Kristi Rosa

Ivonescimab plus chemotherapy significantly improved progression-free survival versus Tevimbra advanced squamous non–small cell lung cancer.

Ivonescimab combined with chemotherapy significantly improved progression-free survival (PFS) compared with Tevimbra (tislelizumab-jsgr) plus chemotherapy in patients with advanced squamous non–small cell lung cancer (NSCLC), according to results from the phase 3 HARMONi-6 study presented at the 

The median PFS was 11.14 months with ivonescimab plus chemotherapy (266 patients) versus 6.9 months with versusTevimbra plus chemotherapy (266 patients), representing a 40% reduction in the risk of disease progression or death. The PFS benefit favored ivonescimab plus chemotherapy across all key subgroups.

“Ivonescimab plus chemotherapy showed meaningful efficacy with a manageable safety profile and may represent a new standard of care for advanced squamous NSCLC,” Dr. Shun Lu, of Shanghai Chest Hospital, said during a presidential symposium.
The multicenter, double-blind, parallel-controlled study enrolled patients with pathologically confirmed stage 3 or 4 squamou
s NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had no prior systemic therapy and no EGFR mutations or ALK rearrangements.

Participants (532 patients) were randomly assigned 1:1 to receive ivonescimab 20 mg/kg every 3 weeks or versusTevimbra 200 mg every 3 weeks plus carboplatin at area under the curve 5 and paclitaxel 175 mg/m2 every 3 weeks for up to 4 cycles, followed by ivonescimab or versusTevimbra every 3 weeks for up to 24 months or until intolerable toxicity.
The primary end point was PFS by independent radiology review committee assessment using RECIST 1.1 criteria. Secondary end points included overall survival, investigator-assessed PFS, objective response rate, disease control rate, duration of response, time to response, and safety.

Baseline characteristics were balanced between arms. Most patients were male, current or former smokers, and had stage 4 disease. PD-L1 tumor proportion scores varied across arms, and a subset had three or more metastatic sites, liver metastases, or brain metastases.

Ivonescimab demonstrated PFS benefit across all PD-L1 subgroups. In all patients, the objective response rate by independent review was 75.9% with ivonescimab versus 66.5% with versusTevimbra. Median duration of response was 11.2 months versus 8.38 months.

Treatment-related side effects occurred in 99.2% of patients receiving ivonescimab versus 98.5% with versusTevimbra. Grade 3 or higher side effects occurred in 63.9% versus 54.3%. Serious side effects occurred in 32.3% versus 30.2%. Most common side effects included alopecia, anemia, decreased neutrophil count, decreased white blood cell count, hypoesthesia, proteinuria, nausea, and fatigue. Immune-related side effects were reported in 27.4% versus 25.3% of patients.

Ivonescimab-related side effects potentially linked to vascular endothelial growth factor inhibition occurred more frequently and were mostly grade 1 or 2, including proteinuria, hemorrhage, hypertension, arterial thromboembolism, venous thromboembolism, and fistula.

“Dr. Myung-Ju Ahn, noted that ivonescimab plus chemotherapy demonstrates clinically meaningful PFS and objective response rate across PD-L1 subgroups, with a low rate of hemorrhage in a high-risk population,” she said. Key unanswered questions include real-world application, translation of PFS benefit to overall survival, need for mature overall survival and quality-of-life data, angiogenic and immune biomarker evaluation, and global validation across diverse populations.

In summary, the findings from the phase 3 HARMONi-6 study highlight the potential of ivonescimab combined with chemotherapy as a highly effective first-line treatment option for patients with advanced squamous NSCLC. The combination demonstrated a substantial improvement in PFS compared with Tevimbra plus chemotherapy, showing consistent benefits across PD-L1 subgroups and supporting its activity in a high-risk population.

While the safety profile was manageable and largely consistent with expectations for chemotherapy and immunotherapy, some side effects were observed more frequently with ivonescimab, though most were low grade.

"Phase III study of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small cell lung cancer (HARMONi-6)," Dr. Shun Lu, et al. Presented at: 2025 ESMO Congress; October 17-25, 2025; Berlin, Germany. Abstract LBA4.

