Sintilimab for Patients with Pretreated EGFR-Mutated Non Small Cell Lung Cancer

SUMMARY: 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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Patients with advanced EGFR-mutated NSCLC, following initial clinical response to first, second and third generation EGFR-TKIs therapies, will inevitably advance to a progressive disease course. These patients often receive platinum-based chemotherapy, with limited clinical benefit. Immune checkpoint inhibitors given alone have low efficacy in the treatment of patients with metastatic NSCLC with oncogenic-driven tumors. There is a highly unmet medical need for these patients with resistant disease.

Sintilimab is an immunoglobulin G4, anti-PD-1 monoclonal antibody, which binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

ORIENT-31 is a prospective, randomized, double-blind, multi-center Phase III study, which evaluated Sintilimab, with or without a Bevacizumab biosimilar injection (IBI305), in combination with chemotherapy (Pemetrexed and Cisplatin), in patients with EGFR-mutated locally advanced or metastatic non-squamous NSCLC, who have progressed following EGFR TKI treatment. Patients were randomized in a 1:1:1 ratio to receive Sintilimab 200 mg IV plus Bevacizumab biosimilar 15 mg/kg IV combined with Pemetrexed 500 mg/m2 IV and Cisplatin 75 mg/m2 IV (Arm A), Sintilimab combined with Pemetrexed and Cisplatin (Arm B), or chemotherapy alone with Pemetrexed and Cisplatin (Arm C), all agents administered every 3 weeks for 4 cycles followed by maintenance treatment with Sintilimab plus Bevacizumab and Pemetrexed in Arm A, Sintilimab and Pemetrexed in Arm B, and Pemetrexed alone in Arm C. Treatment was continued until radiographic disease progression or unacceptable toxicity. Eligible patients included patients with disease progression following first or second generation EGFR TKI and confirmed as T790M negative, or T790M positive but further progressed on third generation EGFR TKI, or patients with disease progression following third generation EGFR TKI as first line treatment. The median age was 57 years, 36% of patients had brain metastasis, 64% of patients had received First or Second generation TKIs without T790M mutation, 28% had received First or Second generation TKIs and then a Third generation TKI for T790M mutation, and 8% patients received first line Third generation TKI. The target accrual was 480 patients and by the data cutoff date of the first interim analysis, 444 patients were enrolled. The Primary endpoint was Progression Free Survival (PFS) as assessed by an Independent Radiographic Review Committee (IRRC). Secondary endpoints included Overall Survival (OS), PFS as assessed by investigators, Objective Response Rate (ORR) and Safety. The median follow up at first interim analysis was 9.8 months.

Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy (Arm A), demonstrated a statistically significant and clinically meaningful improvement in PFS, compared with Arm C (chemotherapy alone group). The median PFS was 6.9 months in Arm A, and 4.3 months in Arm C (HR=0.46; P<0.0001). Additionally, the key Secondary endpoints of ORR and Duration of Response (DOR) were improved in Arm A compared with Arm C, and the results of PFS, ORR and DOR assessed by the investigator were consistent with the results assessed by IRRC. The prespecified PFS futility analysis that compares Arm A to Arm B (Sintilimab and chemotherapy group) did not cross futility stopping boundary. The PFS data of Arm B versus Arm C were immature.

The authors concluded that in this first prospective, double-blind, Phase III study among patients with EGFR mutated NSCLC who had progressed after EGFR TKIs, this quadruple regimen of Sintilimab plus Bevacizumab biosimilar in combination with chemotherapy, significantly improved Progression Free Survival, compared with chemotherapy alone.

VP9-2021: ORIENT-31: Phase III study of sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated nonsquamous NSCLC who progressed after EGFR-TKI therapy. Lu S, Wu L, Jian H, et al. Published:November 19, 2021DOI:https://doi.org/10.1016/j.annonc.2021.10.007.

PSMA Targeted Therapy Improves Overall Survival in Metastatic Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 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. 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. Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen) and the estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

Prostate-Specific Membrane Antigen (PSMA) is a type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer.

Lu-177-PSMA-617 is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with Lu-177-PSMA-617 targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell. The antitumor activity and safety of Lu-177-PSMA-617 have been established previously in a Phase II study (Lancet Oncol. 2018;19:825-833).

