FDA Approves LORBRENA® for Advanced ALK-Positive Lung Cancer

SUMMARY: The FDA on March 3, 2021, granted regular approval to LORBRENA® (Lorlatinib) for patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose tumors are Anaplastic Lymphoma Kinase (ALK)-positive, as detected by an FDA-approved test. The FDA also approved the Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Inc.) as a companion diagnostic for LORBRENA®. Lung cancer is the leading cause of cancer death in both men and women, and accounts for about 14% of all new cancers and 25% of all cancer deaths. The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. 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 discovery of chromosomal rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, and their sensitivity to ALK inhibitors, paved the way to the development of small-molecule ALK Tyrosine Kinase Inhibitors. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8%, as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

ALK inhibitors include first-generation XALKORI® (Crizotinib) and second-generation ALK inhibitors such as ZYKADIA® (Ceritinib), ALECENSA® (Alectinib) and ALUNBRIG® (Brigatinib). Despite the improved efficacy of second-generation ALK inhibitors, recurrent disease due to drug resistance including CNS disease progression, can still develop.

LORBRENA® is a novel third-generation ALK inhibitor that is more potent than second-generation inhibitors, and has the broadest coverage of ALK resistance mutations that have been identified. LORBRENA® crosses the blood-brain barrier and has marked intracranial activity in previously treated patients with baseline CNS disease, including leptomeningeal disease. LORBRENA® received accelerated approval by the FDA in November 2018 for the second or third-line treatment of ALK-positive metastatic NSCLC. However, the efficacy of LORBRENA®, as compared with that of XALKORI®, as first line treatment for advanced ALK-positive NSCLC, has been unclear.

The CROWN trial is a global, open label, randomized, Phase 3 study, in which LORBRENA® was compared with XALKORI®, in patients with previously untreated ALK-positive advanced NSCLC. In this study, 296 treatment naïve advanced NSCLC patients were randomly assigned 1:1 to receive LORBRENA® 100 mg orally once daily (N=149) or XALKORI® 250 mg orally twice daily (N=147) in cycles of 28 days. Treatment was continued until disease progression or unacceptable toxic effects. Eligible patients were required to have ALK-positive tumors detected by the Ventana ALK (D5F3) CDx assay. Patients with asymptomatic treated or untreated CNS metastases were eligible and had to have at least one extracranial measurable target lesion that had not been previously irradiated. Patients were stratified according to the presence of brain metastases and ethnic group (Asian or non-Asian) and crossover between the treatment groups was not permitted. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included independently assessed Objective Response Rate (ORR) and intracranial response.

At a planned interim analysis, treatment with LORBRENA® resulted in statistically significant and clinically meaningful improvement in PFS as assessed by BICR, with a Hazard Ratio of 0.28 (P<0.001), corresponding to a 72% reduction in the risk of disease progression or death. The median PFS was not estimable in the LORBRENA® arm and was 9.3 months for those treated with XALKORI®. The percentage of patients who were alive without disease progression at 12 months was 78% in the LORBRENA® group and 39% in the XALKORI® group, and the Hazard Ratio favored LORBRENA&reg over XALKORI® across all prespecified patient subgroups. The Overall Survival data were immature at the PFS analysis.

The confirmed ORR was 76% with LORBRENA® and 58% with XALKORI®. About 70% of the patients who received LORBRENA® and 27% of those who received XALKORI® had a response that lasted at least 12 months. Additionally, treatment with LORBRENA® was associated with increased intracranial activity compared with XALKORI®. Among patients presenting with measurable brain metastases, the intracranial ORR was 82% with LORBRENA® and 23% with XALKORI®, with a intracranial Complete Response rate of 71% and 8%, respectively. The duration of intracranial response was 12 months or more in 79% and 0% of patients in the LORBRENA® and XALKORI® groups, respectively. The most common adverse events with LORBRENA® were hyperlipidemia, edema, weight gain, peripheral neuropathy, and cognitive effects.

It was concluded that treatment LORBRENA® resulted in a significantly longer Progression Free Survival and a higher frequency of intracranial response, compared to XALKORI®, among patients with previously untreated advanced ALK-positive NSCLC.

First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. Shaw AT, Bauer TM, de Marinis F, et al. N Engl J Med 2020; 383:2018-2029.

Adjuvant Trastuzumab Monotherapy for Older Patients with HER-2 Positive Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Trastuzumab is a humanized monoclonal antibody targeting HER2. Adjuvant and neoadjuvant chemotherapy given along with Trastuzumab reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of Trastuzumab, several other HER2-targeted therapies have become available. The duration of adjuvant Trastuzumab therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

Elderly patients with HER-2 positive breast cancer may not be candidates for adjuvant chemotherapy. Single agent Trastuzumab used as adjuvant treatment without chemotherapy could be of potential benefit, avoiding chemotherapy-induced toxicities. However, the benefit of single agent Trastuzumab has not been investigated in patients older than 70 years. The present study was designed to investigate the efficacy of Trastuzumab monotherapy, compared with Trastuzumab in combination with chemotherapy, incidence of Adverse Events, as well as Quality of Life, in terms of the noninferiority criterion.