Ivonescimab in combination with chemotherapy demonstrates statistically significant and strongly positive results in first-line treatment of squamous non-small cell lung cancer (sq-NSCLC) vs. tislelizumab in combination with chemotherapy. News Release. Akeso. April 23, 2025. Accessed October 19, 2025. https://www.akesobio.com/en/media/akeso-news/250423/

AK112 in combination with chemotherapy in advanced squamous non-small cell lung cancer. ClinicalTrials.gov. May 2, 2025. Accessed October 19, 2025. https://clinicaltrials.gov/study/NCT05840016

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Articles

Ivonescimab combined with chemotherapy significantly improved progression-free survival (PFS) in patients with advanced squamous non-small cell lung cancer (NSCLC) compared to Tevimbra plus chemotherapy, as demonstrated in the phase 3 HARMONi-6 study. The median PFS was 11.14 months with ivonescimab versus 6.9 months with Tevimbra, indicating a 40% reduction in disease progression or death risk. Ivonescimab showed consistent benefits across PD-L1 subgroups and a manageable safety profile, suggesting its potential as a new standard of care for advanced squamous NSCLC.

Ivonescimab Combo Improves Progression-Free Survival in Advanced NSCLC

Neoadjuvant Enhertu then THP improved pathological complete response rate in patients with high-risk, HER2-positive early breast cancer.

Among patients with high-risk, HER2-positive early breast cancer, presurgical, or neoadjuvant, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) followed by paclitaxel, Herceptin (trastuzumab) and Perjeta (pertuzumab, THP) was associated with an improvement in pathologic complete response (pCR) rate compared with dose-dense doxorubicin and cyclophosphamide plus THP (ddAC-THP), data from the phase 3 DESTINY-Breast11 trial has shown.

Findings presented at the 2025 ESMO Congress demonstrated that patients treated with Enhertu followed by THP (321 patients) experienced a pCR rate of 67.3% compared with 56.3% for those given ddAC-THP (320 patients; difference, 11.2%). Notably, the pCR benefit was observed in the hormone receptor–positive population, where the pCR rate was 61.4% in the Enhertu arm (236 patients) versus 52.3% in the ddAC-THP arm (235 patients; difference, 9.1%), as well as the hormone receptor–negative population, where the respective pCR rates for the Enhertu arm (83 patients) and ddAC-THP arm (85 patients) were 83.1% and 67.1% (difference, 16.1%).

Glossary

Pathologic complete response (pCR): this means that when the doctors look at the removed tissue under a microscope, there are no signs of remaining invasive cancer.

Event-free survival (EFS): this is the length of time a person remains alive without their cancer coming back, getting worse, or developing a second cancer.

Pharmacokinetics: this is what your body does to a drug, which includes how the drug is absorbed, distributed, changed, and eventually removed.

Invasive disease-free survival: this is the time a person lives without the return of the invasive cancer or a second invasive cancer, and without death from any cause.

Overall survival: this refers to the percentage of people in a study who are still alive after a certain period of time.

Residual cancer burden (RCB): this is a measure that estimates how much cancer is left in the breast and lymph nodes after neoadjuvant treatment (treatment given before surgery).

ECOG performance status: this is a scale that doctors use to describe a patient's general well-being and how capable they are of performing ordinary daily tasks.

Interstitial lung disease (ILD): this is a group of lung disorders that cause scarring of the lungs, which can make it hard to breathe.

Left ventricular dysfunction: this is a condition where the main pumping chamber of the heart (the left ventricle) is not working as well as it should.

Increased transaminase levels: this is a sign of liver damage or injury that is detected by blood tests measuring the levels of certain liver enzymes.

Neutropenia: this is a condition in which a person has a low number of neutrophils, which are a specific type of white blood cell important for fighting infection.

Peripheral neuropathy: this refers to nerve damage outside of the brain and spinal cord, which can cause numbness, tingling, or pain, often in the hands or feet.

Anemia: this is a condition where your body does not have enough healthy red blood cells to carry adequate oxygen to your tissues, often leading to fatigue.

Stomatitis: this is a general term for inflammation or soreness inside the mouth, which can include mouth sores.

Leukopenia: this is a condition where a person has a low overall number of white blood cells, which can put them at a higher risk of infection.