VISION is an international, randomized, open-label Phase III study in which the benefit of Lu-177-PSMA-617 was evaluated in men with PSMA-positive mCRPC, previously treated with second generation Androgen Receptor signaling pathway inhibitor (XTANDI®-Enzalutamide or ZYTIGA®-Abiraterone acetate), and 1 or 2 taxane chemotherapy regimens. In this trial, 831 patients were randomized 2:1 to receive Lu-177-PSMA-617, 7.4 GBq every 6 weeks for 6 cycles plus Standard of Care as determined by the treating physician (N=551), or Standard of Care only (N=280). Both treatment groups were well balanced and this trial excluded patients treated with XOFIGO® (Radium-223). Enrolled patients had a castrate level or serum/plasma testosterone of lower than 50 ng/dL, and PET imaging with 68 Ga-PSMA-11 was used to determine PSMA positivity by central review. The Primary endpoints were radiographic Progression Free Survival (rPFS) by Independent Central Review (ICR) and Overall Survival (OS). Secondary endpoints included Objective Response Rate (ORR), Disease Control Rate (DCR), and time to first Symptomatic Skeletal Event (SSE). The median study follow up was 20.9 months.

Lu-177-PSMA-617 plus Standard of Care significantly improved rPFS by 60%, compared to Standard of Care alone (median rPFS 8.7 versus 3.4 months, HR=0.40; P<0.001). The median OS was also significantly improved by 38% with Lu-177-PSMA-617 plus Standard of Care compared to Standard of Care alone (median OS 15.3 versus 11.3 months, HR=0.62; P<0.001). All key secondary endpoints including Objective Response Rate, Disease Control Rate, and time to first Symptomatic Skeletal Event were statistically significant, and in favor of Lu-177-PSMA-617 plus Standard of Care.

It was concluded that radioligand therapy with Lutetium-177–PSMA-617 significantly improved radiographic Progression Free Survival and Overall Survival when added to Standard of Care, compared with Standard of Care alone, in men with PSMA-positive metastatic Castration Resistant Prostate Cancer.

Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. Sartor O, de Bono J, Chi KN, et al. N Engl J Med 2021; 385:1091-1103.

FDA Approves EXKIVITY® for Metastatic Non Small Cell Lung Cancer with EGFR exon 20 Insertion Mutations

SUMMARY: The FDA on September 15, 2021, granted accelerated approval to EXKIVITY® (Mobocertinib), for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. The FDA also approved the Oncomine Dx Target Test as a companion diagnostic device to select patients with the above mutations for EXKIVITY® treatment.

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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC, and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

EXKIVITY® is a novel oral EGFR TKI, that was designed to address the unmet need in patients with EGFR exon 20 insertion mutant positive NSCLC. EXKIVITY® was designed to potently inhibit oncogenic variants containing activating mutations in exon 20, with selectivity over Wild Type EGFR.

The present FDA approval of EXKIVITY® was based on an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. This trial was conducted in three parts- Dose escalation or Part 1, to determine the safety profile of EXKIVITY®, Expansion phase or Part 2, to evaluate the antitumor activity of EXKIVITY® in seven histologically and molecularly defined cohorts, and Extension phase or Part 3, to evaluate efficacy of EXKIVITY® in patients with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations, and who have been previously treated.

So, this 3-part, multicenter study has dose-escalation/expansion and extension (EXCLAIM) cohorts. Patients with EGFR exon 20 insertion positive metastatic NSCLC, with ECOG status 0-1, and one or more prior lines of therapy for locally advanced/metastatic disease, received EXKIVITY® 160 mg orally daily, until disease progression or intolerable toxicity. Efficacy was evaluated in 114 patients whose disease had progressed on or after Platinum-based chemotherapy. Among these platinum pretreated patients, the median age was 60 years, 66% were female, 60% were Asian, and 59% had 2 or more prior systemic therapies. The main efficacy outcome measures were confirmed Objective Response Rate (ORR) assessed by blinded Independent Review Committee (IRC) and Duration of Response.

At a median follow up of 14.2 months, the ORR was 28%, with a median Duration of Response of 17.5 months. The median Progression Free Survival was 7.3 months and the median Overall Survival was 24 months. Clinically meaningful improvements were observed for dyspnea, coughing, chest pain, and these benefits were evident by cycle 2, and maintained throughout treatment. The most common adverse reactions were rash, nausea, stomatitis, vomiting, diarrhea, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain.