RESPECT Study is a multicenter, open-label, randomized controlled, prospective, adjuvant, noninferiority trial, in which Trastuzumab monotherapy was compared with Trastuzumab plus chemotherapy, among patients older than 70 years, with HER-2 positive breast cancer. A total of 275 patients, aged 70-80 years with surgically treated HER-2 positive invasive breast cancer, were randomly assigned in a 1:1 ratio to receive either Trastuzumab monotherapy (N=137) or Trastuzumab plus chemotherapy (N=138). Trastuzumab plus chemotherapy treatment consisted of a loading dose of Trastuzumab at 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks for 1 year. Chemotherapy regimens consisted of either Paclitaxel 80 mg/m2 IV weekly for 12 weeks, Docetaxel 75 mg/m2 IV every 3 weeks for 4 cycles, Doxorubicin 60 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (AC) every 3 weeks for 4 cycles, Epirubicin 90 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (EC) every 3 weeks for 4 cycles, Cyclophosphamide 75-100 mg orally, Methotrexate 40 mg/m2, and 5-fluorouracil 500-600 mg/m2 IV (CMF) for 6 cycles, Docetaxel 75 mg/m2 IV and Cyclophosphamide 600 mg/m2 IV (TC) every 3 weeks for 4 cycles or Docetaxel 60-75 mg/m2 IV, Carboplatin AUC 5-6 mg/ml/min IV along with Trastuzumab IV (TCH) every 3 weeks for 6 cycles. Patients treated with Trastuzumab monotherapy received similar doses of loading and maintenance Trastuzumab. Patients were stratified based on Performance Status, Hormone Receptor status and pathologic nodal status. Approximately 44% of patients had Stage I disease, 42% had Stage IIA, 13% had IIB, and 1% had IIIA disease. Approximately 14% of patients received Selective Estrogen Receptor Modulators such as Tamoxifen, and about 69% of patients received Aromatase Inhibitors. The Primary endpoint was Disease Free Survival (DFS) with assessment of prespecified Hazard Ratio (HR) and Restricted Mean Survival Time (RMST) for each treatment group. (RMST has been advocated as an alternative or a supplement to the Hazard Ratio for reporting the effect of an intervention in a randomized clinical trial, and is a measure of average survival from time 0 to a specified time point, and may be estimated as the area under the KM curve up to that point. RMST measure is especially informative for older patient populations in which Quality of Life issues are more important). Secondary endpoints included Overall Survival (OS), Relapse-Free Survival (RFS), Adverse Events (AEs) and Health-Related Quality of Life (HRQoL). The median follow up time was 4.1 years.

The 3-year DFS was 89.5% with Trastuzumab monotherapy versus 93.8% with Trastuzumab plus chemotherapy (HR=1.36; P=0.51) and this study failed to meet the prespecified criterion for noninferiority. However, a preplanned analysis of DFS according to RMST was -0.39 months, suggesting that only 0.39 months of DFS were lost within 3 years, by avoiding chemotherapy. The 3-year RFS was 92.4% with Trastuzumab monotherapy versus 95.3% with Trastuzumab plus chemotherapy (HR=1.33) and the difference in RMST for RFS between treatment groups at 3 years was −0.41 months (P=0.53). There were significant differences noted in clinically meaningful HRQoL deterioration rate at 2 months (31% for Trastuzumab monotherapy versus 48% for Trastuzumab plus chemotherapy; P=.016) and at 1 year (19% versus 38%; P=0.009). Breast cancer-specific survival at 3 years was 99.2% with Trastuzumab monotherapy versus 99.2% with Trastuzumab plus chemotherapy (HR=0.20; P=0.14).

The authors concluded that even though the Primary endpoint of noninferiority for Trastuzumab monotherapy was not met, the Restricted Mean Survival Time revealed that the observed loss of survival without chemotherapy was less than 1 month at 3 years, and Health-Related Quality of Life was better, with lower toxicities. Therefore, Trastuzumab monotherapy can be considered as a reasonable adjuvant therapy option for a select group of elderly patients with favorable outcomes.

Randomized Controlled Trial of Trastuzumab With or Without Chemotherapy for HER2-Positive Early Breast Cancer in Older Patients. Sawaki M, Taira N, Uemura Y, et al. J Clin Oncol. 2020;38:3743-3752.

RUBRACA® in Metastatic Castrate Resistant Prostate Cancer with BRCA Mutations

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 191,930 new cases of Prostate cancer will be diagnosed in 2020 and 33,330 men will die of the disease.

The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

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 two 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. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes 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.

