Caroline Seymour

Lenvima and Keytruda with chemo did not help patients with metastatic esophageal squamous cell carcinoma live longer than Keytruda and chemotherapy alone.

The combination of Lenvima (lenvatinib) and Keytruda (pembrolizumab) with chemotherapy did not help patients with metastatic esophageal squamous cell carcinoma live longer compared with Keytruda and chemotherapy alone, according to results from a phase 3 study presented at the 2025 ESMO Congress.

The median OS in the Lenvima arm was 17.6 months versus 15.5 months in the chemoimmunotherapy arm. The 12- and 24-month OS rates were 65% and 34% in the investigational arm versus 61% and 32% in the control arm.

In patients with a PD-L1 combined positive score (CPS) of at least 10, the median OS was 18 months in the Lenvima arm versus 15.8 months in the control arm. The 12- and 24-month OS rates were 67% and 36% in the investigational arm versus 63% and 31% in the control arm.

“Lenvatinib plus pembrolizumab and chemotherapy did not significantly improve OS as first-line treatment for patients with metastatic ESCC versus pembrolizumab plus chemotherapy,” lead study author Dr. Jong-Mu Sun, of the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Republic of Korea, stated during the presentation.

Overall survival (OS): time from treatment start or diagnosis until death from any cause.

Progression-free survival (PFS): time during and after treatment that a patient lives without cancer growing or spreading.

Duration of response (DOR): length of time a treatment keeps cancer under control after it first responds.

Overall response rate (ORR): percentage of patients whose cancer shrinks or disappears after treatment.

What Are the Key Components of the Trial?

The trial enrolled patients at least 18 years of age with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC. Prior treatment, an ECOG performance status of 2 or higher, and lack of measurable disease per RECIST 1.1 criteria excluded patients from enrollment.

A total of approximately 850 patients were randomly assigned 1:1 to treatment. In the investigational arm, patients received 8 milligrams of oral Lenvima once daily plus 400 milligrams of intravenous (IV) Keytruda every six weeks and either cisplatin plus 5-fluorouracil (FP) or paclitaxel plus cisplatin (TP) every three weeks, or modified FOLFOX6 every two weeks. This was followed by 20 milligrams of Lenvima plus 400 milligrams of Keytruda every six weeks until progression, unacceptable side effects, or withdrawal. In the control arm, patients received 400 milligrams of IV Keytruda every six weeks plus FP or TP every three weeks or modified FOLFOX6 every two weeks in accordance with local standards.

OS served as the primary end point. Secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR) by blinded independent central review, and safety.

A total of 850 patients were randomly assigned to the investigational (423 patients) and control (427 patients) arms: 421 and 426 of whom were treated in the respective arms. In the investigational arm, 2 patients completed treatment and 93 patients remained on therapy. Reasons for discontinuation included progressive disease (206 patients), side effects (72 patients), clinical progression (25 patients), patient decision (18 patients), physician decision (3 patients), and protocol violation (2 patients). In the control arm, 23 patients completed treatment and 70 patients remained on therapy. Reasons for discontinuation included progressive disease (202 patients), side effects (73 patients), clinical progression (22 patients), patient decision (25 patients), physician decision (10 patients), and follow-up loss (1 patient).

Baseline characteristics were well balanced between treatment groups, Sun said. Within the investigational arm, the median age was 64; 49% were above 65. Most patients were male (78%), Asian (66%), and from East Asia (66%). ECOG performance status was 1 in 64% of cases, and most patients had a PD-L1 CPS of 10 or greater (66%). Ninety-nine percent of patients did not have brain metastases and had stage 4B disease. The preferred choice of chemotherapy was modified FOLFOX6 (65%), followed by FP (24%) and TP (10%).

Per the study design, efficacy was evaluated in all randomized patients, whereas safety was limited to all randomized patients who received at least one dose of study therapy. PFS and ORR were not tested for statistical significance since OS was not positive. The data cutoff for this analysis was May 8, 2025, at which point approximately 482 OS events had occurred, or 42 months had passed since the first participant had been randomized.

What Additional Efficacy Data Were Presented?

Sun stated that the OS results were consistent across prespecified subgroups, including PD-L1 status (CPS greater or equal to 10 versus CPS less than 10), region (East Asia versus North America and Western Europe versus rest of the world), and chemotherapy (FP versus TP versus modified FOLFOX).

Additional results indicated that the median PFS in all randomized patients was 7.2 months in the Lenvima arm versus 6.9 months in the control arm. The 12- and 24-month PFS rates were 31% and 12% in the investigational arm versus 23% and 15% in the control arm.

The median PFS in patients with a PD-L1 CPS of at least 10 was 8.1 months in the Lenvima arm versus 6.9 months in the control arm. The 12- and 24-month PFS rates were 36% and 16% in the investigational arm versus 25% and 14% in the control arm.

The ORR was 62.2% in the Lenvima arm versus 54.8% in the chemoimmunotherapy arm. In the Lenvima arm, best responses included complete response (16.3%), stable disease (22%), and progressive disease (8%); 7.3% of patients were not evaluable. In the control arm, best responses included complete response (19.2%), partial response (35.6%), stable disease (29.7%), and progressive disease (8.9%); 5.4% of patients were not evaluable.

The median DOR was 8.1 months in the Lenvima arm and 17% of patients experienced a response lasting 24 months or longer. In the control arm, the median DOR was 6.8 months and 21% of patients experienced a response lasting at least 24 months.

What Were the Key Safety Data That Were Presented?