It was concluded that EXKIVITY® is the first and only oral therapy specifically designed to target EGFR exon 20 insertions, and the present FDA approval is an important addition, designed for this patient population.

Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. Ramalingam SS, Zhou C, Kim TM, et al. J Clin Oncol. 2021;39(suppl 15):9014. DOI:10.1200/JCO.2021.39.15_suppl.9014.

Maintenance RUBRACA® in Patients with Advanced Pancreatic Cancer with a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2

SUMMARY: The American Cancer Society estimates that for 2021, about 60,430 people will be diagnosed with pancreatic cancer and about 48,220 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2021.

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, PALB2, CHEK2 and ATM genes. BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively. BRCA1/2 mutations have been detected in 4-7% of patients with pancreatic cancer, with a 2-6 fold increase in risk, associated with these mutations. These patients tend to be younger. Among pancreatic cancer patients with Ashkenazi Jewish ancestry, the prevalence of BRCA1/2 mutations is 6-19%, with mutations more common for BRCA2. NCCN guideline recommends that germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.

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

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. 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.

LYNPARZA® (Olaparib) is a PARP inhibitor and is presently approved as maintenance therapy for patients with advanced pancreatic cancer demonstrating a germline BRCA1 or BRCA2 pathogenic variant. However, previously published studies have demonstrated the benefit of PARP inhibitors in breast, prostate and ovarian cancer patients, beyond germline BRCA pathogenic variants. Further, there is an unmet need to expand the group of patients with pancreatic cancer who may benefit from therapy with a PARP inhibitor, beyond those with germline BRCA pathogenic variants.

This investigator-initiated, single-arm Phase II study was conducted to assess the role of oral, small molecule PARP inhibitor RUBRACA® (Rucaparib), as maintenance therapy in advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2 genes. This study enrolled 46 patients with advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2, and had received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance, which was defined as growing tumors, new lesions, or a steadily rising tumor marker during or within 8 weeks of platinum therapy. The median age was 62 years, approximately 17% had germline BRCA1, 64% had germline BRCA2, 14% had germline PALB2 and 5% had somatic BRCA2 pathogenic variants. Majority of patients (95%) had metastatic disease and 5% had locally advanced disease. Ashkenazi Jewish founder mutation was found in 24% of patients. The Primary end point was Progression Free Survival (PFS) at 6 months (PFS). Secondary end points included Safety, Objective Response Rate (ORR), Disease Control Rate, Duration of Response, and Overall Survival.

The PFS at 6 months was 59.5% and the PFS at 12 months was 54.8%. The median PFS was 13.1 months and median Overall Survival was 23.5 months. The ORR in those with measurable disease was 42%, and the Disease Control Rate was 67%. The median Duration of Response was 17.3 months. These responses were noted across all germline and somatic pathogenic variants in BRCA1, BRCA2, and PALB2 genes, and no new safety signals were noted.

It was concluded from this study that maintenance RUBRACA® is a safe and effective therapy for platinum-sensitive, advanced pancreatic cancer patients, with a pathogenic variant in BRCA1, BRCA2, or PALB2. The authors added that the finding of efficacy in patients with germline PALB2 and somatic BRCA2 pathogenic variants, expands the population of patients likely to benefit from PARP inhibitors, beyond those with germline BRCA1 and BRCA2 pathogenic variants.

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. Reiss KA, Mick R, O’Hara MH, et al. J Clin Oncol. 2021;39:2497-2505.

Circulating Tumor DNA as a Biomarker in Advanced Colorectal Cancer

SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Cell-free DNA (cfDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis. A specific portion of cfDNA that originates from tumor cells is referred to as circulating tumor DNA (ctDNA), which can be detected in the cell-free component of peripheral blood samples in almost all patients with advanced solid tumors, including advanced colorectal cancer. ctDNA is a valuable biomarker and allows early detection of relapse.Liquid-Biopsy

Patients with metastatic colorectal cancer are often treated with chemotherapy and sometimes surgical intervention. Treatment decisions are based on clinical and pathological characteristics such as tumor size and number of metastatic lesions, which is an arbitrary method of treatment stratification. ctDNA can be a potential biomarker of tumor biology and disease trajectory, and can be an important clinical decision tool. The present study was conducted to systematically review ctDNA in Stage IV colorectal cancer, and assess its potential role as a prospective biomarker, to guide treatment decisions.