Recently published data has shown that deleterious Germline and/or Somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 25% of patients with advanced prostate cancer, including mCRPC. Approximately 12% of men with mCRPC harbor a deleterious BRCA1 or BRCA2 mutation (BRCA1, 2%; BRCA2, 10%). Mutations in BRCA1 and BRCA2 also account for about 20-25% of hereditary breast cancers, about 5-10% of all breast cancers, and 15% of ovarian cancers. 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. HRD therefore indicates an important loss of DNA repair function. The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.MOA-of-RUBRACA

RUBRACA® (Rucaparib) is an oral, small molecule inhibitor of PARP. TRITON2 is an international, multicenter, open-label, single arm, Phase II trial, in which patients with BRCA-mutated mCRPC, who had progressed after one to two lines of next-generation Androgen Receptor-directed therapy and one taxane-based chemotherapy for mCRPC were included. In this study, 115 mCRPC patients with either Germline or Somatic BRCA mutations, with or without measurable disease were enrolled, of whom 62 patients (54%) had measurable disease at baseline. Patients received RUBRACA® 600 mg orally twice daily and concomitant GnRH analog or had prior bilateral orchiectomy. Treatment was continued until disease progression or unacceptable toxicity. The median patient age was 72 years, majority of patients had an ECOG performance status of 0 or 1, 67% of patients had Gleason score of 8 or more at diagnosis, 68% had bone-only disease and 47% had 10 or more bone lesions. The Primary endpoint was Objective Response Rate (ORR) by blinded IRR (Independent Radiology Review), as well as ORR by investigator assessment. Secondary end points included Duration of Response (DOR) in those with measurable disease, locally assessed PSA response rate (50% or more decrease from baseline) rate, Overall Survival (OS), and Safety. The median follow up was 17.1 months.

The confirmed ORR for the IRR-evaluable population was 43.5%, and the confirmed ORR for the investigator-evaluable population was 50.8%. The median DOR was not evaluable and 56% of patients with confirmed Objective Responses had a DOR of 6 months or more. The confirmed PSA response rate was 54.8% and the median time to PSA response was 1.9 months. The Objective Response Rates were similar for patients with a Germline or Somatic BRCA mutations, and for patients with a BRCA1 or BRCA2 mutations. However, a higher PSA response rate was observed in patients with a BRCA2 mutation. The median radiographic Progression Free Survival was 9.0 months per IRR assessment and 8.5 months per investigator assessment. The OS data were not yet mature at the time of the analysis. The most frequent Grade 3 or more treatment related Adverse Event was anemia (25.2%).

It was concluded that RUBRACA® demonstrates promising efficacy in patients with mCRPC with deleterious BRCA mutations. TRITON3 study is evaluating RUBRACA® versus physician’s choice of second-line AR-directed therapy or Docetaxel, in chemotherapy-naïve patients with mCRPC and alterations in BRCA1/2, who progressed on one prior AR-directed therapy.

Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration. Abida W, Patnaik A, Campbell D, et al. on behalf of the TRITON2 investigators. J Clin Oncol. 2020;38:3763-3772.

NERLYNX® Combination Superior to TYKERB® Combination in Advanced HER2-Positive Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease. 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-Directed-Therapy

NERLYNX® (Neratinib) is a potent, irreversible, oral Tyrosine Kinase Inhibitor, of HER1, HER2 and HER4 (pan-HER inhibitor). NERLYNX® interacts with the catalytic domain of HER1, HER2, and HER4 and blocks their downstream signaling pathways, resulting in decreased cell proliferation and increased cell death. Clinical data has suggested that NERLYNX® has significant activity in suppressing HER-mediated tumor growth and is able to overcome tumor escape mechanisms experienced with current HER2-targeted and chemotherapeutic agents. It has been well known that hormone receptor positive breast cancer patients, who are also HER2-positive, have relative resistance to hormone therapy. Preclinical models had suggested that the addition of NERLYNX® could improve responses in ER positive, HER2-positive breast cancer patients. Further, NERLYNX® has clinical activity in patients with HER2-positive metastatic breast cancer. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly reduced the proportion of clinically relevant breast cancer relapses that might lead to death, such as distant and locoregional recurrences outside the preserved breast.

TYKERB® (Lapatinib) is a Tyrosine Kinase Inhibitor of HER2 and EGFR, and in a previously published Phase III study, a combination of TYKERB® plus XELODA® (Capecitabine) was found to be superior to XELODA® alone in women with HER2-positive advanced breast cancer, that has progressed after treatment with regimens that included an Anthracycline, a Taxane, and HERCEPTIN®. (N Engl J Med 2006; 355:2733-2743)

The NALA trial was designed to compare NERLYNX® plus XELODA® versus TYKERB® plus XELODA® in patients with heavily pretreated Stage IV HER2-positive metastatic breast cancer, including those with asymptomatic or stable (treated or untreated) CNS metastases. In this multinational, randomized, active-controlled, Phase III study, 621 patients (N = 621) with metastatic HER2-positive breast cancer who received two or more prior anti-HER2 based regimens in the metastatic setting were randomly assigned in a 1:1 to receive NERLYNX® 240 mg given orally once daily on days 1-21 along with XELODA® 750 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=307) or TYKERB® 1250 mg given orally once daily on days 1-21 along with XELODA® 1000 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (N=314). Approximately 85% of patients had visceral metastases, and about 30% had received at least three anti-HER2 therapies. Patients in the NERLYNX® group also received antidiarrheal prophylaxis with Loperamide. Patients were treated until disease progression or unacceptable toxicity. The Co-Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR) and Duration of Response, Clinical Benefit Rate (CBR), time to intervention for symptomatic metastatic Central Nervous System (CNS) disease and Safety.

