Targeted therapy and immunotherapy are two critical contemporary strategies in the management of lung cancer. Despite their success in extending survival and mitigating symptoms, they introduce complex nursing interventions. This narrative review examines the impact of these treatment strategies on patients' quality of life, assesses the efficacy of current nursing interventions, and proposes strategies for enhancing future nursing practices. A comprehensive analysis of existing literature, covering studies published between 2014 and 2024 in the databases of WOSCC- SCIE, PubMed, CINAHL, and Embase, underscores the pivotal role of nursing in managing treatment-related adverse effects, delivering psychosocial support, and educating patients. Nevertheless, challenges remain in the areas of nursing staff training, resource allocation, and the limited scope of nursing research. Future directions should focus on the development of individualized care plans, the integration of innovative nursing technologies, and the ongoing enhancement of care quality to optimize nursing practices.

LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the final efficacy and safety results of selpercatinib in patients with RET fusion-positive non-small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N = 247) or were treatment-naïve (N = 69). The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients (median follow-up approximately 38 months). Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients (median follow-up approximately 40 months). Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-naïve group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety profile of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion-positive NSCLC.

Lung cancer remains the leading cause of cancer-related deaths, with the five-year survival rate for non-small cell lung cancer (NSCLC) patients as low as 10%. RNA aptamer RA16 has shown potential as a targeted therapy, binding specifically to NSCLC NCI-H460 cells and inhibiting proliferation in murine models. However, its clinical application is limited by poor in vivo stability. To overcome this, we developed RA16-functionalized DNA nanomaterials, combining the aptamer's targeting ability with the stability and high drug-loading capacity of tetrahedral DNA (TD) nanostructures. In vitro assays confirmed the biocompatibility, stability, and high drug-loading capacity of RA16-TD nanoparticles. RA16-TD enhanced cell binding and internalization by 10-fold compared to free RA16. In H460 xenograft mouse models, RA16-TD accumulation at the tumor site was 2.43-fold higher than free RA16 at 72 h postadministration. Furthermore, RA16-TD-loaded Epirubicin showed superior therapeutic efficacy, with a tumor inhibition rate of 77.8%, compared to 44.6% for free Epirubicin and 51.7% for RA16-Epirubicin. These results highlight the potential of RA16-functionalized DNA nanomaterials as a promising platform for targeted therapy in NSCLC, offering avenues for clinical application.

Kinase inhibitors is one of the most approved class by FDA in this century. These proteins are versatile targets that have a huge impact in several pharmacotherapy including against cancer, autoimunne and rare diseases. Thus, the number of patents that aim these targets are increasing and is becoming harder to be innovative in this field. Furthermore, the design of ATP-competitive inhibitors is the major strategy used to develop new kinase inhibitors and there are few regions in the ATP cleft or around it, which are generally explored by the commercially available inhibitor drugs. In this way in this review, we focused in the use of modern enantioselective strategies that were carried out in the last years to prepare new chiral kinase inhibitors as an emerging field that resulted in several new potent innovative approved drugs. Also we suggested new trends in this modern relevant topic and analyzed kinase-drug complexes highlighting the interactions that support the importance of the stereochemistry.

To evaluate the safety and effectiveness of entrectinib, an orally-administered potent multi-kinase inhibitor, for the treatment of proto-oncogene tyrosine-protein kinase-1 (ROS1) gene fusion-positive, unresectable, advanced/recurrent non-small cell lung cancer (NSCLC) in Japan.

Patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC who initiated entrectinib therapy were enrolled in this all-case post marketing surveillance between February 21, 2020 and November 30, 2021. Outcomes were to identify the: (1) type and onset of initial cognitive disorder and ataxia during entrectinib therapy; (2) status of treatment and outcome of drug-related cognitive disorder and ataxia events; (3) incidence of other adverse drug reactions (ADRs) of safety concern: cognitive disorder and/or ataxia, cardiac disorder (excluding QT interval prolongation), QT interval prolongation, syncope, and interstitial lung disease; (4) incidence of serious adverse events (AEs) and ADRs; and (5) effectiveness.

Of the 276 patients who initiated entrectinib, 269 and 260 were included in the safety and effectiveness analysis sets, respectively. Cognitive disorder/ataxia was the most common ADR of safety concern, occurring in 72 patients (26.8 %). The median time to onset of initial cognitive disorder/ataxia symptoms was 2.0 days. Overall, entrectinib dose reduction, interruption, or discontinuation occurred in 9.7 %, 28.3 %, and 15.2 % of patients, respectively. Most ADRs of safety concern were manageable; 86.9 % of patients with ADRs were recovered/recovering. Serious AEs were reported in 42.8 % of patients. The overall response rate (ORR) was 38.8 % and median time to treatment failure was 6.4 months. ORR was 70.8 % versus 26.8 % to 34.7 % with entrectinib as first-line versus second- or later-line treatment, and 65.3 % versus 28.2 % in patients without versus with a history of tyrosine kinase inhibitor treatment.

Consistent with clinical trials, entrectinib is tolerable and effective in Japanese patients with ROS1 gene fusion-positive, unresectable, advanced/recurrent NSCLC.