This meta-analysis included 2823 patients from 28 studies. ctDNA was detectable in 80-90% of patients with metastatic CRC prior to treatment. This analysis found a strong correlation between detectable ctDNA after treatment with surgery or chemotherapy and Overall Survival (HR=2.2; P<0.00001), as well as Progression Free Survival (HR= 3.15; P<0.00001). Further, ctDNA as an early biomarker was able to consistently predict long term prognosis in patients with unresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In patients with surgically resectable disease treated with curative intent, detection of ctDNA offered a lead time of 10 months, over radiological recurrence.

The authors concluded from this analysis that ctDNA is detectable in the majority of resectable and unresectable patients with metastatic colorectal cancer, and the presence of ctDNA is clearly associated with shorter Overall Survival. ctDNA may serve as an early biomarker and dynamic assessment of ctDNA may predict treatment efficacy.

Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Jones RP, Pugh SA, Graham J, et al. Eur J Cancer. 2021 Feb;144:368-381. doi: 10.1016/j.ejca.2020.11.025. Epub 2021 Jan 7.

FDA Approves LUMAKRAS® for KRAS G12C-Mutated Non Small Cell Lung Cancer

SUMMARY: The FDA on May 28, 2021, granted accelerated approval to LUMAKRAS® (Sotorasib), 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. The FDA also approved the QIAGEN therascreen® KRAS RGQ PCR kit (tissue) and the Guardant360® CDx (plasma) as companion diagnostics for LUMAKRAS®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

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

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

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

The CodeBreaK clinical development program for LUMAKRAS® was designed to treat patients with an advanced solid tumor with the KRAS G12C mutation and address the longstanding unmet medical need for these cancers. This program has enrolled more than 800 patients across 13 tumor types since its inception.

CodeBreaK 100 is a Phase I and II, first-in-human, open-label, single arm, multicenter study, which enrolled patients with KRAS G12C-mutant solid tumors. Eligible patients must have received a prior line of systemic anticancer therapy, for their tumor type and stage of disease. The present FDA approval was based on a Phase II trial which enrolled 126 patients with NSCLC, 124 of whom had centrally evaluable lesions by RECIST criteria at baseline. Enrolled patients had locally advanced or metastatic NSCLC with a KRAS G12C mutation, who had progressed on an immune checkpoint inhibitor and/or platinum-based chemotherapy, and those with active brain metastases were excluded. Patient received LUMAKRAS® 960mg orally once daily, until disease progression or unacceptable toxicity. Imaging studies were done every 6 weeks up to week 48 and then once every 12 weeks thereafter. The Primary end point of the trial was Overall Response Rate (ORR) as assessed by blinded Independent Central Review. Secondary end points included Duration of Response (DOR), Disease Control Rate (DCR), time to recovery, Progression Free Survival (PFS), Overall Survival, and Safety. The examination of biomarkers served as an exploratory end point. Patients were followed for a median of 12.2 months.

The ORR was 37.1% and the median Duration of Response was 10 months. Three patients had a Complete Response and the Disease Control Rate was 80.6%. The median Time to response was 1.4 months and 72% of patients had an early rapid response on first CT scan at 6 weeks. Approximately 81% of patients had tumor shrinkage of any magnitude, and the median percentage of best tumor shrinkage among all responders was 60%, and these responses were durable. The median PFS was 6.8 months. In the exploratory biomarker analysis, tumor response to LUMAKRAS® was seen across subgroups, including patients with negative or low expression of PD-L1 and those with STK11 and TP53 mutations. The most common adverse reactions were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. The most common laboratory abnormalities were increase in liver function tests, anemia, hyponatremia and proteinuria.

It was concluded that patients with NSCLC have poor outcomes and limited treatment options following progression on first line treatment. LUMAKRAS® offers a new treatment option for this patient group, and it is the first KRAS-targeted therapy to be approved after nearly four decades of research. A global Phase III study (CodeBreaK 200) is underway, comparing LUMAKRAS® to Docetaxel in patients with KRAS G12C-mutated NSCLC.

CodeBreaK 100: Registrational Phase 2 Trial of Sotorasib in KRAS p.G12C Mutated Non-small Cell Lung Cancer. Li BT, Skoulidis F, Falchook G, et al. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; virtual. Abstract PS01.07.

