P4, N=200, Recruiting, Pfizer | Trial completion date: Jun 2027 --> Dec 2026 | Trial primary completion date: Jun 2027 --> Dec 2026

From the PSA, iruplinalkib had a 90% probability of being cost-effective at a willingness-to-pay threshold of $37,863.56/QALY. Compared to alectinib, iruplinalkib is a cost-effective therapy for patients with ALK-positive crizotinib-resistant advanced NSCLC.

Furthermore, the results from quantitative prediction research suggested that the combination of entrectinib at 600 mg/day with substrates primarily metabolized by hepatic UGT2B15 or intestinal UGT1A7 and UGT1A8 might cause clinical DDIs. Thus, special attention should be paid to avoid adverse reactions induced by DDIs when co-administration of entrectinib and drugs metabolized by UGTs.

On the other hand, there are some approved drugs, such as pembrolizumab for TMB-H or entrectinib or larotrectinib for NTRK fusion gene, for which there is no stand-alone companion diagnostics and the eligibility for these drugs cannot be judged without the results of CGP test. This paper discusses the current status and issues of companion diagnostics in cancer genomic medicine.

P2, N=4, Terminated, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | N=104 --> 4 | Recruiting --> Terminated; Sponsor R&D Strategy Adjustment

P2, N=61, Not yet recruiting, Megan Kruse, MD | Initiation date: Apr 2024 --> Oct 2024

P2, N=45, Recruiting, Centro di Riferimento Oncologico - Aviano

Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.

The follow-up CT scan revealed peritoneal nodules suggestive of peritoneal dissemination, and Entrectinib (a TRK inhibitor) was administered...The present case may offer new insights into the potential introduction of TRK inhibitors as treatments for GISTs with NTRK fusions. Additionally, the presence of abundant lymphoid infiltration in the present case may prompt further research into immunotherapy as a possible additional therapeutic option.

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

Drug synergy was seen using trametinib and rapamycin in combination with entrectinib.

P1, N=198, Active, not recruiting, Shenzhen TargetRx, Inc. | Recruiting --> Active, not recruiting | N=100 --> 198 | Trial completion date: Jun 2024 --> Oct 2025 | Trial primary completion date: Dec 2023 --> Aug 2025

In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

P1, N=24, Not yet recruiting, Bristol-Myers Squibb

After pursuing other alternative treatments, including chemotherapy (ie, carboplatin, etoposide, capecitabine, temozolomide, and paclitaxel), everolimus, and atezolizumab, she returned with significant progression, including innumerable subcutaneous nodules, left pleura metastasis, multiple bone metastases, and brain metastases. To date, she has maintained sustained benefit for at least 1 year from initiation of entrectinib. Here, we present the first case of a female patient with metastatic AC harboring the ETV6-NTRK2 fusion, and successfully treated with entrectinib, providing evidence for the application of entrectinib in patients with NTRK-positive AC, and underscoring the critical role of molecular profiling for such cases.

P4, N=200, Recruiting, Pfizer | Trial completion date: Dec 2026 --> Jun 2027 | Trial primary completion date: Dec 2026 --> Jun 2027

Among patients who exhibited resistance to crizotinib, follow-up treatment of entrectinib and lorlatinib showed remarkable survival benefits. Newer-generation ALK/ROS1-targeted drugs showed efficacy in a cohort of crizotinib resistant ROS1 + patients. These results, when validated, could assist efficiently accruing ROS1 + patients.

We present patient-focused recommendations for the evaluation and management of select AEs associated with lorlatinib developed by clinicians and nurses with extensive lorlatinib expertise in routine clinical practice. The recommendations follow the general framework of "prepare, monitor, manage, reassess" to streamline AE management and assist in practical, actionable, and personalized patient care.

P1, N=15, Not yet recruiting, Nationwide Children's Hospital

Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".

Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.

P2, N=20, Not yet recruiting, MedSIR

P1, N=12, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Oct 2024 --> Jun 2025 | Trial primary completion date: Apr 2024 --> Dec 2024

P1, N=24, Completed, Shenzhen TargetRx, Inc.

P1, N=32, Recruiting, Shenzhen TargetRx, Inc. | Not yet recruiting --> Recruiting

Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.

P2, N=23, Active, not recruiting, Intergroupe Francophone de Cancerologie Thoracique | Trial primary completion date: Jan 2024 --> Jan 2025

P1, N=17, Completed, Suzhou Zelgen Biopharmaceuticals Co.,Ltd | Recruiting --> Completed

Thirty-three (87%) patients experienced treatment-related toxicity and six (16%) patients required dose modification. Lorlatinib was highly efficacious in terms of overall response rate, median PFS and median OS in this small real-world cohort of advanced ALK+ve NSCLC with a manageable safety profile.

P1, N=32, Not yet recruiting, Shenzhen TargetRx, Inc.

The safety profile was consistent with that reported previously, with no new safety signals. This updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced ALK-positive NSCLC with and those without brain metastases.

Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis...Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

The first line (1L) therapies included - ROS1 TKIs in 38, chemotherapy in 20, epidermal growth factor receptor TKI in eight and chemotherapy-bevacizumab in one only...Using ROS1 TKI improves clinical outcomes in all-comers though statistically not significant. To further improve outcomes, future trials should pay special attention to patients with poor PS and find a way to increase the current limited access to TKI.

This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.

After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

P=N/A, N=73, Completed, Pfizer

P1/2, N=69, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Mar 2023 --> Jun 2025

Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib.

P2, N=68, Active, not recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Trial completion date: Jul 2024 --> Nov 2024 | Trial primary completion date: Dec 2023 --> Jul 2024

P2/3, N=30, Recruiting, Cancer Research UK | Initiation date: Dec 2023 --> Jun 2024

P1, N=24, Recruiting, Pfizer | Trial completion date: Dec 2023 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2024