UMIN Clinical Trials Registry (UMIN000046619).

With the rapid advancements in second-generation gene sequencing technologies, a growing number of driver genes and associated therapeutic targets have been unveiled for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). While they are clinically classified as non-small cell lung cancer (NSCLC), they display distinct genomic features and substantial variations in clinical efficacy, underscoring the need for particular attention. Hence, this review provides a comprehensive overview of the latest advancements in driver genes, epigenetic targets, chemotherapy, targeted therapy, and immunotherapy for LUAD and LUSC. Additionally, it delves into the distinctions in signaling pathways and pivotal facets of clinical management specific to these two categories of lung cancer. Moreover, we furnish pertinent details regarding clinical trials pertaining to driver genes and epigenetics, thus establishing a theoretical foundation for the realization of precision treatments for LUAD and LUSC.

ROS1 gene rearrangement is an important target for NSCLC treatment. There is not yet sufficient real-world data on ROS1 diagnostic methods, treatment selection, and clinical outcomes in the Chinese population.

A single-center retrospective collection of patients with a diagnosis of ROS1-positive advanced NSCLC from July 2011 to November 2021 was performed to document the method of ROS1 testing, treatment options, efficacy, and resistance to ROS1 inhibitors in these patients.

The method of ROS1 testing and initial treatment selection were significantly correlated with time. ROS1 testing shifted from FISH (67% pre-2019) to NGS (96.3% post-2019; p < 0.001). First-line ROS1-TKI use increased from 60.0% to 92.0% (p = 0.041). The vast majority of patients (90.0%) chose crizotinib as the initial ROS1 inhibitor, with objective response rates (for patients with target lesions) and median progression-free survival of 82.8% (95% CI: 68.1%-97.9%) and 18.7 months (95% CI: 8.9-28.4 months), respectively. CNS was the most common site of progression for crizotinib (60%, 13/26, including 11 intracranial progressions alone). Compared to patients who received a chemotherapy-based regimen (n = 8) as first-line therapy, patients who received ROS1-TKI (n = 32) as first-line therapy had significantly longer median PFS (18.3 months vs. 3.7 months, p < 0.001). For ROS1 inhibitor-resistant patients, 48.3% of patients underwent rebiopsy throughout the course of their disease, with G2032R being the most common secondary ROS1 mutation (7/8).

With the innovation of diagnostic and therapeutic methods and the expansion of the scope of the health insurance coverage, more and more patients are benefiting from new technologies and targeted drugs. Although crizotinib has brought excellent therapeutic data for ROS1-positive patients, better brain protection strategies should be explored for ROS1-positive patients in the future. In addition, the low rate of rebiopsy in real-world ROS1-positive patients should also be emphasized in clinical practice.

Small cell lung cancer (SCLC) is characterized by an exceedingly low mutation rate in oncogenic driver alterations, and there are currently no articles or case reports documenting SCLC patients carrying ROS1 fusions. Tyrosine kinase inhibitors (TKIs) have demonstrated significant efficacy and safety in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC). However, effective treatment modalities for ROS1 fusion-positive SCLC patients remain poorly defined.

We report the first case of an extensive-stage SCLC (ES-SCLC) patient harboring ROS1 fusion, along with TP53, RB1, PTEN, and TERT mutations. The patient exhibited primary resistance to a 3-week course of crizotinib as first-line treatment. Following this, the patient was administered second-line therapy, including chemotherapy coupled with immune checkpoint inhibitor (ICI) and ICI maintenance treatment, resulting in a partial response (PR). Notably, the clinical response to second-line therapy persisted for over 19 months, surpassing the previously reported efficacy of immuno-chemotherapy in ES-SCLC cases (5.7 months) while maintaining a satisfactory quality of life.

We hypothesize that ROS1 fusion may not function as an oncogenic driver alteration in ES-SCLC. Immuno-chemotherapy, not ROS1-TKIs, might provide superior efficacy in ES-SCLC patients with ROS1 fusion.

Non-small cell lung cancer (NSCLC) is operated commonly by diverse genetic alterations, and oncogenic fusions represent a significant therapeutic role. Common fusions include ALK, ROS1, RET, and NTRK, signaling pathways in tumorigenesis. Recent advances in investigating tumor molecular biology include underlying fusions, including chromosomal rearrangements, highlighting their role as oncogenic drivers. The development of targeted therapies, such as tyrosine kinase inhibitors (TKIs), has impacted most patients' NSCLC treatment. Despite the greater profiles, such as remarkable efficiency and tolerable side effects compared to traditional chemotherapy, challenges, such as acquired mutations, lead to more ongoing research-optimized future NSCLC therapies.

