Jordyn Sava 

Using a 14-gene test to guide chemotherapy significantly improved disease-free survival in patients with early nonsquamous lung cancer.

Among patients with stage 1a to 2a nonsquamous non–small cell lung cancer (NSCLC) identified as high risk by a 14-gene molecular assay who received adjuvant chemotherapy, the interim analysis of the international AIM-HIGH trial revealed a substantial improvement in disease-free survival (DFS) at 24 months, according to data presented at the 2025 ASCO Annual Meeting.

At 24 months, 96% of patients in the chemotherapy arm were alive without disease progression compared with 79% in the observation arm.

A similar improvement in DFS was observed in patients with stage 1a disease. In the chemotherapy arm, 98% of patients were alive without disease progression versus 78% in the observation arm.

"This is the first prospective randomized trial to show improvement in disease-free survival with a molecular risk discriminator in stage 1a through 2a nonsquamous non–small cell lung cancer,” Dr. David Spigel, said during the presentation. “Interim analysis was designed to detect a large discrepancy in outcomes between treated and untreated patients."

Disease-free survival (DFS): time a patient lives without signs of cancer after treatment.

Adjuvant chemotherapy: additional treatment given after surgery to lower the risk of cancer returning.

RiskReveal: a 14-gene test that evaluates lung cancer tumors to predict risk of early recurrence.

ECOG performance status: scale used to assess a patient’s ability to perform daily activities.

Spigel, chief scientific officer at Sarah Cannon Research Institute in Nashville, Tennessee, who presented the findings, highlighted the need for improved outcomes in early-stage NSCLC, noting that the 5-year DFS for even stage 1a disease remains under 65%, contributing to over 100,000 deaths worldwide. While adjuvant therapy is common in later stages, it is not typically recommended for stage 1a and often deferred in stages 1b and 2a.

“RiskReveal is a 14-gene lung cancer assay that examines the gene expression profile for nonsquamous non–small cell lung cancer and is used to identify patients at high risk of early disease. This assay has been prospectively validated in over 1400 patients with nonsquamous non–small cell lung cancer. Identifying patients who are at highest risk of recurrence is a priority in the treatment of non–small cell lung cancer,” Spigel explained.

The AIM-HIGH trial enrolled patients aged 18 years and older with completely resected stage 1a, 1b or 2a nonsquamous NSCLC. Following surgery, tumor tissue was analyzed using a commercially available 14-gene prognostic assay to identify patients at high or intermediate risk of early recurrence. Patients identified as low risk were not included in the study.

The trial randomized high-risk patients to either observation (the standard of care) or four cycles of platinum-based doublet chemotherapy per local standards. Immunotherapy and tyrosine kinase inhibitors were permitted at the investigator's discretion for appropriate patients.

The primary end point of the study was DFS, with routine CT scans and surveillance conducted for 5 years or until recurrence or death.

The interim analysis, which led to early stopping of the trial by the independent data safety monitoring board due to the significant difference observed, included 89 patients in the adjuvant chemotherapy arm and 111 patients in the control arm. Baseline characteristics, including gender, smoking history (predominantly former or current smokers), ECOG performance status (0 or 1), and stage of cancer (1a, 1b, 2a), were well balanced between the two arms.

Specifically, the median age of patients in the adjuvant chemotherapy arm was 63 years versus 66 in the observation arm, 47% of patients in both arms were female, 90% and 86% had a history of smoking, 67% and 65% had an ECOG performance status of 0, 31% and 34% had an ECOG performance status of 1, and 1% in each arm had an unknown ECOG performance status, respectively. A total of 97% of patients in the adjuvant chemotherapy arm had a histology of adenocarcinoma versus 93% in the control arm, and most patients had stage 1b disease (39% versus 41%).

The types of resections (primarily lobectomy) and the choice of adjuvant chemotherapy regimens were also balanced. The side effects observed in the chemotherapy arm were also consistent with the known profiles of platinum-based doublet chemotherapy.

Spigel concluded that the AIM-HIGH trial demonstrated that utilizing this 14-gene assay to precisely direct systemic adjuvant therapy in stage 1a through 2a nonsquamous NSCLC has the potential to substantially reduce the rates of early recurrence and death.

“Utilization of this 14-gene assay to precisely direct systemic adjuvant therapy in stage 1a through 2a nonsquamous non–small cell lung cancer may substantially reduce the rates of early recurrence and death,” Spigel said.

