Transforming the oncology data paradigm by creating, capturing, and retrieving structured cancer data at the point of care: A Mayo Clinic pilot.

INTRODUCTION: Structured data capture requires defined languages such as minimal Common Oncology Data Elements (mCODE). This pilot assessed the feasibility of capturing 5 mCODE categories (stage, disease status, performance status (PS), intent of therapy and intent to change therapy). METHODS: A tool (SmartPhrase) using existing and custom structured data elements was Built to capture 4 data categories (disease status, PS, intent of therapy and intent to change therapy) typically documented as free-text within notes. Existing functionality for stage was supported by the Build. Participant survey data, presence of data (per encounter), and time in chart were collected prior to go-live and repeat timepoints. The anticipated outcome was capture of >50% sustained over time without undue burden. RESULTS: Pre-intervention (5-weeks before go-live), participants had 1390 encounters (1207 patients). The median percent capture across all participants was 32% for stage; no structured data was available for other categories pre-intervention. During a 6-month pilot with 14 participants across three sites, 4995 encounters (3071 patients) occurred. The median percent capture across all participants and all post-intervention months increased to 64% for stage and 81%-82% for the other data categories post-intervention. No increase in participant time in chart was noted. Participants reported that data were meaningful to capture. CONCLUSIONS: Structured data can be captured (1) in real-time, (2) sustained over time without (3) undue provider burden using note-based tools. Our system is expanding the pilot, with integration of these data into clinical decision support, practice dashboards and potential for clinical trial matching.

Plain language summary of PAPILLON: amivantamab plus chemotherapy in untreated EGFR-mutated non-small-cell lung cancer.

What is this summary about? This is a plain language summary of an article that describes the first results of the phase 3 PAPILLON study in patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with Exon 20 insertion (Ex20ins) mutations in the epidermal growth factor receptor (EGFR) gene who had not had any cancer treatment before. Researchers looked at how safe and effective the bispecific antibody amivantamab (brand name: RYBREVANT^®) plus chemotherapy was in comparison to chemotherapy alone.Amivantamab was approved by the US Food and Drug Administration (FDA) in May 2021 for patients with the same type of cancer who got worse after chemotherapy. In March 2024, amivantamab was approved in combination with chemotherapy for previously untreated patients with the same type of cancer. The National Comprehensive Cancer Network^® (NCCN^®) recommends amivantamab plus chemotherapy as a preferred first treatment option for these patients.What were the results? 308 patients were randomly selected to receive amivantamab plus chemotherapy or chemotherapy alone. Patients who received amivantamab plus chemotherapy lived longer without having their disease get worse compared to those who had chemotherapy. Patients who had amivantamab plus chemotherapy also had the risk of their disease getting worse or dying reduced by 60% compared to chemotherapy. After 18 months of treatment, 31% of patients on amivantamab plus chemotherapy did not have their cancer grow or spread compared to 3% with chemotherapy. More than 7 in 10 patients who had amivantamab plus chemotherapy had tumors that shrank by at least 30% or were no longer detectable. This only happened in less than 5 in 10 patients who had chemotherapy alone.All patients had side effects, with the most common being neutropenia (occurring in 59% of patients), paronychia (56%), and rash/red skin bumps (54%/31%) for those treated with amivantamab plus chemotherapy, and anemia (55%), neutropenia (45%), and nausea (42%) for those treated with chemotherapy. Few patients (7%) stopped taking amivantamab due to side effects.What do the results mean? Amivantamab plus chemotherapy worked well to extend the time that patients' cancer did not worsen. Patients had a 60% lower risk of death or having their cancer worsen compared to those who had chemotherapy. These benefits were seen in groups of patients with different characteristics.Amivantamab plus chemotherapy works well, is well tolerated, and is a good treatment option for untreated patients who have advanced NSCLC with EGFR Ex20ins mutations.

Ki-67 Proliferation Index Is Associated With Tumor Grade and Survival in Pleural Epithelioid Mesotheliomas.