Introduction: The use of ALK (anaplastic lymphoma kinase) and ROS1 (ROS1 protoncogene) inhibitors are the standard of care in advanced non-small-cell lung cancer (NSCLC) patients with ALK or ROS1 gene rearrangements (approximately 5.5% of patients). Three generations of inhibitors are available, but there is no direct comparison of their efficacy in homogeneous Caucasian populations in real-world practice. In this retrospective study, we compare the efficacy of crizotinib, brigatinib, and alectinib in NSCLC patients with different clinical courses of the disease. Materials and Methods: One hundred four NSCLC patients with ALK or ROS1 gene rearrangement were enrolled for first-line therapy with ALK inhibitors (crizotinib in 25 patients, brigatinib in 22 patients, and alectinib in 41 patients) or the ROS1 inhibitor (crizotinib in 16 patients) as part of daily clinical practice in two Polish cancer centers. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared according to treatment methods and clinical data. Results: In ALK-rearranged patients, ORR was insignificantly higher in patients treated with second-generation ALK inhibitors than in patients receiving crizotinib (68.25% vs. 48% of patients, p = 0.0547). Median PFS in the crizotinib group was 8 months, and in the group that received second-generation ALK inhibitors this was not reached (HR = 5.2182, 95% CI: 2.6163-10.4079, p < 0.0001). Similarly, median OS was significantly lower in patients treated with crizotinib than in patients receiving second-generation ALK inhibitors (26 vs. not reached, HR = 3.529, 95% CI: 1.5559-7.2258, p = 0.002). The efficacy of crizotinib in patients with ROS1 and ALK gene rearrangement did not differ significantly (ORR-37.5 vs. 48%, median PFS-6 vs. 7 months, median OS-8 vs. 26 months, respectively). In ALK-rearranged patients, multivariate analysis showed that the only factor significantly increasing the risk of progression was liver metastases (HR = 2.1917, p = 0.0418). The risk of death was significantly higher in patients treated with crizotinib (HR = 2.4823, p = 0.0359) and in patients with liver metastases (HR = 3.1266, p = 0.0104). Conclusions: Second-generation ALK inhibitors are more effective than crizotinib in ALK-rearranged patients. Liver metastases, but not brain metastases, are the main clinical factors shortening PFS and OS in NSCLC patients treated with ALK inhibitors.

Taletrectinib is an oral, potent, CNS-active, selective, next-generation ROS1 tyrosine kinase inhibitor (TKI). We report integrated efficacy and safety from registrational taletrectinib studies in ROS1+ non-small cell lung cancer.

TRUST-I and TRUST-II were phase II, single-arm, open-label, nonrandomized, multicenter trials. Efficacy outcomes were pooled from TRUST-I and TRUST-II pivotal cohorts. The safety population comprised all patients treated with once-daily oral taletrectinib 600 mg pooled across the taletrectinib clinical program. The primary end point was independent review committee-assessed confirmed objective response rate (cORR). Secondary outcomes included intracranial (IC)-ORR, progression-free survival (PFS), duration of response (DOR), and safety.

As of June 7, 2024, the efficacy-evaluable population included 273 patients in TRUST-I and TRUST-II. Among TKI-naïve patients (n = 160), the cORR was 88.8% and the IC-cORR was 76.5%; in TKI-pretreated patients (n = 113), the cORR was 55.8% and the IC-cORR was 65.6%. In TKI-naïve patients, the median DOR and median PFS were 44.2 and 45.6 months, respectively. In TKI-pretreated patients, the median DOR and median PFS were 16.6 and 9.7 months. The cORR in patients with G2032R mutation was 61.5% (8 of 13). Among 352 patients treated with taletrectinib 600 mg once daily, the most frequent treatment-emergent adverse events (TEAEs) were GI events (88%) and elevated AST (72%) and ALT (68%); most were grade 1. Neurologic TEAEs were infrequent (dizziness, 21%; dysgeusia, 15%) and mostly grade 1. TEAEs leading to discontinuations (6.5%) were low.

Taletrectinib showed a high response rate with durable responses, robust IC activity, prolonged PFS, favorable safety, and low rates of neurologic adverse events in TKI-naïve and pretreated patients.

Although lung cancer is a major cause of cancer incidence and mortality worldwide, lung cancer studies in sub-Saharan Africa are scarce. Here, we present outputs from a designated lung cancer program in western Kenya, part of the Multi-National Lung Cancer Control Program, which focused on case finding, diagnosis, and treatment.

We retrospectively reviewed patients with pathologically confirmed non-small cell lung cancer (NSCLC) enrolled in this program at Moi Teaching and Referral Hospital from January 2018 to December 2022. Clinical data were analyzed using descriptive statistics, Kaplan-Meier methods, and proportional hazards regression model.

Two hundred forty-nine patients diagnosed with NSCLC were included with a median age at diagnosis of 61 (IQR, 52-70) years. Most patients were married (n = 177; 71%) and nonsmokers (n = 177; 71%) with 58 (23%) having received tuberculosis treatment and 93 (37%) having Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ≥ 2. At diagnosis, adenocarcinoma was the prominent histology (n = 187; 75%) along with clinical stage IV (n = 195; 78% stage IV) or unstaged (n = 40; 16%) disease. Most patients received chemotherapy and radiotherapy (n = 176; 71%) with few palliative care referrals (n = 2; 0.8%). The median overall survival (OS) was only 3.7 months (IQR, 2.7-5.4). ECOG PS (3 or 4) and being unstaged were predictors of poor 1-year OS.