"An international, multicenter, prospective randomized trial of adjuvant chemotherapy for stage 1A-2A non-small cell lung cancer identified as high risk by a 14-gene molecular assay" by Dr. David Spigel, et al., American Society of Clinical Oncology Annual Meeting.

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Articles

The AIM-HIGH trial demonstrated significant improvement in disease-free survival (DFS) for high-risk stage 1a to 2a nonsquamous non-small cell lung cancer (NSCLC) patients identified by a 14-gene molecular assay who received adjuvant chemotherapy. At 24 months, 96% of chemotherapy patients were alive without disease progression, compared to 79% in the observation group. This trial is the first to show DFS improvement using a molecular risk discriminator in early-stage NSCLC, highlighting the potential of targeted adjuvant therapy to reduce early recurrence and mortality rates.


Using a 14-gene test to guide chemotherapy significantly improved disease-free survival in patients with early nonsquamous lung cancer.


Targeted Chemo Improves Survival in Early-Stage Lung Cancer

Patritumab deruxtecan doesn't improve OS vs chemotherapy in EGFR+ advanced/metastatic NSCLC: © stock.adobe.com.

Among patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC), patritumab deruxtecan (HER3-DXd) treatment did not improve overall survival outcomes compared with platinum-based chemotherapy treatment, according to data from the phase 3 HERTHENA-Lung02 study which were shared at the 

The median overall survival was 16.0 months in the patritumab deruxtecan arm versus 15.9 months in the chemotherapy arm. The median follow-up was 18.7 versus 18.6 months in the two arms, respectively.

Based on these overall survival data, Merck previously withdrew its biologics license application seeking FDA approval of patritumab deruxtecan for use in this setting.

Previously reported results from the primary analysis of the HERTHENA-Lung02 trial showed that patritumab deruxtecan significantly reduced the risk of disease progression or death versus chemotherapy. The median progression-free survival was 5.8 months with patritumab deruxtecan versus 5.4 months with chemotherapy. The nine-month probability of progression-free survival was 29% versus 19%, respectively. The progression-free survival benefit was sustained across most subgroups, including those defined by age, sex, geographic region, brain metastases at baseline, smoking status and ECOG performance score.

The confirmed objective response rate was 35.2% with patritumab deruxtecan versus 25.3% with chemotherapy. The disease control rate was 80.5% with patritumab deruxtecan versus 75.8% with chemotherapy. The median time to response was 1.5 months in each arm and the median duration of response was about 5.5 months in both arms.

Intracranial efficacy was evaluated in 105 and 95 patients in the treatment and control arms, respectively. The median intracranial response was 5.4 versus 4.2 months, respectively. The confirmed intracranial objective response rate was 19.0% and 11.6% in the two arms, respectively. The intracranial complete response rate was 12.4% versus 4.2% and the intracranial disease control rate was 68.6% and 61.1%, respectively. The median intracranial time to response and median intracranial duration of response were 2.1 versus 2.6 months and 4.5 versus 4.2 months, respectively.

The safety evaluable population included 290 and 280 patients in the patritumab deruxtecan and chemotherapy arms, respectively. The investigators considered the toxicities to be generally manageable and similar to prior research with the study treatments. Grade 3 (severe) or higher treatment-related side effects occurred in 57.9% versus 46.1% of the treatment and control arms, respectively. Serious treatment-related side effects were reported for 22.4% versus 12.5% of the two arms, respectively. There were four treatment-related side effect-linked deaths in the patritumab deruxtecan arm compared with one in the chemotherapy arm. Of note, the incidence of adjudicated interstitial lung disease was 5.2% for the patritumab deruxtecan arm.

HERTHENA-Lung02 Design and Patient Characteristics

The open-label phase 3 HERTHENA-Lung02 trial enrolled patients with locally advanced or metastatic NSCLC harboring an EGFR mutation. Patients had to have disease progression after received one or two prior lines of an U.S. Food and Drug-approved EGFR TKI, including a third-generation TKI.

Patient characteristics were well balanced between the patritumab deruxtecan (n = 293) and chemotherapy (293 patients) arms. The median age across both arms was 64 years (range, 34-86), about 60% of patients were female, and about 60% of patients were Asian. Just under two-thirds of patients were never-smokers, and the median time since initial diagnosis was 24.2 months (range, 2.5-146.1). About two-thirds of patients had an ECOG performance score of one, with the remainder having an ECOG performance score of zero. About 44% of patients had a history of brain metastasis, with about one-third having brain metastases at baseline.

