Independent Central Review. Secondary end points included the Duration of Response, Progression Free Survival, Overall Survival, and safety. The median follow up was 12.9 months and the median duration of treatment was 5.7 months.

Of 112 patients with measurable disease at baseline, the confirmed Objective Response Rate was 42.9% and the median Duration of Response was 8.5 months. The median Progression Free Survival was 6.5 months, and the median Overall Survival was 12.6 months, at a median follow up of 15.6 months. Among 33 patients with previously treated, stable CNS metastases, the intracranial confirmed Objective Response Rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients and 53% were Grade 1 or 2 toxicities. KRAZATI® was discontinued in 6.9% of patients due to adverse events.

It was concluded that among patients with previously treated KRAS G12C-mutated NSCLC, KRAZATI® showed significant clinical efficacy without new safety signals and encouraging intracranial activity. The researchers added that these are the first clinical data demonstrating CNS-specific activity of a KRAS G12C inhibitor in this patient population.

Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. Jänne PA, Riely GJ, Gadgeel SM, et al. N Engl J Med 2022; 387:1238-1239

Sustained Benefit with Adjuvant VERZENIO® in High-Risk 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. 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. 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. Majority of these patients are diagnosed with early stage disease and 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. CDK 4 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, 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.

VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. VERZENIO® is structurally distinct from other CDK 4 and 6 inhibitors (such as Ribociclib and Palbociclib) and is 14 times more potent against Cyclin D1/CDK 4 and Cyclin D3/CDK 6, in enzymatic assays, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only VERZENIO® causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that VERZENIO® may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors. It has also been shown to cross the blood-brain barrier.

The International monarchE trial, is an open-label, randomized, Phase III study, which included 5637 patients, who were pre- and postmenopausal, with HR-positive, HER2-negative early breast cancer, and with clinical and/or pathologic risk factors that rendered them at high risk for relapse. The goal of monarchE was to evaluate the additional benefit of adding a CDK4/6 inhibitor to endocrine therapy in the adjuvant setting, for patients with HR-positive, HER2-negative, high risk, early breast cancer. The researchers defined high risk as the presence of four or more positive axillary lymph nodes, or 1-3 three positive axillary lymph nodes, with either a tumor size of 5 cm or more, or histologic Grade 3 disease (Cohort 1). A smaller group of patients with 1-3 positive axillary lymph nodes and centrally determined Ki-67 score of 20% or more were enrolled in Cohort 2. Ki-67 score was also determined centrally in Cohort 1 patients, but Ki-67 determination was not required for enrollment in this cohort. Following completion of primary therapy which included both adjuvant and neoadjuvant chemotherapy and radiotherapy, patients were randomly assigned (1:1) to VERZENIO® 150 mg orally twice daily for 2 years plus 5-10 years of physician’s choice of endocrine therapy as clinically indicated (N=2808), or endocrine therapy alone (N=2829). The median patient age was 51 years, about 43% of the patients were premenopausal, and 95% of patients had prior chemotherapy. Approximately 60% of patients had 4 or more positive lymph nodes. The Primary endpoint was Invasive Disease-Free Survival (IDFS) in the Intent to Treat (ITT) population (Cohorts 1 and 2). Secondary end points included IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), Distant Relapse-Free Survival (DRFS), Overall Survival (OS), and Safety. The researchers reported updated results from an interim analysis to assess overall survival, as well as Invasive Disease-Free Survival and Distant Relapse-Free Survival, with additional follow-up.

At a median follow-up of 42 months (3.5 years), the median Invasive Disease-Free Survival (IDFS) was not reached in either group, and the IDFS benefit previously reported was sustained. The risk of developing invasive disease was reduced by 33.6% (HR=0.664; nominal P<0.0001). The 4-year IDFS rate was 85.8% for patients treated with VERZENIO® plus endocrine therapy, compared to 79.4% for patients treated with endocrine therapy alone, reflecting an absolute difference of 6.4% (compared to 2.8% at two years). The majority of the IDFS events were distant metastatic disease. Adjuvant VERZENIO® also reduced the risk of developing metastatic disease by 34.1% (HR=0.659; nominal P<0.0001). The 4-year DRFS rate was 88.4% for patients treated with VERZENIO® plus endocrine therapy, compared to 82.5% for patients treated with endocrine therapy alone, an absolute difference of 5.9% (compared to 2.5% at two years). As was noted in the previous analyses, a high Ki-67 score correlated with increased risk of recurrence, but this IDFS and DRFS benefit was seen across all prespecified subgroups, regardless of Ki-67 score. Overall Survival (OS) data were immature at the time of this analyses. However, fewer deaths were observed in the VERZENIO® plus endocrine therapy group, compared to endocrine therapy alone. There were no new safety findings, and overall results were consistent with the safety profile for VERZENIO®.