“DESTINY-Breast11 showed the highest reported pCR rate in HER2-positive early breast cancer for a registrational study in the neoadjuvant setting, despite — if you want to do cross-trial comparisons — a high prevalence of hormone receptor–positive disease and a high-risk population,” lead study author Dr. Nadia Harbeck said in a presentation of the data.

Harbeck is director of the Breast Center and chair for Conservative Oncology at the Department of OB&GYN at LMU University Hospital in Munich, Germany.

How Was the DESTINY-Breast11 Trial Designed?

Harbeck noted that current neoadjuvant standard-of-care (SOC) regimens for HER2-positive early breast cancer have remained unchanged for more than a decade. As such, investigators sought to evaluate Enhertu–based treatment in this population with the goal of improving efficacy and safety versus the current SOC.

Patients were randomly assigned to receive Enhertu followed by THP; ddAC-THP; or Enhertu alone, followed by surgery in all arms. In the first arm, 321 patients received four cycles of Enhertu followed by four cycles of THP. In the second, ddAC was administered for four cycles, followed by four cycles of THP. In the final arm, patients received Enhertu alone for eight cycles.

Notably, the Enhertu monotherapy arm was closed in March 2024, following a recommendation from the study’s independent data monitoring committee.

After surgery, study protocols called for the following treatments, irrespective of arm:

pCR: radiotherapy and concomitant Herceptin with or without Perjeta for up to one year

Non-pCR: radiotherapy and Kadcyla for up to 14 cycles

Hormone receptor–positive disease: endocrine therapy

The study’s primary end point was pCR rate. Secondary end points included event-free survival (EFS), safety, pharmacokinetics, invasive disease-free survival, overall survival and health-related quality of life. Residual cancer burden (RCB) was an additional outcome measured during the study.

At data cutoff, 16.9% of patients in the Enhertu plus THP arm discontinued a study drug, including Enhertu (2.8%) paclitaxel (14.4%) Herceptin (2.2%) and Perjeta (2.2%); 97.2% of patients in this arm proceeded to surgery. In the ddAC-THP arm, 13.8% of patients had discontinued any study treatment, including AC (2.9%) paclitaxel (12%) Herceptin (3%) and Perjeta (3.7%); 93.8% of patients in this arm underwent surgery. In the Enhertu monotherapy arm (286 patients), 18.4% of patients discontinued study treatment and 95.8% underwent surgery.

Regarding post-neoadjuvant treatments, 99.1% of evaluable patients in the Enhertu arm who achieved a pCR (226 patients) underwent any adjuvant therapy, comprising any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (1.8%) and any Herceptin-containing regimen (94.2%). In the ddAC-THP, 98.4% of patients who achieved a pCR (190 patients) underwent any adjuvant therapy, including any cytotoxic chemotherapy regimen (5.8%), any Kadcyla–containing regimen (2.1%) and any Herceptin-containing regimen (91.6%).

For patients who did not achieve a pCR, any adjuvant therapy was administered to 89.5% of patients in the Enhertu plus THP arm (95 patients) and 82.3% of patients in the ddAC-THP arm (130 patients). In the experimental group, adjuvant therapies included any cytotoxic chemotherapy regimen (10.5%) any Kadcyla–containing regimen (52.6%) and any Herceptin-containing regimen (38.9%). These respective rates were 9.2%, 56.9% and 26.2% in the control group.

In the Enhertu plus THP and ddAC-THP arms, the median age was 50 years and 50 years, respectively. All patients in both arms were female. The highest proportion of patients in each arm was from Asia (Enhertu plus THP, 47.4%; ddAC-THP, 47.5%) and were Asian (49.8%; 49.1%). Most patients had an ECOG performance status of 0 (86.6%; 87.5%) had immunohistochemistry 3+ HER2-positive disease (87.2%; 88.4%) had cT0-2 tumors (54.8%; 58.8%) and had positive lymph nodes (89.4%; 87.8%).

What Were the Other Efficacy Outcomes for Enhertu Plus THP Versus ddAC-THP?