FDA Approves TRUSELTIQ® for Metastatic Cholangiocarcinoma

SUMMARY: The FDA on May 28, 2021, granted accelerated approval to TRUSELTIQ® (Infigratinib), a kinase inhibitor for adults with previously treated, unresectable, locally advanced or metastatic Cholangiocarcinoma with a Fibroblast Growth Factor Receptor 2 (FGFR2) fusion or other rearrangement, as detected by an FDA-approved test. The FDA also approved FoundationOne® CDx (Foundation Medicine, Inc.) for selection of patients with FGFR2 fusion or other rearrangement as a companion diagnostic device for treatment with TRUSELTIQ®.

Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection, whereas a majority of patients at diagnosis have advanced disease. The 5-year survival is less than 5%, with limited progress made over the past two decades.

Approximately 75% of patients are diagnosed with late-stage disease, and are often treated with Gemcitabine plus Cisplatin, based on the findings of the ABC-02 study. Second line treatment options include FOLFOX regimen, which is associated with a Response Rate of about 5%, median Progression Free Survival (PFS) of about 4 months, and median Overall Survival (OS) of about 6 months. There is therefore an unmet need for new effective therapies. FGFRs (Fibroblast Growth Factor Receptors) play an important role in tumor cell proliferation and survival, migration and angiogenesis. Activating fusions, rearrangements, translocations and gene amplifications in FGFRs result in dysregulation of FGFR signaling, and may contribute to the pathogenesis of various cancers, including Cholangiocarcinoma. FGFR2 fusions or rearrangements occur almost exclusively in intrahepatic Cholangiocarcinoma, where they are observed in 10-16% of patients.FGFR-Signaling-Pathway

TRUSELTIQ® (Infigratinib) is an orally administered, ATP-competitive, Tyrosine Kinase Inhibitor of FGFR, which targets the Fibroblast Growth Factor Receptor (FGFR) protein, blocking downstream activity. In clinical studies, TRUSELTIQ® demonstrated a clinically meaningful Overall Response Rate (ORR) and Duration of Response (DOR).

The present FDA approval was based on a multicenter, open-label, single-arm, Phase II trial that enrolled 108 patients with previously treated, unresectable, locally advanced or metastatic Cholangiocarcinoma, with an FGFR2 fusion or rearrangement as determined by local or central testing. Patients received TRUSELTIQ® 125 mg orally daily for 21 days of each 28-day cycle, until unacceptable toxicity or disease progression. All patients had received at least 1 prior line of systemic therapy and 54% had received 2 or more prior lines of treatment. The median age was 53 years and all patients received prophylaxis with the oral phosphate binder Sevelamer carbonate. The co-Primary endpoints were Objective Response Rate (ORR) by Independent Central Review, and Duration of Response (DOR). Secondary endpoints included Progression Free Survival (PFS), Disease Control Rate (DCR), Overall Survival (OS), Safety and Pharmacokinetics. The median follow up was 10.6 months.

The ORR was 23%, with a median Duration of Response of 5.0 months. Among responding patients, 32% had a Duration of Response of 6 months or more. The median PFS was 7.3 months. The most common toxicities were hyperphosphatemia, increased creatinine, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodysesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting. Serious toxicities included hyperphosphatemia and retinal pigment epithelial detachment and monitoring for these adverse reactions during treatment is recommended.

It was concluded that TRUSELTIQ® administered as second or later line treatment was associated with promising anticancer activity, and represents a new therapeutic option for patients with Cholangiocarcinoma and FGFR fusions/rearrangements. A Phase III study of TRUSELTIQ® versus Gemcitabine/Cisplatin is ongoing, in the first-line setting.

Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. Javle MM, Roychowdhury S, Kelley RK, et al. DOI: 10.1200/JCO.2021.39.3_suppl.265 Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021) 265-265.

FDA Approves Bispecific Antibody RYBREVANT® for Metastatic Non Small Cell Lung Cancer

SUMMARY: The FDA on May 21, 2021, granted accelerated approval to RYBREVANT® (Amivantamab-vmjw), a bispecific antibody directed against Epidermal Growth Factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after Platinum-based chemotherapy. FDA also approved the Guardant360® CDx (Guardant Health, Inc.) as a companion diagnostic for RYBREVANT®.

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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions, and occur in about 2-3% patients with NSCLC and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5 year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available and platinum-doublet chemotherapy remains the standard of care for these patients.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors.

