pf-06463922 and Adenocarcinoma-of-Lung

Treatment options for heavily treated anaplastic lymphona kinase (ALK )-positive nonsmall cell lung cancer (NSCLC) patients, who typically bear-resistant mechanisms to ALK tyrosine kinase inhibitors (TKIs), are usually limited to chemotherapy, which elicits limited clinical benefit and may incur severe toxicity. It is clinically relevant to explore other revenues for these patients. poly (ADP-ribose) polymerase (PARP) inhibitors, such as olaparib are currently approved to treat BReast CAncer gene 1/2 ( BRCA1/2 )-mutated patients in a few tumor types. There have been a trial and two case reports of an olaparib-containing regimen in treating epidermal growth factor receptor (EGFR)-positive or driver-negative NSCLC. We report a case of a 27-year-old female nonsmoker diagnosed with ALK -rearranged metastatic lung adenocarcinoma. She was treated with alectinib and acquired ALK p.I1171N and p.V1180L mutations. Germline BRCA2 p.F2801fs was also identified. After sequential lines of ceritinib and chemotherapy, lorlatinib was chosen as the fourth-line therapy and maintained control for 6 months. Shortly after progression, the patient was admitted to the ICU due to critically severe stenosis caused by a tracheal mass and soon relieved by embolization and stenting. Afterward lorlatinib plus olaparib was started and elicited a rapid response within 1 month. The progression-free survival was 6 months as of the latest follow-up, with the best response of partial response. To the best of our knowledge, this case is the first to provide clinical evidence of antitumor activity of olaparib plus ALK TKI in ALK -positive, g BRCA -mutated metastatic NSCLC. Together with previous reports in EGFR -positive or driver-negative patients, our finding warrants further studies on PARP inhibition in BRCA1/2 -mutated NSCLC.

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; BRCA2 Protein; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Tracheal Stenosis

Topics: Adenocarcinoma of Lung; Aminopyridines; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 12; Chromosomes, Human, Pair 15; Humans; Lactams; Lung Neoplasms; Mice; Mice, Nude; Microtubule-Associated Proteins; Neoplasm Proteins; Oncogene Proteins, Fusion; Pyrazoles; Receptor Protein-Tyrosine Kinases; Xenograft Model Antitumor Assays

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

Acquired mutations in anaplastic lymphoma kinase (

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Humans; Lactams; Lung Neoplasms; Male; Mutation; Pyrazoles

Patients with

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Immune Checkpoint Inhibitors; Lactams; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Nivolumab; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Sulfones; Time Factors; Treatment Outcome; Tumor Microenvironment

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Carbazoles; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Muscle, Skeletal; Oncogene Proteins, Fusion; Piperidines; Protein Kinase Inhibitors; Pyrazoles

ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance.. Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance.. NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020.. ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC.

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Male; Middle Aged; Mutation, Missense; Paclitaxel; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

The FAM179A gene has recently been screened as a new fusion partner fusing to the anaplastic lymphoma kinase gene (ALK) in plasma cell-free DNA (cfDNA) of patients with non-small-cell lung cancer (NSCLC). However, the response of patients with NSCLC harboring the FAM179A-ALK fusion to ALK inhibitors remains unknown. In this study we report a novel FAM179A-ALK rearrangement variant (F1, A19) identified by next-generation sequencing in an NSCLC patient with multiple brain metastases (M1c). This patient responded sensitively to lorlatinib as evaluated by brain MRI and chest CT, followed up using plasma cfDNA. The conclusion is that we found a novel FAM179A-ALK rearrangement variant (F1, A19) and provided evidence of its sensitivity to ALK inhibitors.

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Protein Kinase Inhibitors; Pyrazoles

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation, Missense; Paclitaxel; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Topics: Adenocarcinoma of Lung; Albumins; Aminopyridines; Antibodies, Monoclonal, Humanized; Humans; Immune Checkpoint Inhibitors; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation, Missense; Paclitaxel; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Pneumonia; Prognosis; Pyrazoles; Pyrimidines

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later because of spinal cord lesions. Brigatinib induced partial remission and was followed by lorlatinib and, later on, alectinib, when new metastases arose in the spinal cord and brain. Each of these drugs promoted complete remission of the recent lesions. In November 2018, imaging showed multiple cerebral metastases. As radiotherapy was not an option because of previous irradiation, and as chemotherapy cannot be expected to be active in the brain, the patient underwent brigatinib rechallenge, which led to partial remission. All of the central nervous system relapses were symptomatic, with symptoms resolved rapidly during treatment. This case of a patient with EML4-ALK-rearranged non-small-cell lung cancer shows that sequential treatment with next-generation ALK tyrosine kinase inhibitors, including rechallenge, can induce profound remission even in heavily pretreated patients, especially if the central nervous system is the site of progression.

Topics: Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Organophosphorus Compounds; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Spinal Cord Neoplasms

Topics: Adenocarcinoma of Lung; Adult; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Mutation; Point Mutation; Pyrazoles

Topics: Adenocarcinoma of Lung; Aminopyridines; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Nephrosis, Lipoid; Pyrazoles

Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next-generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aminopyridines; Anaplastic Lymphoma Kinase; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Receptor Protein-Tyrosine Kinases; Spinal Cord Neoplasms