Findings also showed that 81.3% of patients in the Enhertu plus THP arm had no RCB (RCB-0) or minimal RCB (RCB-1) in resected breast or lymph node tissue compared with 69.1% in the ddAC-THP arm (difference, 12.2%). In the hormone receptor–positive population, the RCB-0 plus RCB-1 rates were 78% for Enhertu plus THP versus 64.7% for ddAC-THP; these respective rates were 90.4% and 81.2% in the hormone receptor–negative population.

Investigators also reported an EFS trend favoring Enhertu plus THP, with data at 4.5% maturity. Maturity for the data cutoff of the trial’s final analysis is predicted at approximately 10%. The 24-month EFS rates were 96.9% in the Enhertu plus THP arm versus 93.1% in the ddAC-THP arm.

What Is the Side Effect Profile of Enhertu Plus THP?

Any-grade side effects occurred in 98.1% of patients in the Enhertu plus THP arm compared with 98.7% of patients in the ddAC-THP arm. The respective rates of grade 3 (severe) or higher side effects were 37.5% and 55.8%. Any-grade serious side effects were reported in 10.6% and 20.2% of patients, respectively.

In the Enhertu plus THP arm, side effects led to dose any dose reduction, any drug interruption and any treatment discontinuation in 18.1%, 37.8% and 14.1% of patients, respectively. In the ddAC-THP group, these rates were 19.2%, 54.5% and 9.9%, respectively. Side effects led to death in 0.6% of patients in both arms. Side effects led to delays in surgery in 3.4% of patients in the experimental arm versus 2.6% of patients in the control arm.

Regarding side effects of special interest, any-grade drug-related adjudicated interstitial lung disease (ILD) was 4.4% in the Enhertu plus THP arm versus 5.1% in the ddAC-THP arm. The rates of grade 3 or higher ILD were 0.6% and 1.9%, respectively. Grade 5 (fatal) ILD occurred in one patient (0.3%) in both groups. Any-grade left ventricular dysfunction occurred in 1.3% of patients in the experimental arm versus 6.1% of patients in the control arm. The rates of grade 3 or higher left ventricular dysfunction were 0.3% and 1.9%, respectively, although no grade 5 events were reported in either group.

Any-grade treatment-emergent side effects reported in at least 20% of patients in either arm included nausea (Enhertu plus THP, 64.7%; ddAC-THP, 51.6%) diarrhea (58.8%; 54.2%) alopecia (47.5%; 49.0%) fatigue (41.3%; 54.8%) increased transaminase levels (34.4%; 33.7%) neutropenia (29.1%; 44.2%) constipation (29.1%; 24.4%) vomiting (28.8%; 21.2%) peripheral neuropathy (25.9%; 20.8%) anemia (22.8%; 49.7%) stomatitis (18.4%; 27.9%) and leukopenia (17.2%; 23.4%).

What Data Were Reported for Enhertu Monotherapy in HER2+ Early Breast Cancer?

In the Enhertu monotherapy arm, patients were allowed to remain on therapy or immediately switch to local SOC. If patients switched therapy, they were classified as having a non-pCR.

Findings from the monotherapy arm showed that 286 patients achieved a pCR rate of 43% at the primary analysis and 51.4% at a prespecified supplementary analysis. EFS data were similar between Enhertu monotherapy and ddAC-THP, and the 24-month EFS rate in the Enhertu monotherapy group was 94.4%.

Regarding safety, 97.5% of patients treated with Enhertu alone (283 patients) experienced any-grade side effects, 22.6% had grade 3 or higher side effects, and 10.2% had any-grade serious side effects. Side effects led to dose reduction, drug interruption and treatment discontinuation in 6.7%, 18% and 7.8% of patients, respectively. One patient (0.4%) experienced a side effect that led to death. Side effects led to surgical delay in 6.4% of patients.

The rate of any-grade drug-related adjudicated ILD was 4.9% in the Enhertu monotherapy arm, although all instances were grade 1 (mild) or 2 (moderate). Left ventricular dysfunction occurred in 0.7% of patients, all at grade 1 or 2.

Based on data from DESTINY-Breast11, the U.S. Food and Drug Administration (FDA) accepted a supplemental biologics license application seeking the approval of neoadjuvant Enhertu followed THP for the treatment of adult patients with high-risk HER2-positive (IHC 3+ or in situ hybridization–positive) stage 2/3 breast cancer.