RYBREVANT® is a fully-human bispecific antibody directed against EGFR and MET receptors. RYBREVANT® binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, RYBREVANT® downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, RYBREVANT® can bypass primary and secondary TKI resistance at the active site.

The present FDA approval was based on CHRYSALIS, an ongoing multicenter, non-randomized, open label, multicohort, Phase I clinical trial (NCT02609776) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The purpose of study is to evaluate the safety, pharmacokinetics, and preliminary efficacy of RYBREVANT® as a monotherapy and in combination with Lazertinib, and to determine the recommended Phase 2 dose (RP2D) (monotherapy), recommended Phase 2 combination dose (RP2CD) (combination therapy), and to determine recommended Phase 2 Dose (RP2q3W) with combination chemotherapy (RYBREVANT® in combination with standard of care Carboplatin and Pemetrexed) in 21 day treatment cycle for participants with advanced NSCLC.

In this analysis of the Phase 1 CHRYSALIS study, researchers assessed the efficacy and safety of RYBREVANT® in patients with NSCLC and EGFR exon 20 insertion mutations, who had progressed on prior Platinum-based chemotherapy, and were treated at the recommended Phase II dose of RYBREVANT® 1050 mg (1400 mg for patients weighting 80 kg or more). The median patient age was 61 years, 51% were female, and median prior lines of therapy was one. The Primary endpoint was Overall Response Rate (ORR). Secondary endpoints included Duration of Response (DOR), Clinical Benefit Rate, Progression Free Survival (PFS) and Overall Survival (OS).

It was noted that among this post-platinum cohort of patients (N=81), at a median follow up of 9.7 months, the ORR was 40%, with 4% Complete Reponses and 36% achieving Partial Responses (PR). Responses were durable with median Duration of Response of 11.1 months, with 63 % having responses of at least six months or greater duration. The median PFS was 8.3 months and median OS was 22.8 months. The Clinical Benefit Rate (PR or more, or Stable Disease of 11 weeks or more) was 74%. The most common adverse reactions (20% or more) were rash, infusion-related reactions, paronychia, fatigue, musculoskeletal pain, stomatitis, nausea, vomiting, constipation, edema, cough and dyspnea.

The authors concluded that RYBREVANT® demonstrated robust and durable antitumor activity in patients with EGFR exon 20 insertion mutations, with a manageable safety profile.

Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer. Sabari JK, Shu CA, Park K, et al. Presented at: IASLC 2020 World Conference on Lung Cancer Singapore. January 28-31, 2021. Abstract OA04.04

AI Derived Molecular Signature Predicts First-line Oxaliplatin-Based Chemotherapy Benefit in Advanced CRC

SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the overall death rate has continued to drop, deaths from CRC among people younger than 55 years have increased 1% per year from 2008 to 2017, with 12% of CRC cases diagnosed in people under age 50. Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness.

First line treatment of metastatic CRC include Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine ( FOLFOX or FOLFIRI), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. However numerous studies have failed to clearly establish that any of these combination regimens would be superior for any given patient based on clinical factors. In the TRIBE2 Phase III study, upfront FOLFOXIRI plus Bevacizumab and reintroduction after progression resulted in significant improvement in median Overall Survival (OS), compared to mFOLFOX6 plus Bevacizumab followed by FOLFIRI plus Bevacizumab, in patients with metastatic CRC. Majority of patients with mCRC receive FOLFOX-based first-line treatment, even though neuropathy almost always limits its use beyond 4 months. Oxaliplatin has also become a first line treatment option as part of FOLFOXIRI in mCRC, as part of FOLFIRINOX in advanced Pancreatic cancer and as a part of FOLFOX for other cancers such as GE Junction and Gastric cancer. A biomarker predicting the relative efficacy of these regimens is presently lacking. However, the availability of large, combined clinical and molecular datasets has enabled the development of a machine-learning approach.

The authors conducted this study to determine a patients’ likelihood of benefit from first-line treatment with FOLFOX followed by FOLFIRI versus FOLFIRI followed by FOLFOX, by taking advantage of an advanced machine-learning approach, to identify a molecular signature (FOLFOXai), predictive of treatment benefit from FOLFOX chemotherapy, by analyzing a combined dataset of comprehensive molecular profiling results and clinical outcomes data.