The approximate breakdown of EGFR activating mutations was 60% with Ex19del, 39% with L858R, and 1% with dual Ex19del and L858R. Regarding prior EGFR TKIs, three-fourths of patients had previously received only third-generation EGFR TKIs, while one-fourth had received both third- and first/second-generation TKIs. Over 90% of patients had prior Tagrisso (osimertinib).

Patients received patritumab deruxtecan at 5.6 mg/kg (IV) every three weeks or platinum-based chemotherapy. Chemotherapy consisted of four cycles of pemetrexed plus either cisplatin or carboplatin, followed by optional maintenance pemetrexed in patients whose disease did not progress after the initial four combination cycles.

Progression-free survival per blinded independent central review was the primary end point, with secondary end points consisting of overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, clinical benefit rate, disease control rate, time to response, intracranial progression-free survival, quality of life and safety.

Regarding next steps, study investigators said, “Evaluation of the association of biomarkers, including HER3 IHC, with efficacy parameters in HERTHENA-Lung02 and their suitability as a predictive biomarker is ongoing.”

Mok T, Yu H, Lim SM, Patritumab deruxtecan (HER3-DXd) in resistant EGFR-mutated (EGFRm) advanced non-small cell lung cancer (NSCLC) after a third-generation EGFR TKI: The phase 3 HERTHENA-Lung02 study. 

. 2025;43(suppl 17):8506. doi: 10.1200/JCO.2025.43.16_suppl.8506

Patritumab deruxtecan did not improve overall survival compared to platinum-based chemotherapy in EGFR mutation-positive NSCLC patients, as shown in the HERTHENA-Lung02 study. Despite a slight progression-free survival advantage, Merck withdrew its FDA application for the drug. The study highlighted a higher objective response rate and disease control rate with patritumab deruxtecan, but also noted increased severe side effects. The trial included patients with prior EGFR TKI treatment, and further biomarker analysis is ongoing to assess predictive efficacy.

Patritumab deruxtecan treatment did not improve suvival end points versus those treated with chemotherapy in EGFR+ advanced/metastatic NSCLC.

Patritumab Deruxtecan Does Not Improve Survival Outcomes vs Chemo in EGFR+ NSCLC 

Padcev plus Keytruda showed promising clinical activity in UTUC lesions, with a 35% ORR in measurable lesions and an 87.5% disease control rate in primary tumors.

Among patients with upper tract urothelial carcinoma (UTUC) lesions, the combination of Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) resulted in promising clinical activity, study results have shown.

Results from a small retrospective analysis were shared in a poster at the 2025 ASCO Genitourinary Cancers Symposium.

The study, conducted by a team of researchers from the Johns Hopkins Departments of Medical Oncology and Urology, showed that in primary lesions for 16 patients treated with Padcev alone or Padcev plus Keytruda, the overall response rate (ORR) was 25% (four patients), consisting of all partial responses. Primary lesions for an additional 10 patients showed stable disease, for a disease control rate of 87.5% (14 patients). Two patients had progressive disease.

Among all patients with measurable target lesions at baseline (20 patients) the ORR was 35% (seven patients), consisting of all partial responses. An additional seven patients had stable disease for a disease control rate of 70% (14 patients). Six patients had progressive disease.

Overall response rate: Patients in a clinical trial who responded partially or completely to treatment.

In describing the rationale for their retrospective study, the authors explained that patients with UTUC are often ineligible for standard perioperative care with cisplatin due to renal dysfunction related to disease and surgery. They added that, “Given the unprecedented activity of [Padcev] plus [Keytruda] [previously demonstrated] in advanced urothelial carcinoma, and safety in impaired renal function, the assessment of this combination in earlier disease settings for patients with UTUC is an urgent need.”

For their analysis, the researchers included patients with intact primary UTUC tumors who had received single-agent Padcev or Padcev plus Keytruda at Johns Hopkins. They collected baseline patient characteristics through chart review. The study parameters defined primary tumor as any lesion located in the ureter and/or renal pelvis.

The researchers identified 50 patients with UTUC treated with Padcev alone or Padcev plus Keytruda at Johns Hopkins between December 2017 and June 2024. Of these patients, 22 had intact primary tumors and were thus included in the retrospective analysis. Baseline characteristics showed that the median patient age was 72 years, 59% (13 patients) were male, and 77.3% (17 patients) were White. Tumor analysis showed that 86.4% of patients (19 patients) had pure urothelial histology and 81.8% of patients (18 patients) had visceral metastases.