The FDA has assigned a target action date of May 18, 2026, under the Prescription Drug User Fee Act.

“DESTINY-Breast11 results support [Enhertu plus] THP as a more effective and less toxic neoadjuvant treatment compared with ddAC-THP, and it may become the preferred regimen for patients with high-risk HER2-positive early breast cancer,” Harbeck concluded in her presentation.

“DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC),” by Dr. Nadia Harbeck et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 291O.

Enhertu (fam-trastuzumab deruxtecan-nxki) followed by paclitaxel, Herceptin, and Perjeta demonstrated superior pathologic complete response (pCR) rates compared to dose-dense doxorubicin and cyclophosphamide plus THP in high-risk, HER2-positive early breast cancer patients, as shown in the DESTINY-Breast11 trial. The trial highlighted significant pCR improvements in both hormone receptor-positive and negative populations. Enhertu plus THP also showed a favorable safety profile with fewer severe side effects. The FDA is reviewing a supplemental biologics license application for this regimen, with a decision expected by May 2026.

Presurgical Enhertu Combo Elicits Response Benefit in HER2+ Early Breast Cancer

Among patients with EGFR-mutated non-small cell lung cancer Tagrisso plus chemotherapy was associated with an improvement in survival.

Among patients with EGFR-mutated non-small cell lung cancer, including those with poor prognostic factors, treatment with Tagrisso (osimertinib) with platinum-based chemotherapy and pemetrexed was associated with an improvement in survival compared with Tagrisso alone across subgroups, according to data from an exploratory analysis of the phase 3 FLAURA2 trial.

Previously reported data from the trial’s final overall survival (OS) analysis showed that patients treated with Tagrisso plus chemotherapy (279 patients) achieved a median OS of 47.5 months versus 37.6 months for those treated with Tagrisso alone (278 patients).

The exploratory analysis, which was presented at the 2025 ESMO Congress, examined outcomes for patients based on the following six prognostic factors:

Plasma EGFR mutations in circulating tumor DNA

“Hazard ratios for OS favored the combination arm, regardless of baseline prognostic factors, and were consistent with the overall population,” lead study author Dr. Pasi A. Jänne said in a presentation of the data. Jänne is a senior physician, senior vice president for Translational Medicine, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and the David M. Livingston, MD, Chair at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School in Boston.

What Were the FLAURA2 OS Outcomes by Prognostic Subgroup?

In patients harboring CNS metastases at baseline, the median OS was 40.9 months for Tagrisso plus chemotherapy (116 patients) compared with 29.7 months for Tagrisso monotherapy (110 patients). The three-year OS rates in this subgroup were 57% and 40%, respectively. In patients without CNS metastases at baseline, the median OS was not reached for Tagrisso plus chemotherapy (163 patients) versus 43.9 months for Tagrisso alone (168 patients).

Patients harboring EGFR exon 21 L858R mutations treated with Tagrisso plus chemotherapy (106 patients) achieved a median OS of 38.1 months versus 32.4 months for Tagrisso alone (107 patients). The respective three-year OS rates were 54% and 42%. In patients harboring EGFR exon 19 deletions, the median OS was not reached for Tagrisso plus chemotherapy (172 patients) versus 43 months for Tagrisso alone (169 patients).

Among patients with EGFR mutations detected in plasma ctDNA, the median OS was 38.4 months for Tagrisso plus chemotherapy (148 patients) versus 32.5 months for Tagrisso monotherapy (161 patients). The three-year OS rates in this subgroup were 53% for Tagrisso plus chemotherapy versus 42% for Tagrisso alone. In patients without EGFR mutations detected in plasma ctDNA, the median OS was not reached and not reached for the combination (65 patients) and Tagrisso monotherapy (48 patients), respectively.

In the subgroup of patients with liver metastases at baseline, Tagrisso plus chemotherapy (43 patients) generated a median OS of 36.6 months compared with 28 months for Tagrisso alone (66 patients). The three-year OS rates were 54% and 35%, respectively. In patients without liver metastases at baseline, the median OS was 49.6 months for Tagrisso plus chemotherapy (236 patients) versus 41.8 months for Tagrisso alone (212 patients).