Patients with NSCLC enrolled in this program presented with advanced disease and poor survival. Despite a designated case finding effort, late diagnosis remained common and highlights a need for locally relevant interventions targeting community and provider education as well as innovative diagnostics that can improve early recognition of lung cancer. These interventions must also be paired with access to proven treatments including molecular therapies and palliative care which can extend lung cancer survival.

Approximately half of lung adenocarcinomas in East Asia harbor epidermal growth factor receptor (EGFR) mutations. EGFR testing followed by tissue-based next-generation sequencing (NGS), upfront tissue-based NGS, and complementary NGS approaches have emerged on the front line to guide personalized therapy. We study the cost effectiveness of exclusionary EGFR testing for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma.

This economic evaluation was conducted from the perspective of the healthcare sector with a lifetime horizon. Simulated patients were entered into a joint model combining decision trees and partitioned survival models upon diagnosis of advanced lung adenocarcinoma. We compared exclusionary EGFR testing with upfront tissue-based NGS and complementary NGS approaches. The model inputs were derived from regional estimates (prevalence of targetable gene alterations), trials (testing accuracy, survival outcomes, and adverse events), ACT Genomics (testing costs), National Health Insurance payments, retail prices (drug costs), and hospital cohorts (utility values). All costs were made equivalent to 2023 US dollars. An annual discount rate of 3% was applied. We adopted a willingness-to-pay threshold of US$70,000 per quality-adjusted life-year. One-way deterministic and probabilistic analyses were performed.

The incremental cost-effectiveness ratio of exclusionary EGFR testing versus upfront tissue-based NGS was US$15,521 per quality-adjusted life-year, whereas the incremental net monetary benefit was US$2530. The costs of osimertinib and pembrolizumab were the major determinants. The incremental net monetary benefit of exclusionary EGFR testing versus complementary NGS approach was US$2174, and its major determinants included the true-negative rate of EGFR testing and the prevalence rate of an EGFR mutation. Given the willingness-to-pay thresholds of US$35,000, US$70,000, and US$105,000 (1, 2, and 3 per capita gross domestic product) per quality-adjusted life-year, the probabilities that exclusionary EGFR testing would be cost effective were 79.1%, 95.6%, and 91.2%, respectively.

Our analysis suggests that exclusionary EGFR testing is a cost-effective strategy for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma.

Multigene sequencing technologies provide a foundation for targeted therapy and precision oncology by identifying actionable alterations and enabling the development of treatments that substantially improve clinical outcomes. This review emphasizes the importance of having a molecular compass guiding treatment decision-making through the multitude of alterations and genetic mutations, showcasing why NGS plays a pivotal role in modern oncology.

The development of targeted therapy with small-molecule tyrosine kinase inhibitors and immunotherapy with immune checkpoints inhibitors has ushered in the era of precision medicine in treating lung cancer, which remains the leading cause of cancer-related deaths worldwide. Both targeted therapy and immunotherapy have significantly improved the survival of patients with metastatic non-small-cell lung cancer (NSCLC). Additionally, recent groundbreaking studies have demonstrated their efficacy in both the perioperative setting and following concurrent chemoradiotherapy in early-stage NSCLC. Despite significant advancements in first-line treatment options, disease progression remains inevitable for most patients with advanced NSCLC, necessitating the exploration and optimization of subsequent therapeutic strategies. Emerging novel agents are expanding treatment options in the first-line setting and beyond. Recently, emerging bispecific antibodies have shown enhanced efficacy. For instance, amivantamab has been approved as a treatment for epidermal growth factor receptor (EGFR)-mutant NSCLC, including those with EGFR exon 20 insertion mutations. Additionally, antibody-drug conjugates (ADCs), including HER2-targeting trastuzumab deruxtecan, TROP2-targeting ADCs, HER3-targeting patritumab deruxtecan, and MET-targeting telisotuzumab vedotin, have demonstrated promising outcomes in several clinical trials. This review summarizes the recent advancements and challenges associated with the evolving NSCLC therapeutic landscape.