At a median follow up of 29.9 months, treatment with NERLYNX® with XELODA® significantly improved the median PFS, compared to those receiving TYKERB® with XELODA® (HR=0.76; P=0.006). This represented a 24% reduction in the risk of disease progression or death for those receiving a combination of NERLYNX® and XELODA®. The PFS rate at 12 months was 29% versus 15% respectively. The median OS was 21 months for patients receiving NERLYNX® and XELODA® compared to 18.7 months for those receiving TYKERB® and XELODA® (HR=0.88; P=0.20) and this was not statistically significant. The ORR was numerically higher with NERLYNX® and XELODA® combination in patients with measurable disease (32.8% versus 26.7%), and there was a statistically significant improvement in the Clinical Benefit Rate (45% versus 36%; P=0.03). The median Duration of Response was 8.5 versus 5.6 months respectively (HR=0.50; P=0.0004), favoring the NERLYNX® combination. The time to intervention for symptomatic CNS disease was significantly delayed with NERLYNX® combination versus TYKERB® combination, with an overall cumulative incidence of 22.8% versus 29.2% respectively (P= 0.043). The most common toxicities of any grade in the study population were diarrhea, nausea, palmar-plantar erythrodysesthesia syndrome, and vomiting. Treatment related toxicities were similar between arms, but there was a higher rate of Grade 3 diarrhea with the NERLYNX® combination (24% versus 13% respectively).

It was concluded from this study that a combination of NERLYNX® and XELODA® significantly improved Progression Free Survival, with a trend towards improved Overall Survival, and also resulted in a delayed time to intervention for symptomatic CNS disease, among patients with heavily pretreated advanced HER2-positive breast cancer. This is the first study to demonstrate superiority of one HER2-directed Tyrosine Kinase Inhibitor over another, in HER2-positive metastatic breast cancer.

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With 2 or More HER2-Directed Regimens: Phase III NALA Trial. Saura C, Oliveira M, Y Feng Y-H, et al. for the NALA Investigators. J Clin Oncol. 2020;38:3138-3149.

Chemotherapy-Free First Line Induction and Consolidation Treatment for Acute Lymphocytic Leukemia

SUMMARY: It is estimated that 6150 individuals will be diagnosed with Acute Lymphocytic Leukemia (ALL) in the US and 1520 patients will die of the disease. ALL is more common in children, but can occur at any age and arises from malignant transformation of B- or T-cell progenitor cells. These cells express surface antigens that define their respective lineages. Precursor B-cell ALL cells typically express CD10, CD19, and CD34 on their surface, along with nuclear Terminal deoxynucleotide Transferase (TdT), whereas precursor T-cell ALL cells commonly express CD2, CD3, CD7, CD34, and TdT.

Philadelphia Chromosome (Chromosome 22) is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. Approximately 20% of adults and a small percentage of children with ALL are Philadelphia Chromosome (Ph) positive, and in the majority of children and in more than 50% of adults with Ph-positive ALL, the molecular abnormality (fusion protein) is different from that in Ph-positive Chronic Myelogenous Leukemia (p190 versus p210).

Adult patients with Ph-positive ALL are rarely cured with chemotherapy and the prognosis in these patients has markedly improved with the availability of BCR/ABL targeted Tyrosine Kinase Inhibitors (TKIs). Use of these TKIs with or without chemotherapy can result in a Complete Hematologic Remission in 94-100% of patients, irrespective of age. Eligible patients are then usually referred for allogeneic Hematopoietic Stem Cell Transplant (allo HSCT). To increase the chance of cure and decrease the likelihood of relapse, sustained decrease in Minimal Residual Disease is required, with a reduction in the tumor burden to less than 1 tumor cell in 10,000 bone marrow mononuclear cells.BLINATUMOMAB-(BLINCYTO)-(Engages-Two-Different-Targets-Simultaneously)

BiTE® technology (Bispecific T cell Engager antibody) engages the body’s immune system to detect and target malignant cells. These modified antibodies are designed to engage two different targets simultaneously, thereby placing the patient’s T cells within reach of the targeted cancer cell and facilitating apoptosis of the cancer cell. BiTE® antibodies are currently being investigated to treat a wide variety of malignancies. BLINCYTO® (Blinatumomab) is a BiTE® antibody designed to activate the patients T cells with its anti-CD3 group and then bind them to tumor cells with its anti-CD19 group, thus promoting cellular cytotoxicity. CD19 is a protein expressed on the surface of B-cell derived leukemias and lymphomas

The Italian GIMEMA investigators adopted a chemotherapy-free induction strategy and conducted a Phase II single-group trial, in which adults (no upper age limit) with newly diagnosed Ph-positive ALL, received first line therapy with SPRYCEL® (Dasatinib) plus glucocorticoids, followed by two cycles of BLINCYTO® (Blinatumomab). This study enrolled 63 patients with newly diagnosed Ph-positive ALL, and patients received prephase treatment with a glucocorticoid for 7 days before they received SPRYCEL®, and glucocorticoids were continued for an additional 24 days and discontinued on day 31. SPRYCEL® 140 mg orally once daily was administered as induction therapy for 85 days.