For patients with bone metastases, the median OS was 40.2 months for Tagrisso plus chemotherapy (132 patients) versus 32.3 months for Tagrisso monotherapy (142 patients). The three-year OS rates were 55% and 42%, respectively. In patients without bone metastases, the median OS was not reached and 44.5 months for Tagrisso plus chemotherapy (147 patients) and Tagrisso alone (136 patients), respectively.

Finally, in patients harboring TP53 alterations, those given Tagrisso plus chemotherapy (46 patients) experienced a median OS of 51.1 months versus 43.1 months for those administered Tagrisso alone (40 patients). The three-year OS rates were 65% and 58%, respectively. In patients with TP53 wild-type disease, the median OS was not reached for Tagrisso plus chemotherapy (33 patients) and not reached for Tagrisso alone (34 patients).

Notably, prior data from this study supported the February 2024 FDA approval of Tagrisso plus platinum-based chemotherapy for use in patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.

FLAURA2 enrolled patients at least 18 years of age with previously untreated, pathologically confirmed locally advanced or metastatic nonsquamous NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. Patients were also required to have a World Health Organization performance status of 0 or 1. Patients with stable CNS metastases were allowed to enroll, and brain scans were mandatory at baseline.

Patients were randomly assigned to receive Tagrisso at 80 mg per day in combination with pemetrexed at 500 mg/m

 and carboplatin at area under the curve 5 or cisplatin at 75 mg/m

 once every three weeks for four cycles, followed by Tagrisso at 80 mg once per day plus pemetrexed at 500 mg/m

 once every three weeks as maintenance therapy; or Tagrisso alone at 80 mg per day. Treatment beyond disease progression was permitted at investigator discretion.

“FLAURA2: exploratory overall survival analyses in patients with poorer prognostic factors treated with osimertinib ± platinum-pemetrexed as first-line treatment for EGFR-mutated advanced NSCLC,” by Dr. Pasi A. Jänne, et al. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA77.

“Tagrisso plus chemotherapy demonstrated a median overall survival of nearly four years, the longest benefit ever reported in a global Phase III trial in EGFR-mutated advanced lung cancer,” news release; https://www.astrazeneca.com/media-centre/press-releases/2025/tagrisso-plus-chemotherapy-demonstrated-a-median-overall-survival-of-nearly-four-years.html

“FDA approves osimertinib with chemotherapy with chemotherapy for EGFR-mutated non-small cell lung cancer,” FDA; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-chemotherapy-egfr-mutated-non-small-cell-lung-cancer

The FLAURA2 trial explored the efficacy of Tagrisso (osimertinib) combined with platinum-based chemotherapy and pemetrexed in patients with EGFR-mutated non-small cell lung cancer (NSCLC). The combination therapy improved overall survival (OS) compared to Tagrisso alone, even in patients with poor prognostic factors such as CNS, bone, and liver metastases. The trial's findings supported the FDA approval of this combination for advanced NSCLC with specific EGFR mutations. The study highlighted the significant survival benefits across various subgroups, emphasizing the potential of combination therapy in this patient population.

Tagrisso Plus Chemo Offers Survival benefit in EGFR+ NSCLC

Responses also occurred in patients who had received at least two prior ROS TKIs, with an ORR of 38%.

Among patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) who had previously received one to four lines of prior ROS1 tyrosine kinase inhibitor therapy with or without chemotherapy, treatment with zidesamtinib resulted in an objective response rate (ORR) of 44% and a complete response (CR) rate of 1%, clinical trial results have shown.

Data from the phase 1/2 ARROS-1 trial were presented at the International Association for the Study of Lung Cancer (IASLC) 2025 World Conference on Lung Cancer and showed that among those who had previously received either Xalkori (crizotinib) or Rozlytrek (entrectinib) with or without chemotherapy, the ORR was 51% with a CR rate of 2%. The ORR in patients who had received only Xalkori with or without chemotherapy was 68%; the ORR in patients who had received only Rozlytrek with or without chemotherapy was 33%.