It was concluded that adjuvant VERZENIO® combined with endocrine therapy continued to demonstrate statistically significant and clinically meaningful improvement in Invasive Disease Free Survival and Distant Relapse Free Survival, among patients with HR-positive, HER2-negative, node-positive, high risk, early breast cancer, regardless of Ki-67 status. These benefits were sustained after patients completed 2 years of adjuvant treatment with VERZENIO®, with an absolute increase at 4 years. The authors added that further follow-up is needed to establish whether Overall Survival can be improved with VERZENIO® plus endocrine therapy in this patient group.

Abemaciclib plus endocrine therapy for hormone receptor-positive, HER2-negative, node-positive, high-risk early breast cancer (monarchE): results from a preplanned interim analysis of a randomised, open-label, phase 3 trial. Johnston SRD, Toi M, O’Shaughnessy J, et al. The Lancet Oncology. Published:December 06, 2022. DOI:https://doi.org/10.1016/S1470-2045(22)00694-5

Unprecedented Progression Free Survival with SARCLISA® plus KYPROLIS® and Dexamethasone in Relapsed Multiple Myeloma

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, 34,470 new cases will be diagnosed in 2022 and 12,640 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 CD 38 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 2022 remains an incurable disease.

KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone Proteasome Inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. CD38 is a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® (Daratumumab) is a human IgG1 antibody that targets CD38, and was approved for use in combination with KYPROLIS® and Dexamethasone in 2020, for the treatment of patients with multiple myeloma, who had received 1-3 prior lines of therapy. This was based on the CANDOR open label, Phase III trial, in which the triplet combination of DARZALEX®, KYPROLIS® and Dexamethasone resulted in a 37% reduction in the risk of progression or death, compared with KYPROLIS® and Dexamethasone. 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.

SARCLISA® (Isatuximab-irfc) is a CD38-targeting IgG1monoclonal antibody, similar to DARZALEX®, but unlike DARZALEX®, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, SARCLISA® targets a specific epitope on the CD38 receptor, and this distinction from DARZALEX® allows use of SARCLISA® in cases when DARZALEX® fails. Additionally, SARCLISA® infusions are less cumbersome. The FDA in 2021, approved SARCLISA® in combination with KYPROLIS® (Carfilzomib) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy.

IKEMA trial is a multicenter, randomized, open label, Phase III study, in which the efficacy and safety of SARCLISA® in combination with KYPROLIS® and Dexamethasone was evaluated among patients with relapsed and/or refractory multiple myeloma, who had received 1-3 prior lines of therapy. In this study, 302 eligible patients were randomized 3:2 to receive SARCLISA® plus KYPROLIS® and Dexamethasone (N=179) or KYPROLIS® and Dexamethasone alone (N=123). SARCLISA® was given at 10 mg/kg IV weekly for 4 weeks and then every 2 weeks. KYPROLIS® was given at 20 mg/m2 IV on days 1 and 2 and then at 56 mg/m2 IV thereafter twice weekly for 3 of 4 weeks and Dexamethasone was given at 20 mg twice weekly. Treatment was continued until disease progression or unacceptable toxicity. The median age was 64 years, 23% had 3 or more prior lines of therapy, 90% of patients had prior treatment with Proteasome Inhibitor, 78% had prior treatment with Immunomodulatory drug (IMiD) and 24% had high-risk cytogenetics. The Primary endpoint was Progression Free Survival (PFS) as determined by an Independent Review Committee (IRC). Key Secondary endpoints included Overall Response Rate (ORR), rate of Very Good Partial Response (VGPR) or better, Complete Response (CR) rate, Minimal Residual Disease (MRD) negativity rate (10-5 by NGS), and Overall Survival (OS). The authors have now reported updated efficacy and safety results from IKEMA trial.

At a median follow-up of 44 months, the median PFS was 35.7 months in the SARCLISA® group and 19.2 months in the KYPROLIS® and Dexamethasone group (HR=0.58; 95.4% CI). The PFS benefit with SARCLISA® group was consistent across subgroups, including among patients with high-risk cytogenetics and those who were refractory to Lenalidomide. SARCLISA® plus KYPROLIS® and Dexamethasone also delayed the time to next treatment and prolonged PFS2. The median time to next treatment was 44.9 months with SARCLISA® combination and 25.0 months with KYPROLIS® and Dexamethasone (HR=0.55; 95% CI). The median PFS2 was 47.2 months and 35.6 months respectively (HR=0.68; 95% CI). The Complete Response (CR) rate or stringent CR rate was 44.1% in the SARCLISA® combination group and 28.5% in the KYPROLIS® and Dexamethasone group. MRD negativity was achieved in 33.5% of patients in the SARCLISA® combination group and 15.4% in the KYPROLIS® and Dexamethasone group. The rate of MRD negativity among patients with a CR or stringent CR was 26.3% in the SARCLISA® combination group and 12.2% in the KYPROLIS® and Dexamethasone group. No new safety signals were identified.