Background and Clinical Significance: Molecular testing plays a crucial role in lung cancer diagnosis and management. While single-gene tests (SGTs) remain an important diagnostic tool, developments in novel methods such as next generation sequencing (NGS) provide a more precise mutational profile and enable the targeted treatment of a larger scope of mutation-driven cancers. Case presentation: We present a case of a patient with a rare EGFR variant lung adenocarcinoma, who was misdiagnosed using a SGT. The initial treatment with immunotherapy was unsuccessful. Conclusions: The patient could have benefited if NGS had been performed instead of traditional real-time polymerase chain reaction (RT-PCR) and if adequate tyrosine kinase inhibitor treatment was initiated at the time of diagnosis.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Since 2024, the non-small-cell lung cancer (NSCLC) landscape has undergone a transformative shift, driven by 11 FDA approvals. Recent advances in molecular profiling, targeted therapies, and immunotherapies have revolutionized NSCLC management, ushering in an era of personalized treatment with improved patient outcomes. The increased adoption of low-dose computed tomography (LDCT) for screening has enhanced early detection, enabling intervention at more curable stages. Molecular diagnostics now play a pivotal role in guiding treatment strategies, with actionable genomic alterations (AGAs) informing the use of EGFR, ALK, ROS1, KRAS, NRG1, and other targeted inhibitors in both early and advanced settings. For instance, targeted therapies are increasingly being integrated into early-stage management, with adjuvant osimertinib for EGFR-mutated NSCLC and alectinib for ALK-positive NSCLC demonstrating substantial survival benefits. Immunotherapy, particularly immune checkpoint inhibitors, has become a cornerstone of treatment for AGA-negative NSCLC, either as monotherapy or in combination with chemotherapy, and is increasingly being utilized in the perioperative setting. Furthermore, emerging therapies such as bispecific antibodies, antibody-drug conjugates (ADCs), and novel immunotherapeutic agents show promise in addressing resistance mechanisms and improving outcomes in advanced-stage disease. Although new challenges arise, the evolving NSCLC treatment paradigm continues to prioritize precision medicine, offering hope for prolonged survival and enhanced quality of life for patients.

Lorlatinib, a third-generation tyrosine kinase inhibitor (TKI), targets both ALK and ROS1 rearrangements in non-small cell lung cancer (NSCLC). It is approved for ALK-positive patients after progression on prior TKIs but lacks FDA or EMA approval for ROS1-positive NSCLC. This study evaluates lorlatinib's efficacy and safety in both ALK- and ROS1-positive patients through a compassionate use program in Spain.

We analyzed ALK-positive patients treated from November 2016 to February 2019 and ROS1-positive patients treated from November 2016 to March 2021. Eligible patients had Stage IV NSCLC with confirmed ALK or ROS1 rearrangements and prior TKI therapy. For ALK-positive patients, at least two prior TKIs were required if crizotinib was used first. For ROS1-positive patients, prior crizotinib was required.

In 61 ALK-positive patients, 59 % had brain metastasis, and 85.2 % received at least two prior ALK TKIs. The overall response rate (ORR) was 32.8 %, with a median progression-free survival (PFS) of 11.2 months. Intracranial ORR was 47.6 %, with higher efficacy in patients with evaluable brain metastasis. In patients with 1, 2, or ≥3 lines of previous TKIs, we observed a median PFS of 15.1, 11.1 and 7.6 months, respectively. Among 42 ROS1-positive patients, 59 % had brain metastasis, and 61.9 % received ≥2 prior therapies. The confirmed ORR was 47.6 %, with 16.7 % complete responses. Median PFS was 10 months. Patients receiving crizotinib alone had a median PFS of 10 months, while those with two prior TKIs had a median PFS of 8.5 months. Intracranial response was 44.4 %, rising to 57.1 % in patients evaluable with brain metastasis. No new safety signals were observed.

Lorlatinib demonstrated consistent efficacy and manageable safety in both ALK- and ROS1-positive NSCLC patients treated under the compassionate use program in Spain. These real-world findings support its use as an effective treatment option in heavily pretreated patients.

We evaluated the efficacy and safety of lorlatinib in ALK- and ROS1-positive NSCLC patients within a compassionate use program in Spain. Among 61 ALK-positive patients, including 59 % with brain metastasis and 85.2 % treated with at least 2 prior ALK TKIs, lorlatinib achieved a confirmed overall response rate (ORR) of 32.8 % and a median progression-free survival (PFS) of 11.2 months. In 42 ROS1-positive patients previously treated with crizotinib, lorlatinib showed an ORR of 47.6 % and a median PFS of 10 months, confirming its clinical activity despite the lack of FDA or EMA approval for this indication.

ROS1 rearrangements define a molecular subset of non-small cell lung cancer (NSCLC) by accounting for 1%-2% of cases. Targeted therapy with ROS1 tyrosine kinase inhibitors (TKIs) has significantly improved the outcomes for these patients. First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%. However, the emergence of resistance mechanisms, including solvent-front mutations such as ROS1 G2032R, and limited blood-brain barrier penetration have limited the long-term efficacy of early-generation agents. Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges. These agents show enhanced central nervous system (CNS) penetration and activity against on-target ROS1 resistance mutations. Repotrectinib, a potent, CNS-penetrant ROS1 inhibitor, has demonstrated superior activity in both TKI-naive and -resistant tumors, including those harboring the G2032R mutation. Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability. Ongoing research is focused on optimizing sequencing strategies for ROS1 inhibitors and exploring combination approaches to prevent or overcome resistance. In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life.

Across the landscape of oncogene-addicted non-small-cell lung cancer (NSCLC), various tyrosine kinase inhibitors (TKIs) have been introduced in the last twenty years. During the 2024 Annual ESMO meeting new therapeutic options were presented for EGFR exon 20 insertion mutation, ALK fusion and ROS1 fusion positive advanced stage NSCLC. For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI. The vast majority of these patients also received platinum-doublet chemotherapy. For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib. The median number of prior anticancer therapies was 3. Intracranial responses were seen in lorlatinib naïve- and lorlatinib pretreated patients and toxicity was manageable. In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib. Iruplinalkib showed a superior median PFS (36.8 versus 14.55 months for crizotinib), but no difference in 36-month overall survival (OS) rate. Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in patients that were pretreated with crizotinib and an ORR of 38% in patients pretreated with repotrectinib. In this review, we will discuss the relevant study results presented at ESMO 2024 for these three genomic drivers and hypothesize on their respective place in the sequence of treatment options.