Of the 22 patients with intact primary tumors, 59.1% (13 patients) received Padcev alone and 40.9% (nine patients) received Padcev plus Keytruda. Three patients began their Padcev regimen at a reduced dose. The median number of Padcev cycles received was four. The median treatment duration was 3.3 months.

The combination of Padcev and Keytruda is currently approved by the FDA for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

In their conclusion, the researchers wrote, “Larger prospective studies are needed to assess the efficacy of this promising regimen in the perioperative setting for patients with this rare and aggressive disease.”

Primary tumor response to enfortumab vedotin with/without pembrolizumab in patients with upper tract urothelial cancer, by Dr. Evangelia Vlachou, et al., 

A retrospective analysis of patients with upper tract urothelial carcinoma (UTUC) treated with Padcev (enfortumab vedotin) and Keytruda (pembrolizumab) demonstrated promising clinical activity. The study, conducted by Johns Hopkins researchers, revealed a 25% overall response rate (ORR) in primary lesions and a 35% ORR in measurable target lesions. The disease control rate was 87.5% for primary lesions and 70% for target lesions. The study highlights the potential of this combination therapy for patients ineligible for standard cisplatin-based care due to renal dysfunction.

Results from a small retrospective analysis of patients with upper tract urothelial carcinoma lesions were shared at the 2025 ASCO Genitourinary Cancers Symposium.

Padcev Plus Keytruda Shows Promise for Upper Tract Urothelial Carcinoma Lesions

Talzenna plus Xtandi improved overall survival in HRR-deficient mCRPC by 14 months and reduced death risk by 38%, per TALAPRO-2 trial data.

Among patients with metastatic castration-resistant prostate cancer (mCRPC), new final overall survival (OS) data from the TALAPRO-2 trial confirm that the combination of Talzenna (talazoparib) plus Xtandi (enzalutamide) provides a significant survival benefit, according to findings presented at the 

The trial demonstrated an 8.8-month improvement in median OS, with the combination therapy extending survival to 45.8 months compared with 37 months with Xtandi alone, representing a 20.4% reduction in the risk of death.

Patients with homologous recombination repair (HRR)-deficient tumors had an even greater 38% reduction in the risk of death, translating to a 14-month OS improvement. In this group, the median OS with Talzenna plus Xtandi was 45.1 months and 31.1 months in the placebo and Xtandi arm. However, the benefit extended beyond patients who were HRR-deficient, as those without DNA repair mutations also saw an OS gain of approximately nine months.

“TALAPRO-2 is the first PARP inhibitor plus [androgen receptor pathway inhibitor (ARPI)] combination study to show not only a statistically significant, but also a clinically meaningful improvement in overall survival in patients with metastatic CRPC in unselected and in HRR-deficient [patients],” Dr. Neeraj Agarwal, FASCO, professor of medicine, Presidential Endowed Chair of Cancer Research, director, the Genitourinary Oncology Program, the Center of Investigational Therapeutics, the Huntsman Cancer Institute (HCI), University of Utah.

ECOG performance status of 1 or lower: patients are fully active (0) or restricted in strenuous activity but ambulatory and able to perform light work (1).

Overall survival (OS): time from treatment initiation to death from any cause.

Metastasis: spread of cancer from the primary site to distant organs.

Castration-resistant: prostate cancer that progresses despite androgen deprivation therapy.

HRR-deficient: tumors with homologous recombination repair gene mutations, affecting DNA repair.

PARP inhibitor plus androgen receptor pathway inhibitor (ARPI): combination therapy targeting DNA repair and androgen signaling in prostate cancer.

Radiographic progression-free survival (rPFS): time until radiographic disease progression or death.

Looking at OS in subgroups of patients with no alterations detected by both circulating tumor DNA and tumor tissue, those with no BRCA alterations detected had a median OS of 48.4 months in the Talzenna and Xtandi arm and 37.1 months in the placebo and Xtandi arm. For those with no HRR alterations detected, the median OS in the Talzenna plus Xtandi arm was 46.6 months and 37.4 months for those given placebo and Xtandi.

In patients with BRCA1/2 alterations, the median OS was not reached in the Talzenna plus Xtandi arm versus 28.5 months in the placebo plus Xtandi arm. For those with non-BRCA1/2 HRR alterations, the median OS was 42.4 versus 32.6 months.