It was concluded that the addition of SARCLISA® to KYPROLIS® and Dexamethasone resulted in unprecedented median Progression Free Survival, Complete Response Rate and MRD negativity with a non-Lenalidomide regimen, and is the longest Progression Free Survival with a Proteasome Inhibitor backbone in the relapsed multiple myeloma setting. The authors added that SARCLISA® combination was well tolerated with manageable safety and a favorable benefit-risk profile, and this updated efficacy data support SARCLISA® in combination with KYPROLIS® and Dexamethasone as a standard of care treatment for patients with relapsed or refractory multiple myeloma.

VP5-2022: Updated progression-free survival (PFS) and depth of response in IKEMA, a randomized phase III trial of isatuximab, carfilzomib and dexamethasone (Isa-Kd) vs Kd in relapsed multiple myeloma (MM). Moreau P, Dimopoulos MA, Mikhael J, et al. ESMO Virtual Plenary. May 19-20, 2022. DOI:https://doi.org/10.1016/j.annonc.2022.04.013

IMBRUVICA® (Ibrutinib)

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The FDA on August 24, 2022, approved IMBRUVICA® (Ibrutinib) for pediatric patients ≥ 1 year of age with chronic Graft Versus Host Disease (cGVHD) after failure of 1 or more lines of systemic therapy. Formulations include capsules, tablets, and oral suspension. IMBRUVICA® is a product of Pharmacyclics LLC.

ENHERTU® (fam-trastuzumab deruxtecan-nxki)

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The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki) for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. ENHERTU® is a product of Daiichi Sankyo, Inc.

Long Term Lung Cancer Survival Rates with Low Dose CT Screening

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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.

In the National Lung Screening Trial (NLST) with Low Dose CT (LDCT) screening for lung cancer, there was a 20% reduction in mortality. Following the publication of the results of NLST, the NCCN issued guideline in 2011, and the United States Preventive Services Task Force (USPSTF) recommended lung cancer screening with Low Dose CT scan in high-risk patients. The CMS in 2015 determined that there was sufficient evidence to reimburse for this preventive service. The USPSTF expanded the criteria for lung cancer screening in 2021 and recommended annual screening with Low-Dose CT for adults aged 50-80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.

Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of lung cancer screening programs. Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. Despite the favorable stage shift as a result of lung cancer screening, low Health Care Provider knowledge of the lung cancer screening guidelines represents a potential barrier to implementation.

The Early Lung Cancer Action Project (ELCAP) in 1992 initiated a study of the early diagnosis of lung cancer in cigarette smokers using annual spiral CT screening. This study showed that more than 80% of individuals diagnosed with lung cancer as a result of annual CT screening had clinical Stage I cancer (Lancet 1999;354:99-105). In a subsequent large collaborative study (International Early Lung Cancer Action Program-IELCAP), 31,567 asymptomatic individuals at risk for lung cancer were screened with Low-Dose CT from 1993 through 2005. This study suggested that for those participants with Stage I lung cancer, the estimated 10-year survival rate was 88%, and among those with clinical Stage I lung cancer who underwent surgical resection within 1 month after the diagnosis, the survival rate was 92%. This study provided strong evidence that annual spiral CT screening can detect lung cancer that is curable (N Engl J Med 2006; 355:1763-1771).

The researchers herein provided the 20-year lung cancer-specific survival of participants, IELCAP enrolled, since its start in 1992. This prospective, international, multicenter study enrolled 87,416 participants, current, former and never smokers, 40 years of age and older, as of December 31, 2021. Participants were screened for lung cancer using Low-Dose CT for early detection of lung cancer with particular attention to lung cancer manifesting on CT images as solid, part solid and nonsolid consistency.

The 20-year lung cancer-specific survival for patients who underwent CT screenings and were diagnosed with early-stage lung cancer was 80%. The lung cancer-specific survival for patients with nonsolid and part-solid consistency cancerous lung nodules who underwent CT screenings was 100%, and 73% for patients with solid nodules. The lung cancer-specific survival for clinical Stage IA participants was 86%, regardless of consistency. For participants with pathologic Stage IA lung cancers 10 mm or less in average diameter, the 20-year lung cancer-specific survival was 92%.

The researchers concluded that after 20 years, their previous estimates of lung cancer survival rates are now confirmed, and this study adds further evidence of the high curability of lung cancer diagnosed by CT screening. These data demonstrate the importance of routine and early lung cancer screening.

20-year Lung Cancer Survival Rates in the International Early Lung Cancer Action Program (IELCAP). Henschke C, Yankelevitz DF, Libby DM, et al. Presented at: Radiological Society of North America; November 27-December 1, 2022; Chicago, IL.