The researchers leveraged AI algorithms and comprehensive molecular profiling data to develop a machine-learning approach, and identified a 67-gene molecular signature (FOLFOXai), predictive of clinical benefit from FOLFOX chemotherapy, in previously untreated patients with mCRC. The molecular signature included genes involved in mediating WNT signaling (BCL9 and CDX2), epithelial-to-mesenchymal transition (EMT; INHBA, PRRX1, PBX1, and YWHAE), chromatin remodeling (EP300, ARID1A, SMARC4, and NSD3), DNA repair (WRN and BRIP1), NOTCH signaling (MAML2), and cell-cycle regulation (CNTRL and CCNE1). They then validated the putative molecular signature from a large Real World Evidence (RWE) database, a subset of cases from the randomized controlled Phase III TRIBE2 study, as well as RWE data from patients with advanced Esophageal/Gastro Esophageal Junction cancers (EC/GEJ cancers) or Pancreatic Ductal AdenoCarcinoma (PDAC) who received first-line treatments with Oxaliplatin-containing regimens.

The researchers utilized Real World Evidence (RWE) outcomes dataset from the Caris Life Sciences Precision Oncology Alliance registry, and insurance claims data from more than 10,000 physicians. The training cohort or dataset included patients who had a diagnosis of mCRC, received treatment with FOLFOX-based combination therapy, completed at least one full cycle of therapy, and completed Next-Generation DNA analysis of at least one colorectal cancer sample using a 592-gene panel. Patients were excluded if they had prior chemotherapy, including adjuvant therapy.

Two separate RWE validation cohorts were also generated, and patients in these cohorts had a diagnosis of mCRC, received first-line treatment with FOLFOX/Bevacizumab (FOLFOX/Bevacizumab cohort) or FOLFIRI-based treatment (FOLFIRI cohort), completed at least one full cycle of therapy, completed Next-Generation DNA analysis of at least one CRC sample using a 592-gene panel, and switched to an Irinotecan-containing regimen (FOLFOX/bevacizumab cohort) or to FOLFOX (FOLFIRI cohort).

For algorithm training, a TTNT (Time To Next Treatment) of 270 days was chosen to define whether a patient benefitted from receiving first-line FOLFOX. Patients with TTNT of less than 270 days were referred to as having decreased benefit to FOLFOX and others were referred to as having increased benefit. Validation studies used Time To Next Treatment (TTNT), Progression Free Survival (PFS), and Overall Survival (OS) as the primary endpoints.

A total of 105 patients with mCRC from the RWE dataset who had received first-line FOLFOX-based treatment and who had been profiled by Caris Life Sciences, were included in the training cohort. The first validation cohort included 412 patients (with RWE data on treatments and death dates) treated with FOLFOX/Bevacizumab and 55 patients who had received FOLFIRI as first-line treatments. Additional RWE datasets included 333 patients with advanced PDAC and EC/GEJC treated in first line with Oxaliplatin-containing regimens, and blinded retrospective-prospective analysis of samples from patients enrolled in the Phase III TRIBE2 study, with completed Next Generation Sequencing (NGS) analysis.

The researchers noted that
1) A 67-gene signature was cross-validated in a training cohort (N=105) which demonstrated the ability of FOLFOXai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit.
2) The gene signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI.
3) Blinded analysis of TRIBE2 samples confirmed that FOLFOXai was predictive of overall survival in both Oxaliplatin-containing arms (FOLFOX HR=0.629; P=0.04 and FOLFOXIRI HR=0.483; P=0.02).
4) FOLFOXai was also predictive of benefit from Oxaliplatin-containing regimens in advanced Esophageal/Gastro Esophageal Junction cancers, as well as Pancreatic Ductal AdenoCarcinoma.

It was concluded from this analysis that application of FOLFOXai molecular signature could lead to improvements of treatment outcomes for patients with mCRC and other cancers, because patients predicted to have less benefit from Oxaliplatin-containing regimens might benefit from alternative regimens, thus providing critical guidance for the choice of first line therapy. The authors added that this is the first clinically validated, machine-learning powered molecular predictor of chemotherapy efficacy in these diseases, with immediate relevance for the initial therapeutic decision-making process.

Clinical Validation of a Machine-learning–derived Signature Predictive of Outcomes from First-line Oxaliplatin-based Chemotherapy in Advanced Colorectal Cancer. Abraham JP, Magee D, Cremolini C, et al. Clin Cancer Res 2021;27:1174-1183.

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.