Background and Objectives: ROS1 rearrangement is a rare but targetable alteration in non-small-cell lung cancer (NSCLC), occurring in 1-2% of cases. Crizotinib, a tyrosine kinase inhibitor, has demonstrated efficacy in clinical trials, but real-world data remain limited. This study evaluates the safety and efficacy of crizotinib in ROS1-rearranged NSCLC patients in a real-world setting. Materials and Methods: This multicenter, retrospective research included 43 individuals with advanced/metastatic NSCLC and confirmed ROS1 rearrangements. Patients were treated with crizotinib in first- or second-line settings. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The median follow-up was 45.8 months. The ORR for first-line crizotinib was 72.1%, with a DCR of 79%. The median PFS was 20.9 months (95% CI: 6.02-35.69), and the median OS was 52.7 months (95% CI: 13.08-92.31). ECOG performance status was a significant prognostic factor for ORR (p = 0.02). The most common adverse events were fatigue (16.2%), elevated transaminases (13.9%), and vision disorders (11.6%). All reported adverse events were grade 1 or 2, with no grade ≥ 3 events observed. Conclusions:Crizotinib demonstrated significant efficacy and a favorable safety profile in real-world individuals with ROS1-rearranged NSCLC. These findings align with pivotal trials, underscoring crizotinib's role as a standard treatment for this molecular subset. Further prospective studies are warranted to explore intracranial efficacy and long-term outcomes.

Lung cancer treatment has changed in the last twenty years since the discovery of EGFR mutations. In this article, we will review the current state of the art for non-small cell lung cancer (NSCLC) actionable genomic alterations (AGA). AGAs are mostly found in lung adenocarcinomas, a subtype of non-small cell lung cancers. We will focus on the current treatment for EGFR mutations, ALK fusions, ROS1 fusions, BRAF V600E mutations, MET exon 14-skipping mutations, RET fusions, KRAS G12C mutations, ERBB2 mutations (also called HER2 mutations), and NTRK fusions. We will also touch on the key toxicities associated with these medications. Treatments are mostly available for the metastatic stage, but we will also discuss adjuvant therapy for EGFR mutations and ALK fusions, as well as stage III post-chemoradiotherapy treatment for EGFR lung cancer.

In non-small cell lung cancer, the presence of an oncogenic driver is frequently documented. Advances in molecular biology have enabled the identification of so-called rare oncogenic addictions, with an incidence of less than 5%, such as ROS-1 and RET rearrangements, and MET, BRAF and HER2 mutations. Targeted therapies have shown strong tumor responses with a better tolerance profile compared to chemotherapy. Consequently, targeted therapies have revolutionized the therapeutic landscape, particularly as immune checkpoint inhibitors are often ineffective in the presence of an oncogenic driver. To ensure optimal management in the era of personalized medicine, it is recommended to screen for oncogenic addictions, including rare ones, at diagnosis. In this review, we discuss the targeted therapies available in France and the promising future molecules for managing rare oncogenic drivers. Targeted therapies have already proven their efficacy as first-line treatments for ROS-1 and RET alterations, and as second-line treatments for MET and BRAF mutations.

The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.

ROS1 chromosomic rearrangement is a rare oncogenic driver, and patients with this rearrangement benefit from specific targeted treatments in the first-line setting. However, therapeutic options are limited in pretreated patients. Brigatinib is a validated drug for ALK rearrangements, and also has an in vitro activity against ROS1. In vivo efficacy is also suggested in some clinical series.

We aimed to specifically study brigatinib in patients with pretreated advanced non-small-cell lung cancer (NSCLC).

We retrospectively collected data from 20 centers in France. Brigatinib was delivered through a compassionate use program in France between 2018 and 2020. The primary endpoint was progression-free survival. Secondary endpoints were the objective response rate, overall survival, and tolerance.

Twenty-five patients treated with brigatinib were included in our study. All patients were pretreated, and all of them previously received crizotinib. Median progression-free survival was 3.8 months (95% confidence interval 2.8-7.1). The objective response rate was 32%, with a disease control rate of 48%. Three patients had a prolonged response of more than 18 months at the end of data collection. We did not identify factors predictive of prolonged response. There were no grade 4 or 5 toxicities.

Brigatinib may represent an interesting therapeutic option for patients who have progressed after standard treatments.