Responses also occurred in patients who had received at least two prior ROS TKIs, with an ORR of 38%. Patients who were previously exposed to Augtyro (repotrectinib) experienced an ORR of 47%, with duration of response (DOR) ranging from 3.5 months to 17.2 months. Patients who had received prior Ibtrozi (taletrectinib) had an ORR of 43%, with a DOR ranging from 5.2 months to seven-plus months. 

 patients who responded partially or completely to treatment.

the time a patient lives without their disease spreading or worsening.

“In the pivotal dataset for TKI pretreated patients with advanced ROS1-positive NSCLC, zidesamtinib demonstrated a clinical profile consistent with its preclinical design goals,” Dr. Alexander E. Drilon, lead study author and chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, said during the presentation. “[We saw] durable activity, including in heavily pretreated patients who have exhausted available options, including prior [Augtyro] and [Ibtrozi], and patients with the ROS1 G2032R resistance mutation.”

What Was the Design of the ARROS-1 Trial?

ARROS-1 is a global, first-in-human trial evaluating the safety and efficacy of zidesamtinib in patients with advanced ROS1-positive NSCLC and other solid tumors. Phase 1 evaluated the agent at doses ranging from 25 mg to 150 mg once daily in ROS1 TKI–pretreated patients with ROS1-positive solid tumors. In phase 2, patients with either ROS1 TKI–pretreated or naive disease received the recommended phase 2 dose (RP2D) of 100 mg once daily.

A total of 514 patients had been enrolled in the pooled phase 1 and 2 populations. The pivotal safety population included 432 patients with advanced ROS1-positive NSCLC who had received the RP2D of the agent. The pivotal efficacy population included 117 patients with ROS1 TKI–pretreated NSCLC with measurable disease by BICR who had been treated by May 31, 2024, and had at least six months of DOR follow-up. Preliminary findings for the ROS1 TKI–naive cohort were also shared for the 35 patients who had been treated by August 31, 2024.

Baseline characteristics of the pivotal efficacy population revealed that the median age was 57 years. Most patients were female (56%), never smokers (68%) and resided in North America (42%) or Europe (32%). Most patients had an ECOG performance status of 1 (62%) versus 0 (38%), and 49% had active central nervous system (CNS) disease. A secondary ROS1 mutation was present in 36% of cases (G2032R, 22%).

The median number of prior anticancer therapies was two, and 53% of patients had received prior chemotherapy. A total of 47% of patients had received prior Xalkori (51%) or Rozlytrek (49%). Only four patients (3%) received either Augtyro or Ibtrozi. Among patients who had received at least two prior lines of therapy (50%), 93% had received Lorbrena (lorlatinib), Augytro or Ibtrozi.

What DOR and PFS Data Were Shared During IASLC 2025 World Conference on Lung Cancer?

At a median follow-up of 11.1 months, the median PFS was 9.7 months in patients who had received any prior ROS1 TKI. The median DOR was 22 months. The percentages of patients who remained in response for at least six, 12 and 18 months were 84%, 78% and 62%, respectively. The six-, 12-, and 18-month PFS rates were 57%, 48% and 40%, respectively.

At a median follow-up of 11.8 months, the median PFS was 23.8 months in patients who had received one prior ROS1 TKI. The median DOR was 22 months. The percentages of patients who remained in response for at least six, 12 and 18 months were all 93%. The six-, 12- and 18-month PFS rates were 70%, 68% and 68%, respectively.

Drilon also reported that there were no progression events in patients who received only Xalkori. The 6-, 12-, and 18-month PFS rates were all 89% and the median was not reached in this population.

A total of 71% and 56% of patients who received at least two prior ROS1 TKIs remained in response for six and 12 months, respectively.

Did Zidesamtinib Show Activity in the CNS and in ROS1

Among patients who had received any prior ROS1 TKI and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR, and 12-month DOR rates were 54%, 79% and 60%, respectively.

Among patients who had previously received Xalkori or Rozlytrek and had an acquired ROS1 G2032R mutation, the ORR, six-month DOR and 12-month DOR rates were 83%, 80% and 80%, respectively.

Drilon also noted that responses occurred in patients with the ROS1 G2032R mutation after treatment with two or more prior ROS1 TKIs, including Lobrena or Augtyro, as well as in other mutational subtypes, including G1957A, L1982V, S1986F, F2004C/V, G2032K, and D2033N.