Patients who completed the induction phase received consolidation treatment with BLINCYTO® 28 mcg per day, and before each BLINCYTO® cycle, Dexamethasone 20 mg was administered. A minimum of two cycles of BLINCYTO® was mandatory and up to three additional cycles were allowed. Levetiracetam 500 mg twice daily was administered during treatment with BLINCYTO®, to prevent CNS adverse events. SPRYCEL® was continued during treatment with BLINCYTO®, and after BLINCYTO® administration, except in those patients in whom a T315I mutation was detected during the induction phase. Lumbar punctures were performed at diagnosis, at days 14, 22, 43, 57, and 85, and at the end of each BLINCYTO® cycle, for a total of 12 procedures. The choice of postconsolidation treatment, including allogeneic HSCT and subsequent administration of a Tyrosine Kinase Inhibitor, was at the discretion of the investigators. The median patient age was 54 years, 54% of the patients were women, and the median WBC was 13,000 per cubic millimeter. Of the 63 enrolled patients, 65% had the p190 fusion protein, 27% had the p210 fusion protein, and 8% had both. The most frequent molecular aberration was IKZF1 deletion (54%). The Primary endpoint was sustained molecular response in the bone marrow after this treatment.

Complete Hematologic Response was observed in 98% of the patients at the end of SPRYCEL® induction therapy (day 85), and the molecular response rate was 29%, and this percentage increased to 60% after two cycles of BLINCYTO®, with further increase in molecular responses after additional cycles of treatment with BLINCYTO®. At a median follow up of 18 months, Overall Survival was 95% and Disease Free Survival (DFS) was 88%. The probability of DFS among patients who had a molecular response at the end of induction therapy (day 85) was 100%, as compared with 85% among patients with a non-molecular response. There was no significant difference noted in the DFS between patients with p190 and those with p210. Patients who had an IKZF1 deletion along with additional genetic aberrations had lower Disease Free Survivals. Mutations in the ABL1 gene were detected in 6 patients who had increased Minimal Residual Disease during induction therapy, and all these mutations were cleared by BLINCYTO®. A total of 24 patients received an allogeneic HSCT, and the transplantation-related mortality was 4%. The most common adverse events of any grade were pyrexia, cytomegalovirus infection/reactivation and neutropenia.

The authors concluded that a chemotherapy-free induction and consolidation first-line treatment with SPRYCEL® and BLINCYTO®, that was based on a targeted and immunotherapeutic strategy respectively, was associated with high incidences of molecular response and survival, with fewer Grade 3 or higher adverse events, in adults with Philadelphia chromosome-positive ALL.

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. Foà R, Bassan R, Vitale A, et al. for the GIMEMA Investigators. N Engl J Med 2020; 383:1613-1623

Universal Genetic Testing Detects More Inherited Mutations Than Guideline Based Approach

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, and germline testing 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. Very few studies have compared the prevalence of germline findings in patients with cancer, not selected by practice guidelines, and the impact of universal testing strategy for inherited germline variants in patients with cancer has remained unclear. The purpose of this present study was to determine if universal genetic testing in patients with cancer identifies more inherited cancer predisposition variants than a guideline-based approach, and also find out if there is an association between universal genetic testing and clinical management.

The authors in this prospective, multicenter cohort study, assessed germline genetic alterations among patients with solid tumors, receiving care at Mayo Clinic Cancer Centers and Mayo Clinic Health System community oncology practice in the US, between April 2018, and March 2020, as a part of 2 year Interrogating Cancer Etiology Using Proactive Genetic Testing (INTERCEPT) program. Patients were NOT selected based on cancer type, stage of disease, family history of cancer, race/ethnicity, age at diagnosis, multifocal tumors, or personal history of multiple malignant neoplasms. Clinical, demographic, and family history data and pathologic information were collected on all patients from medical records or self-administered questionnaires.Single-Gene-versus-MultiGene-Testing

Germline sequencing using a Next-Generation Sequencing panel of 84 genes was offered at no cost, utilizing the Invitae Multi-Cancer Panel. Whole Genome Sequencing, deletion and duplication analysis, and variant interpretation were performed and Pathogenic Germline Variants (PGV) were classified as High (relative risk more than 4), Intermediate (relative risk, 2-4), or Low (relative risk less than 2) penetrance, or recessive medically actionable variants. Test results were disclosed to the patient, and those with Pathogenic Germline Variants (PGVs) were invited for genetic counseling.