Gene fusions are one of the most important molecular biomarkers for tumor diagnosis, classification and targeted therapy. How to accurately detect them is a key issue in clinical work. In this study, a custom-designed integration of DNA and RNA-based next generation sequencing (NGS) assay including 16 targeted therapy related genes was developed and validated to identify gene fusions in solid tumors. This assay accurately identified all 10 different types of fusion in 8 commercial fusion spiked-in reference standards and 29 fusions including 16 different fusion forms in 60 clinical solid tumor samples previously identified by clinical testing methods. In addition, a TPM3::NTRK1 fusion was additionally identified and validated by Sanger sequencing, which showed a false-negative result for the previous result. Mutational abundance limit of detection for the assay was assessed with a series of dilution experiments. These fusions can be stably detected when the mutational abundance is down to 5% for DNA and 250-400 copies/100 ng for RNA. The intra-assay and inter-assay reproducibility was observed in three samples and three replicates. This integration of DNA and RNA-based NGS assay shows excellent performance on formalin-fixed, paraffin-embedded samples, results at different levels can complement each other, thereby facilitating precise diagnosis and treatment.

Head-to-head evidence comparing repotrectinib against other approved ROS1 tyrosine kinase inhibitors (TKIs) is not currently available. The objective of this study was to indirectly compare progression-free survival (PFS), the objective response rate (ORR), and the duration of response (DoR) for repotrectinib vs. crizotinib and vs. entrectinib in patients with TKI-naïve ROS1+ locally advanced or metastatic non-small-cell lung cancer (aNSCLC).

Using evidence from a systematic literature review, unanchored matching-adjusted indirect comparisons (MAICs) were used to estimate population-adjusted hazard ratios (HRs) for PFS and DoR and odds ratios (ORs) for ORR for repotrectinib vs. crizotinib and vs. entrectinib among patients with TKI-naïve aNSCLC. The MAICs were adjusted for imbalances in baseline patient characteristics that were pre-specified as being prognostic or predictive of treatment effects. Weighted Cox (for PFS and DoR) and logistic (for ORR) regression models were fit. Supplementary analyses (SAs) explored the impact of missing data and modeling assumptions on effect estimates.

The evidence base was formed by TRIDENT-1 EXP-1 (repotrectinib; N = 71), a pooled set of five trials involving crizotinib (N = 273), and the pooled ALKA-372-001/STARTRK-1 and -2 trials (entrectinib; N = 168). After population adjustment, repotrectinib was associated with statistically significant improvements in PFS relative to crizotinib (HR = 0.44; 95% confidence interval [CI]: 0.29, 0.67) and entrectinib (HR = 0.57; 95% CI: 0.36, 0.91). Differences in ORR and DoR were not statistically significant but numerically favored repotrectinib. SAs were consistent with the main analyses across all comparisons.

The analysis demonstrated the strong benefits of repotrectinib in PFS, which was robust across different SAs and supported by numerically favorable results for DoR (where available) and ORR. These results, alongside the published TRIDENT-1 clinical data, further support repotrectinib as a potential new standard of care for TKI-naïve patients with ROS1+ aNSCLC.

We aimed to describe treatment patterns, time on treatment (ToT) and overall survival (OS) for patients with advanced non-squamous, EGFR+, ALK+ and ROS1+ NSCLC in Norway.

We extracted data on patients ≥ 18 years diagnosed with advanced non-squamous NSCLC between 2015 and 2022 from the Cancer Registry of Norway and data on cancer drug therapy from the Norwegian Patient Registry and the Norwegian Prescribed Drug Registry. ToT was measured from the date treatment was collected or administered until the last dispensing was depleted or last hospital drug administration. OS was measured from date of diagnosis until death.

In total, 5,279 patients were included, of whom 449 EGFR+, 131 ALK+ and 38 ROS1+. 75% of EGFR+ patients, 88% of ALK+ patients, and 58% of ROS1+ patients received at least one systemic treatment within the first three months after diagnosis. Median follow-up was 13, 19, and 4 months for EGFR+, ALK+, and ROS1+, respectively. The median ToT in first line (1L) for EGFR+ patients was 11 months for osimertinib (CI: 10.1-NA) and 9 months (CI: 8.2-11.2) for afatinib, dacomitinib, erlotinib and gefitinib. For ALK+ patients, median ToT in 1L was 20 months (CI: 14.7-23.7for alectinib, 11 months (CI: 4.7-NA) for brigatinib, and 7 months (CI: 2.9-21.6) for crizotinib. For the five ROS1+ patients treated with crizotinib in 1L, median ToT was 5 months (CI: 2.4-NA). For all patients with a targetable genomic alteration, unadjusted median OS was higher (p-value = 0.025) for patients diagnosed in 2020-2022 (median OS: 23 months, CI: 19.5-NA) compared to patients diagnosed in 2015-2019 (median: 19 months, CI: 16.5-21.2).

ToT for targeted therapies was shorter than progression-free survival in clinical trials. However, patients eligible for targeted therapy still had a survival improvement during the study period.

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades.

The treatment of non-small-cell lung cancer (NSCLC) has progressed from histology-oriented cytotoxic therapy to the era of molecular biology-oriented targeted therapy and immunotherapy. As the first tyrosine kinase inhibitor (TKI) targeting the ROS1 pathway, crizotinib is widely used as a first-line regimen for ROS1-rearranged NSCLC. However, due to the paucity of solid data from randomized, controlled phase III clinical studies, clinicians often require more systematic, real-world data-based guidance for its optimal clinical use. As one of the leading countries of real-world research on crizotinib, China has contributed significantly to data on standardization of the therapeutic use of crizotinib, including its clinical treatment patterns, the timing and duration of treatment and drug resistance monitoring and management.