Within the population of patients who had measurable CNS lesions at baseline and had received any prior ROS1 TKI, the intracranial ORR (IC-ORR), six-month IC-DOR and 12-month IC-DOR rates were 48%, 79% and 71%, respectively.

Within the population of patients who had measurable CNS lesions at baseline and had received Xalkori only, the IC-ORR, six-month IC-DOR and 12-month IC-DOR rates were 85%, 91% (95% CI, 51%-99%), and 91% (95% CI, 51%-99%), respectively. The IC-CR rates were 20% and 54% in patients who had received any prior ROS1 TKI or crizotinib as their only prior TKI, respectively.

Drilon explained that CNS responses were observed also in patients who had received at least 1 prior brain-penetrant TKI, including entrectinib, lorlatinib, repotrectinib, or taletrectinib. In this population, the IC-ORR was 37% (95% CI, 23%-53%), including 4 IC-CRs. No CNS progression occurred in patients who entered the study without brain metastases at baseline.

What Was the Safety Profile of Zidesamtinib in the ARROS-1 Trial?

All patients had received at least one dose of the study drug. The median duration of exposure was five months. Treatment-emergent side effects that occurred in at least 15% of patients who received the RP2D of zidesamtinib included peripheral edema (all grade, 36%; grade 3 or higher, 0.7%), constipation (17%; 0%), elevated blood creatine phosphokinase ([CPK]; 16%; 3.5%), fatigue (16%; 0.7%) and dyspnea (15%; 3.0%).

Ten percent of patients required dose reduction because of a treatment-emergent side effect, the most common being peripheral edema (eight patients), increased blood CPK (four patients), peripheral sensory neuropathy (four patients), arthralgia (three patients), and paresthesia (three patients). Two percent of patients discontinued treatment because of a treatment-emergent side effect, and the most common reason was pneumonia (three patients).

“[The agent was] generally well tolerated, with low rates of dose reduction and treatment discontinuation, and a safety profile consistent with its ROS1-selective, TRK-sparing design,” Drilon reported.

The only treatment-related adverse effect that occurred in more than 15% of patients was peripheral edema (29%).

What Were the Preliminary Data in the ROS TKI–Naive Cohort?

The ORR in this cohort was 89%, and 96% of patients remained in response for at least 12 months. The IC-ORR was 83% and there were no cases of CNS progression among confirmed CNS responders.

“Encouraging preliminary data in a TKI-naïve population support ongoing investigation in the frontline setting,” Drilon concluded.

Pivotal data from the trial will serve as the basis for the developer’s ongoing rolling new drug application submission for the agent to the Food and Drug Administration in the TKI-pretreated population. According to the developer, the company is expected to complete the application in the third quarter of 2025.

Drilon AE, Cho BC, Lin JJ, et al. Pivotal ARROS-1 efficacy and safety data: zidesamtinib in TKI-pretreated patients with advanced/metastatic ROS1+ NSCLC. Presented at: 2025 International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4540.

Nuvalent presents pivotal data from ARROS-1 clinical trial of zidesamtinib for TKI pre-treated patients with advanced ROS1-positive NSCLC at WCLC 2025. News release. Nuvalent. September 7, 2025. Accessed September 7, 2025. https://www.prnewswire.com/news-releases/nuvalent-presents-pivotal-data-from-arros-1-clinical-trial-of-zidesamtinib-for-tki-pre-treated-patients-with-advanced-ros1-positive-nsclc-at-wclc-2025-302548220.html

Zidesamtinib demonstrated promising efficacy in advanced ROS1-positive NSCLC patients previously treated with ROS1 TKIs, achieving an ORR of 44% and a CR rate of 1%. The ARROS-1 trial highlighted its effectiveness, particularly in those with prior Xalkori or Rozlytrek exposure, and in patients with the ROS1 G2032R resistance mutation. The trial also showed significant CNS activity and a favorable safety profile, with peripheral edema being the most common side effect. Preliminary data in TKI-naïve patients were encouraging, supporting further investigation in frontline settings.

Patients with advanced, pretreated ROS1-positive NSCLC treated with zidesamtinib saw an objective response rate of 44%.

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