The authors compared multi-gene panel testing with guideline-based testing, using guidelines from the National Comprehensive Cancer Network (NCCN) and the National Society of Genetic Counselors (NSGC) and the American College of Medical Genetics (ACMG), to determine whether genetic testing was indicated for a particular patient. For patients who met the guidelines, the only genes tested were those recommended by the tumor-specific guideline. This study included patients with a broad mix of cancer types at various stages. The final analytic cohort consisted of 2984 patients, out of the 3095 patients enrolled in the study. The mean patient age was 61 years, 53% were male and 44% of patients had Stage IV disease at the time of genomic analysis. A family history of cancer in a first-degree relative was reported in 34% of the participants. The goals of this study were to examine the proportion of Pathogenic Germline Variants (PGVs) detected with a universal testing strategy compared with a targeted testing strategy based on clinical guidelines, as well as uptake of cascade genetic testing in families, when offered at no cost.

It was noted that Pathogenic Germline Variants (inherited mutation in a gene) associated with the development of their cancer was found in 13.3% of patients, including moderate and high-penetrance cancer susceptibility genes. In this study, 1 in 8 patients had a PGV, half of which would not have been detected using a guideline-based testing approach. Of those with a high-penetrance PGVs, 28.2% had modifications in their treatment, based on the finding. About 6.4% had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. However, only 17.6% of participants with PGVs had family members undergoing no-cost cascade genetic testing when offered.

It was concluded that in this large, prospective, multicenter cohort study with a broad mixture of cancer types and stages, universal multigene panel testing was associated with increased detection of clinically actionable heritable variants, compared with a targeted testing strategy based on clinical guidelines. Approximately 30% of patients with high-penetrance variants had modifications in their treatment, suggesting that wider clinical implementation of universal genetic testing and acceptance in oncology practice, may be beneficial.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome. Samadder NJ, Riegert-Johnson D, Boardman L, et al. JAMA Oncol. Published online October 30, 2020. doi:10.1001/jamaoncol.2020.6252

LYNPARZA® Superior to Chemotherapy in BRCA Mutated Platinum Sensitive Advanced Ovarian Cancer

SUMMARY: It is estimated that in the United States, approximately 21,750 women will be diagnosed with ovarian cancer in 2020 and 13,940 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5 year Overall Survival rate of about 20-30%.

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 two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination 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. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13, and they regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. 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).MOA-of-LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. LYNPARZA® is a PARP inhibitor that traps PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, leading to cumulative DNA damage and tumor cell death.

Previously published studies demonstrated a durable response to LYNPARZA® administered as treatment (rather than maintenance), in women with heavily pretreated relapsed ovarian cancer and a germline BRCA mutation, with an Objective Response Rate (ORR) of 42% in the subgroup of patients with platinum-sensitive disease, who had received at least 3 prior chemotherapy regimens. Single-agent nonplatinum chemotherapy is often used in heavily pretreated women with relapsed ovarian cancer. The authors conducted this study to evaluate whether LYNPARZA® monotherapy improves outcomes, compared with physician’s choice single-agent nonplatinum chemotherapy, in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA mutation, who have received at least 2 prior lines of platinum-based chemotherapy.

SOLO3 is an International, randomized, controlled, open label Phase III trial, that compared LYNPARZA® with non-platinum chemotherapy, in patients with platinum sensitive, relapsed ovarian cancer, and a germline BRCA1/2 mutation. This study included 266 patients who were randomly assigned 2:1 to LYNPARZA® 300 mg orally given twice a day (N=178) or physician’s choice of single-agent chemotherapy (N=88), which could be either Pegylated Liposomal Doxorubicin (PLD) 50 mg/m2 IV on day 1 every 4 weeks, Paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks, Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks or Topotecan 4 mg/m2 IV on days 1, 8, and 15 every 4 weeks. Eligible patients had relapsed high-grade serous or high-grade endometrioid ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer, with at least 1 measurable and/or nonmeasurable lesion, that could be accurately assessed at baseline, by CT or MRI, and was suitable for repeated evaluation. Patients had received at least 2 prior lines of platinum-based chemotherapy for ovarian cancer and were platinum sensitive (progression more than 6 months after the end of the last platinum-based regimen). Treatment groups were well balanced and the median patient age was 59 years. The Primary end point was Objective Response Rate (ORR) in those with measurable disease, as assessed by Blinded Independent Central Review (BICR). The key Secondary end point was Progression Free Survival (PFS) assessed by BICR in the intent-to-treat population.

