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.

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