Pleural epithelioid mesothelioma (PEM) is divided into low and high grades based on nuclear atypia, mitoses, and necrosis in the tumor. Assessing mitoses and nuclear atypia tend to be labor-intensive with limited reproducibility. Ki-67 proliferation index was shown to be a prognostic factor in PEM, but its performance has not been directly correlated with tumor grade or mitotic score. This study evaluated the potential of Ki-67 index as a surrogate of tumor grade. We also compared the predictability of mitoses and Ki-67 index for overall survival (OS). Ninety-six PEM samples from 85 patients were identified from the surgical pathology file during 2000-2021 at our institution, and all glass slides were reviewed by 2 pulmonary pathologists to confirm the diagnosis and assign the tumor grade. Digital image analysis (DIA) was done for Ki-67 index. The agreement on tumor grading between 2 reviewers was moderate (kappa value = 0.47). The correlation between mitotic count (average count by 2 reviewers) and Ki-67 index was 0.65. The areas under the curve for predicting tumor grade by mitotic score and Ki-67 index were 0.84 and 0.74 (reviewer 1) and 0.85 and 0.81 (reviewer 2), respectively. High Ki-67 index and mitoses were significantly associated with poor OS ( P =0.03 and 0.0005, using 30% and 10/2 mm 2 as cutoffs, respectively). In conclusion, Ki-67 index by DIA was associated with tumor grade as well as mitotic count, and its predictability for OS was comparable to that of mitotic score, thus being a potential surrogate for tumor grade.

Impact of EML4-ALK Variants and Co-Occurring TP53 Mutations on Duration of First-Line ALK Tyrosine Kinase Inhibitor Treatment and Overall Survival in ALK Fusion-Positive NSCLC: Real-World Outcomes From the GuardantINFORM database.

INTRODUCTION: Tyrosine kinase inhibitors (TKIs) are first-line treatment options for ALK-positive (ALK+) NSCLC. Factors such as variant allele frequencies (VAFs), EML4-ALK fusion variant, and concurrent TP53 mutations (TP53mt) in circulating tumor DNA (ctDNA) may affect treatment outcomes. We evaluated their effects on time to discontinuation (TTD) of first-line treatment with next-generation ALK TKIs in a real-world setting. METHODS: Adults with advanced or metastatic NSCLC and ctDNA-detected ALK fusion who received first-line next-generation ALK TKI monotherapy were identified in GuardantINFORM. Effects of ALK fusion VAF, EML4-ALK variants, and TP53mt detection on TTD were evaluated. RESULTS: A total of 307 patients with ALK fusion in baseline ctDNA received first-line alectinib (n = 280), brigatinib (n = 15), lorlatinib (n = 9), or ceritinib (n = 3); 150 patients (49%) had ALK-fusion VAF greater than or equal to 1%. Among 232 patients with EML4-ALK fusions (v1, 50%; v3, 36%), TP53mt co-occurred with v1 in 42 (18%) and v3 in 32 (14%). Patients with VAF less than 1% versus greater than or equal to 1% had a median TTD of 32.2 (95% confidence interval [CI]: 20.7-not estimable [NE]) versus 14.7 months (10.4-19.9; hazard ratio [HR] = 1.57 [95% CI: 1.09-2.26]; p = 0.0146). Median TTD was 13.1 (9.5-19.9) versus 27.6 months (17.3-NE) in patients with versus without TP53mt detected (HR = 1.53 [1.07-2.19]; p = 0.0202) and 20.3 (14.4-NE) versus 11.5 months (7.4-31.1) in patients with v1 versus v3 (HR = 1.29 [0.83-2.01]; p = 0.2641). Patients with TP53mt and v3 had a median TTD of 7.4 months (95% CI: 4.2-31.1). CONCLUSION: High ctDNA VAF, EML4-ALK v3, and TP53mt were associated with early discontinuation of first-line ALK TKIs.

Senescent fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity.

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identified senescent p16 Ink4a + cancer-associated fibroblasts with a secretory phenotype that promotes fatty acid uptake and utilization by aggressive lung adenocarcinoma driven by Kras and p53 mutations. Furthermore, rewiring of lung cancer metabolism by p16 Ink4a + cancer-associated fibroblasts also altered tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identified XL888, a HSP90 inhibitor, that cleared p16 Ink4a + cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced lung adenocarcinoma significantly reduced tumor burden concurrent with the loss of plastic tumor cells. Our study identified a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

Leveraging the pleural space for anticancer therapies in pleural mesothelioma.