It was noted that ORR was significantly higher in the LYNPARZA® group than in the chemotherapy group (72.2% versus 51.4%; Odds Ratio=2.53; P=0.002), suggesting a 2.53 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. In the subgroup who had received 2 prior lines of treatment, the ORR with LYNPARZA® was 84.6% and 61.5% with chemotherapy (Odds Ratio= 3.44), suggesting a 3.44 times higher likelihood of responding to LYNPARZA®, than to chemotherapy. The median time to onset of response was 2 months with LYNPARZA®, versus 3.5 months with chemotherapy, and the median Duration of Response was 9.4 months and 10.2 months respectively. The PFS also significantly favored LYNPARZA® versus chemotherapy (13.4 versus 9.2 months; HR=0.62; P=0.013). Adverse events were consistent with the established safety profiles of LYNPARZA® and chemotherapy. The most common Grade 3 or more adverse events were anemia in the LYNPARZA® group and PPE (Palmar-Plantar Erythrodysesthesia) and neutropenia in the chemotherapy group.

It was concluded that treatment with LYNPARZA® resulted in statistically significant and clinically relevant improvements in Objective Response Rate and Progression Free Survival, compared with nonplatinum chemotherapy, in patients with germline BRCA-mutated, platinum-sensitive, relapsed ovarian cancer, who had received at least 2 prior lines of platinum-based chemotherapy. This chemotherapy-free treatment option will be welcome news for patients with germline BRCA-mutated advanced ovarian cancer.

Olaparib Versus Nonplatinum Chemotherapy in Patients With Platinum-Sensitive Relapsed Ovarian Cancer and a Germline BRCA1/2 Mutation (SOLO3): A Randomized Phase III Trial. Penson RT, Valencia RV, Cibula D, et al. J Clin Oncol. 2020;38:1164-1174.

Adjuvant TAGRISSO® in Resected EGFR-Mutated Non-Small Cell Lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian).
Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy. The authors reported the results from the unplanned interim analysis.

It was noted that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo.

In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo.

The benefit favoring TAGRISSO® with respect to DFS was observed consistently across all predefined subgroups including disease Stages IB, II, and IIIA and use or nonuse of adjuvant chemotherapy. The benefit with TAGRISSO® was greater at more advanced stages of disease (among patients with Stage IIIA disease, the overall HR was 0.12, among those with Stage II disease, the HR was 0.17, and among those with Stage IB disease, the HR was 0.39). At 2 years, 98% of the patients in the TAGRISSO® group and 85% of the patients in the placebo group were alive without CNS-related disease (HR for CNS disease recurrence or death=0.18). This indicated an 82% reduction in the risk of CNS disease recurrence or death with TAGRISSO®. The Overall Survival data were immature at the time of this interim analysis. Adverse Events were consistent with the known safety profile of TAGRISSO®.

The authors concluded that adjuvant TAGRISSO® is the first targeted agent in a global randomized trial, to show a statistically significant and clinically meaningful improvement in Disease Free Survival, among patients with Stage IB/II/IIIA EGFR mutation-positive NSCLC, and provides an effective new treatment strategy for this patient group.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. Wu Y-L, Tsuboi M, He J, et al. for the ADAURA Investigators. N Engl J Med 2020; 383:1711-1723.

GILOTRIF® in EGFR Positive Non Small Cell Lung Cancer Harboring Uncommon Mutations

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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.

Approximately 10-15% of Caucasian patients, and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations. The majority of patients have classical EGFR mutations which are either Exon 19 deletions or L858R substitution mutation in Exon 21, and for those patients with EGFR mutation-positive NSCLC, EGFR-TKIs are the first choice of treatment. However, around 5-20% of tumors harbor Major uncommon mutations, such as G719X, L861Q and S768I, as well as other more rare mutations, and these uncommon EGFR mutations show heterogeneity in their response to EGFR-TKIs. Compared with other EGFR mutations, G719X, L861Q and S768I substitution mutations are associated with a poorer prognosis and have limited treatment options.

GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® demonstrated clinical activity against Major uncommon EGFR mutations such as G719X, L861Q and S768I which is more often seen in Asian patients, and is FDA approved in this setting. There are however, few clinical data regarding the efficacy of the available EGFR-TKIs against other uncommon EGFR mutations, and there is no knowledge of ethnic differences in prevalence and outcomes.

This study investigated the efficacy of GILOTRIF® in EGFR mutation positive NSCLC among Asian and non-Asian patients with uncommon mutations. Uncommon mutations were classed into five categoriesMajor uncommon (G719X, L861Q and S768I), Compound, Exon 20 insertions, T790M Mutation, and Other. Patients may have more than uncommon mutation.

The researchers conducted a pooled analysis from randomized clinical trials and Real-World Studies and examined the activity of GILOTRIF® in Asian and non-Asian patients with NSCLC and uncommon EGFR mutations, who had not received prior treatment with EGFR TKIs. All identified patients included in this study had outcome data such as Time to Treatment failure (TTF) or Objective Response Rate (ORR) available. The total number of evaluable patients were 298 (N=298), of whom 60% were Asian (N=178) and 40% were Non-Asian (N=120). The median patient age ranged from 60-66 years across the different mutation groups. Approximately 40% of patients had Major uncommon mutations such as G719X, L861Q and S768I, 24% had Exon 20 insertions, 12% had T790M mutations and 24% had Compound and Other mutations. When broken by ethnicity, among Asian patients, approximately 62% had Major uncommon mutations, 14% had Compound mutations and 16% had Exon 20 insertions. Among non-Asian patients, 35% had Major uncommon mutations, approximately 7% had Compound mutations and 39% had Exon 20 insertions. The Endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Treatment Failure (TTF), and outcomes were compared in Asian and non-Asian EGFR-TKI-naïve patients.