To investigate the prognostic factors for stage IIb and IIIa lung adenocarcinoma following radical surgery and to explore the molecular mechanisms underlying these prognostic markers, focusing on the role of PIK3C2G.

A retrospective analysis of patients with stage IIb or IIIa lung adenocarcinoma who underwent radical surgery between January 2017 and June 2023 was conducted. Baseline clinical and pathological data, surgical methods, and postoperative treatments were analyzed to assess overall survival (OS). Univariate and multivariate Cox regression analyses were conducted to identify prognostic factors. Whole-exome sequencing (WES) was performed on a subset of the patients with preserved tumor tissues and no matched targeted therapies to identify high-frequency mutated genes. Functional experiments in A549 lung adenocarcinoma cells were performed to evaluate the role of the significant genes in tumor progression through cell proliferation, migration, invasion, apoptosis, and cell cycle assays.

The survival analysis of 877 stage IIb and IIIa lung adenocarcinoma cases revealed significant differences in clinical characteristics and outcomes. Stage IIb patients had a median OS of 58 months compared to 37 months for stage IIIa, with 5-year OS rates of 46.9% and 30.5%, respectively. Univariate and multivariate Cox regression identified pathological stage, number of positive lymph nodes, age, and targeted therapy as independent prognostic factors. WES of 184 patients with no matched targeted therapies revealed high-frequency mutations in genes such as TP53 and PIK3C2G, with the latter emerging as the most significant prognostic marker. Functional assays demonstrated that the knockdown of PIK3C2G in A549 cells significantly reduced proliferation, migration and invasion while promoting apoptosis and disrupting cell cycle progression.

PIK3C2G was identified as a significant prognostic marker in stage IIb and IIIa lung adenocarcinoma, with functional data supporting its therapeutic potential. Taken together, this study integrates clinical and molecular findings, which could be used as a reference to guide personalized treatment strategies.

Non-small-cell lung cancer (NSCLC) is a highly heterogeneous disease that is frequently associated with a host of known oncogenic alterations. Advances in molecular diagnostics and drug development have facilitated the targeting of novel alterations such that the majority of NSCLC patients have driver mutations that are now clinically actionable. The goal of this review is to gain insights into clinical research and development principles by summary, analysis, and discussion of data on agents targeting known alterations in oncogene-driven, advanced NSCLC beyond those in the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK). A search of published and presented literature was conducted to identify prospective trials and integrated analyses reporting outcomes for agents targeting driver gene alterations (except those in EGFR and ALK) in molecularly selected, advanced NSCLC. Clinical efficacy data were extracted from eligible reports and summarized in text and tables. Findings show that research into alteration-directed therapies in oncogene-driven, advanced NSCLC is an extremely active research field. Ongoing research focuses on the expansion of new agents targeting both previously identified targets (particularly hepatocyte growth factor receptor (MET), human epidermal growth factor receptor 2 (HER2), and Kirsten rat sarcoma viral oncogene homolog (KRAS)) as well as novel, potentially actionable targets (such as neuregulin-1 (NRG1) and phosphatidylinositol 3-kinase (PI3K)). The refinement of biomarker selection criteria and the development of more selective and potent agents are allowing for increasingly specific and effective therapies and the expansion of clinically actionable alterations. Clinical advances in this field have resulted in a large number of regulatory approvals over the last 3 years. Future developments should focus on the continued application of alteration therapy matching principles and the exploration of novel ways to target oncogene-driven NSCLC.

While targeted therapies have transformed the treatment landscape of oncogene-addicted non-small cell lung cancer (NSCLC), the influence of sex on treatment outcomes remains insufficiently understood.

This systematic review aimed to investigate the impact of sex on clinical outcomes in patients with NSCLC harboring driver fusions treated with targeted therapies enrolled in clinical trials.

A comprehensive literature search was conducted using PubMed, Embase, and relevant conference abstracts to identify phase III randomized and early clinical trials that reported sex-specific data, including progression-free survival (PFS), overall survival (OS), overall response rate, and adverse events (AEs), in patients with fusion-positive NSCLC treated with tyrosine kinase inhibitors (TKIs).

This review involved 10 studies reporting PFS data and 3 studies with OS data, focusing on first-line treatments for ALK fusion (9 studies) and RET fusion-positive (1 study) NSCLC. Pooled analysis of hazard ratios (HRs) for PFS and OS in ALK inhibitors trials revealed no significant differences in survival outcomes based on sex. Additionally, none of the studies provided data on sex-based differences in response rates or toxicities, highlighting a significant knowledge gap regarding the impact of sex on secondary outcomes in targeted therapy.

This review found no significant sex-related differences in survival outcomes among patients treated with ALK inhibitors. However, the lack of data on sex-specific response and toxicity emphasizes the need for future research to better understand the role of sex in modulating treatment outcomes and treatment decisions with TKIs.