Most patients with pleural mesothelioma (PM) present with symptomatic pleural effusion. In some patients, PM is only detectable on the pleural surfaces, providing a strong rationale for intrapleural anticancer therapy. In modern prospective studies involving expert radiological staging and specialist multidisciplinary teams, the population incidence of stage I PM (an approximate surrogate of pleura-only PM) is higher than in historical retrospective series. In this Viewpoint, we advocate for the expansion of intrapleural trials to serve these patients, given the paucity of data supporting licensed systemic therapies in this setting and the uncertainties involved in surgical therapy. We begin by reviewing the unique anatomical and physiological features of the PM-bearing pleural space, before critically appraising the evidence for systemic therapies in stage I PM and previous intrapleural PM trials. We conclude with a summary of key challenges and potential solutions, including optimal trial designs, repurposing of indwelling pleural catheters, and new technologies.

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.

PURPOSE: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial.

Importance: Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. Objective: To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. Design, Setting, and Participants: This was a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. Intervention: Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8 mg/m2) or placebo. All patients received intravenous pemetrexed (500 mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. Main Outcomes and Measures: The primary end point was overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. Results: Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95% CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95% CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95% CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (95% CI, 5.8-7.4 months) with pegargiminase-chemotherapy as compared with 5.6 months (95% CI, 4.1-5.9 months) with placebo-chemotherapy (HR, 0.65; 95% CI, 0.46-0.90; P = .02). Grade 3 to 4 adverse events with pegargiminase occurred in 36 patients (28.8%) and with placebo in 21 patients (16.9%); drug hypersensitivity and skin reactions occurred in the experimental arm in 3 patients (2.4%) and 2 patients (1.6%), respectively, and none in the placebo arm. Rates of poststudy treatments were comparable in both arms (57 patients [45.6%] with pegargiminase vs 58 patients [46.8%] with placebo). Conclusions and Relevance: In this randomized clinical trial of arginine depletion with pegargiminase plus chemotherapy, survival was extended beyond standard chemotherapy with a favorable safety profile in patients with nonepithelioid pleural mesothelioma. Pegargiminase-based chemotherapy as a novel antimetabolite strategy for mesothelioma validates wider clinical testing in oncology. Trial Registration: ClinicalTrials.gov Identifier: NCT02709512.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

The Timing, Trajectory, and Incidence of Immune-Related Adverse Events in NSCLC Treated With Atezolizumab.

Introduction: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors can have complicated clinical courses. We comprehensively evaluated the timing, trajectory, and incidence of both single and multiple irAEs for NSCLC treated with atezolizumab. Methods: Data were pooled from 2457 patients who participated in the IMpower130, IMpower132, and IMpower150 clinical trials investigating the use of atezolizumab in metastatic NSCLC as part of a chemoimmunotherapy regimen. Longitudinal irAE data with landmark analysis, time-to-onset, changes in grading severity, and occurrence of multiple events were summarized. Results: In general, 1557 patients were treated with atezolizumab and 900 patients were in the control groups. Median follow-up was 32.3 and 23.5 months, respectively. In the atezolizumab group, 753 patients (48.4%) experienced at least one irAE. In the control group, 289 patients (32.1%) experienced at least one nonimmune adverse event that was attributed to an irAE. In the atezolizumab group, the most common irAEs were rash, hepatitis, and hypothyroidism. Furthermore, 13% of the patients experienced two irAEs and 4% experienced three irAEs. Within 5 months of treatment, the cumulative incidence for any irAE was 39.2%. Median time-to-onset varied from 1 to 10 months based on the specific irAE. Grade 1 to 2 irAEs increased in severity for 33% of the patients. Conclusions: We identified dynamic clinical patterns for irAEs in patients treated with atezolizumab, including variations in time-to-onset, incidence of multiple irAEs, and frequency of irAEs increasing in severity. These results can guide clinical management and future reporting of adverse events to enable comprehensive longitudinal analyses.