This analysis showed that the efficacy of GILOTRIF® was unaffected by ethnicity, and the Overall Response Rate (ORR) among tumors with Major uncommon mutations was 66% in Asian patients versus 59% in non-Asian patients, and the median Duration of Response (DoR) was 14.7 months compared with 15.9 months respectively. Among those with Major uncommon mutations, the ORR in tumors harboring G719X mutation was 62% in Asian patients and 65% in non-Asian patients. Among those tumors with a L861Q mutation, the ORRs were 60% versus 50%, respectively and among those with a S768I mutation, the ORRs were 80% versus 25%, respectively. The Overall Response Rate (ORR) among tumors with Compound mutations was 81% in Asian patients versus 100% in non-Asian patients and the median Duration of Response (DoR) was 11.5 months compared with 18.6 months respectively. Among patients who harbored Exon 20 insertions, the ORR with GILOTRIF® in Asian patients was 21% versus 23% in non-Asian patients, with a Duration of Response of 11 months and 10.7 months, respectively.

It was concluded that GILOTRIF® shows clinical activity against uncommon EGFR mutations in both Asian and non-Asian patients, with durable clinical responses, and should be considered as a first-line treatment option in Asian and non-Asian patients with Major uncommon (G719X, L861Q and S768I) and Compound EGFR mutations.

Afatinib in Asian and non-Asian patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC harboring major uncommon mutations. Yang JC-H, Schuler M, Popat S, et al. Presented at: 2020 IASLC North America Conference on Lung Cancer; October 16-17, 2020; Virtual. Abstract MO01.36.

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

SUMMARY: The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.
KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of Colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that Sotorasib inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The authors conducted a multicenter, open label Phase I trial of Sotorasib, in patients with advanced solid tumors harboring the KRAS-G12C mutation. This trial consisted of dose escalation and expansion cohorts and included a total of 129 patients, of whom 59 patients had NSCLC, 42 had Colorectal cancer, and 28 patients had other tumor types (Appendiceal, Endometrial, Pancreatic cancers and Melanoma). Sotorasib was administered orally once daily and each treatment cycle was 21 days. The planned dose levels for the escalation cohorts were 180, 360, 720, and 960 mg. Treatment was continued until disease progression or unacceptable toxicity. The median patient age was 62 years and most of the enrolled patients were heavily pretreated and had received a median of 3 previous lines of anticancer therapy for metastatic disease. Among the NSCLC patient cohort, approximately 90% of patients were current or former smokers and had received anti- Programmed cell Death protein-1 (PD-1) or PD-Ligand 1 (PD-L1) therapies. All patients had received previous platinum-based chemotherapy. The Primary endpoint was safety, including the incidence of dose-limiting toxicities and key Secondary end points were pharmacokinetics and Objective Response Rates. The Sotorasib dose of 960 mg daily was identified as the dose for the expansion cohort. The median follow up was 11.7 months and the median duration of treatment was 3.9 months, with 57% of patients having received treatment for 3 months or more, and 29% of patients, for 6 months or more.

Among those patients with NSCLC, 32.2% of the patients had a confirmed Objective Response (Complete or Partial Response at all dose levels, and 88% had disease control (Objective Response or Stable disease), with a median Progression Free Survival of 6.3 months. Responses were rapid and were seen at week 6, and these responses were durable and ongoing at a median follow up of nearly a year.

Among the colorectal cancer subgroup, at a median follow up of 12.8 months, 7% had a confirmed response, and 74% had disease control, with a median duration of stable disease of 5.4 months and median PFS of 4 months. Responses were also observed in patients with Pancreatic, Endometrial, and Appendiceal cancers and Melanoma. It has been postulated that the inconsistent tumor responses noted between NSCLC and Colorectal cancer suggests either that KRAS-G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways such as Wnt or EGFR pathways may mediate oncogenic signaling beyond KRAS. The authors suggest that a viable option would be to combine Sotorasib with therapies that block additional pathways, as was shown by studies in BRAF V600E-mutant Colorectal cancer. Approximately 57% of patients had treatment-related Adverse Events, of whom, about 12% had Grade 3 or 4 events. These toxicities included abnormal liver function studies, anemia, lymphopenia and diarrhea.

It was concluded Sotorasib showed promising anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS-G12C mutation. Studies evaluating Sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are under way

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. Hong DS, Fakih MG, Strickler JH, et al. N Engl J Med 2020; 383:1207-1217.