The trial’s primary end point, radiographic progression-free survival (rPFS), also saw a substantial improvement. Patients receiving Talzenna plus Xtandi had a median rPFS of 33.1 months, compared with 19.5 months with Xtandi alone.

In the HRR-deficient cohort, patients given Talzenna plus Xtandi had a median rPFS of 30.7 months, compared with 12.3 months with Xtandi alone.

For safety, there were no new safety signals seen after an additional two years of follow-up in either patient population. While grade 3 (severe) or 4 (life-threatening) anemia was the most common side effect, occurring in 49% of patients in the unselected population and 43.4% in the HRR-deficient population, it was largely manageable with dose adjustments. Patients also reported that their quality of life was maintained, even with the extended treatment duration.

In the unselected patient population, the rate of discontinuation due to side effects was 21.6%, which was similar to that seen in the primary analysis, and 8.5% of patients discontinued Talzenna treatment due to anemia. In the HRR-deficient population, the rate of discontinuation of Talzenna due to side effects was 13.1% and 4.5% of patients discontinued treatment due to anemia.

Overall, these data support the broad use of this combination in both HRR-deficient and non-deficient populations.

“We are very encouraged, very happy with these results and also there were no safety signals seen. So, we really hope this combination makes a difference in our patients lives,” added Agarwal.

The phase 3, double-blind, placebo-controlled TALAPRO-2 trial was designed to test whether combining the PARP inhibitor Talzenna with Xtandi could provide longer-lasting disease control and improve survival outcomes in patients with HRR gene-mutated mCRPC compared with placebo plus Xtandi.

Male patients aged 18 and older were eligible to enroll in the study if they had progressive disease at study entry, an ECOG performance status of 1 or lower, and a life expectancy of at least 12 months. Those who had been previously treated with a second-generation ARPI, PARP inhibitor, cyclophosphamide or mitoxantrone for prostate cancer; clinically significant cardiovascular disease; or significant renal or hepatic dysfunction were ineligible for participation.

A total of 805 patients were randomly assigned in cohort 1 to receive Talzenna 0.5 milligrams (mg) with Xtandi 160 mg per day (402 patients) or placebo and Xtandi 160 mg per day (403 patients). Randomization was stratified by HRR gene alteration status. The study’s primary end point was rPFS.

One hundred percent of patients underwent prospective tumor tissue testing before enrollment. In this cohort, 20% of patients were found to have HRR alterations. For specific gene alterations, BRCA1, BRCA2, ATM and CDK12 mutations were evenly distributed between the treatment arms. Notably, BRCA1 and BRCA2 alterations were present in approximately 7% of patients.

In June 2023, the Xtandi combination for the treatment of HRR gene-mutant mCRPC, supported by data from TALAPRO-2. The data the FDA considered at the time showed that the combination led to a 55% reduction in the risk of disease progression or death. The median rPFS at the time was not reached with Talzenna and Xtandi versus 21.9 months with placebo plus Xtandi.

“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line (1L) treatment in patients (pts) with homologous recombination repair (HRR)-deficient metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial.” By Dr. Karim Fizazi, et al. 

“Final overall survival (OS) with talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 TALAPRO-2 trial,” by Dr. Neeraj Agarwal et al. 

“Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial,” by Dr. Neeraj Agarwal, et al. 

For more news on cancer updates, research and education,

don’t forget to subscribe to CURE®’s newsletters here.

The TALAPRO-2 trial demonstrated that combining Talzenna (talazoparib) with Xtandi (enzalutamide) significantly improves overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). The combination therapy extended median OS by 8.8 months compared to Xtandi alone, with a notable 20.4% reduction in the risk of death. Patients with homologous recombination repair (HRR)-deficient tumors experienced even greater benefits. The trial also showed improved radiographic progression-free survival (rPFS) and manageable safety profiles, supporting the combination's use in both HRR-deficient and non-deficient populations.

Patients with HRR-deficient metastatic castration-resistant prostate cancer experienced a 14-month gain in OS and a 38% lower death risk with Talzenna plus Xtandi.

Jordyn Sava

Targeted Chemo Improves Survival in Early-Stage Lung Cancer

Patritumab Deruxtecan Does Not Improve Survival Outcomes vs Chemo in EGFR+ NSCLC

Padcev Plus Keytruda Shows Promise for Upper Tract Urothelial Carcinoma Lesions

Talzenna Plus Xtandi May Improve Survival in mCRPC

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