The median duration of treatment exposure was 7.1 months in the Lenvima arm versus 5.6 months in the control arm. In the investigational arm, any-grade side effects occurred in 99.5% of patients (grade 3 [severe] or higher, 81.2%; grade 5 [death], 9.7%). Side effects leading to drug discontinuation occurred in 33.3% of patients. Treatment-related side effects occurred in 97.1% of patients.

In the control arm, any-grade side effects occurred in 99.3% of patients (grade 3 or higher, 79.1%; grade 5, 11.5%). Side effects leading to drug discontinuation occurred in 39% of patients. Treatment-related side effects occurred in 96.5% of patients.

Side effects that occurred in at least 15% of patients in either arm in order of frequency were decreased neutrophil count, nausea, hypertension, diarrhea, decreased platelet count, anemia, hypothyroidism, stomatitis, decreased white blood cell count, fatigue, decreased appetite, palmar plantar erythrodysesthesia syndrome, proteinuria, aspartate aminotransferase increase, vomiting, rash, weight decrease, constipation, alanine aminotransferase increase, pyrexia, increased lipase, increased amylase, peripheral neuropathy, hypoalbuminemia, and pneumonia.

Immune-mediated side effects and infusion reactions in the experimental arm included adrenal insufficiency, colitis, encephalitis, gastritis, hepatitis, hyperthyroidism, hypophysitis, hypothyroidism, infusion reactions, myocarditis, myositis, nephritis, pancreatitis, pneumonitis, severe skin reactions, thyroiditis, type 1 diabetes mellitus, and vasculitis.

“Safety profiles were generally consistent with the known safety profiles of Lenvima in combination with Keytruda and chemotherapy or the Keytruda plus chemotherapy regimen,” Sun concluded.

“Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Pembrolizumab and Chemotherapy in Untreated Metastatic Esophageal Squamous Cell Carcinoma” by Dr. Jong-Mu Sun, et al., ESMO Congress 2025.

“Efficacy and Safety of Pembrolizumab Plus Lenvatinib Plus Chemotherapy in Participants With Metastatic Esophageal Carcinoma” by Dr. Jong-Mu Sun, et al., ClinicalTrials.gov.

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Articles

The combination of Lenvima (lenvatinib) and Keytruda (pembrolizumab) with chemotherapy did not significantly improve overall survival (OS) in patients with metastatic esophageal squamous cell carcinoma (ESCC) compared to Keytruda and chemotherapy alone. The median OS was slightly higher in the Lenvima arm, but not statistically significant. Progression-free survival (PFS) and overall response rate (ORR) showed modest improvements. Safety profiles were consistent with known data, with high rates of side effects in both treatment arms. The study involved 850 patients, with balanced baseline characteristics.

Lenvima Combo Fails to Extend Survival in Esophageal Cancer

For patients with relapsed/refractory mantle cell lymphoma Lunsumio plus Polivy was associated with durable responses. Image generated by Google Gemini.

Among patients with relapsed/refractory mantle cell lymphoma (MCL) with prior exposure to BTK inhibition, treatment with Lunsumio (mosunetuzumab-axgb) plus Polivy (polatuzumab vedotin-piiq) was associated with durable responses and was found to be well tolerated, clinical trial results have shown.

Findings from an MCL dose-expansion cohort of a phase 2 trial were presented at the 2025 SOHO Annual Meeting.

Among all treated patients (42 patients), the overall response rate (ORR) was 88%; the complete response (CR) and partial response (PR) rates were 79% and 9%, respectively. The efficacy of this combination was observed across high-risk patient subgroups, including those at least 70 years of age (18 patients; ORR, 83%; CR rate, 78%; PR rate, 5%), those who had received prior CAR-T cell therapy (11 patients; 91%; 82%; 9%), those with a Ki-67 score of at least 50% (28 patients; 93%; 79%; 14%), those with pleomorphic or blastoid MCL (16 patients; 94%; 69%; 25%), and those with TP53 mutations or deletions (13 patients; 100%; 92%; 8%).

Overall response rate: patients who responded partially or completely to treatment.

Progression-free survival: the time a patient lives without their disease spreading or worsening.

Overall survival: the time a patient lives, regardless of disease status.

“[Lunsumio] and [Polivy], in my opinion, is going to be a good off-the-shelf option for relapsed/refractory MCL before or after CAR T-cell therapy,” lead study author Dr. Michael L. Wang, said in the presentation.

Wang is a professor in the Department of Lymphoma/Myeloma and the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

What Was the Rationale for Investigating Lunsumio in Combination With Polivy in Patients With MCL?

Lunsumio is a CD20xCD3-directed, T-cell engaging bispecific antibody. Polivy is a CD79-directed antibody-drug conjugate.

“The two are complementary in their mechanisms of action,” Wang noted. “They were synergistic in preclinical studies.”

Previous findings from the dose-expansion large B-cell lymphoma (LBCL) cohort (98 patients) of the phase 2 study showed that at a median follow-up of 23.9 months, Lunsumio plus Polivy elicited an ORR of 59.2% and a CR rate of 45.9%. Furthermore, the median duration of CR was not reached.

What Was the Design of the MCL Portion of the Phase 2 Study of Lunsumio Plus Polivy in Relapsed/Refractory MCL?

This phase 2 study is investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of Lunsumio plus Polivy in patients with B-cell non-Hodgkin lymphoma, including LBCL, follicular lymphoma and MCL.

Patients received the investigational combination in a fixed-duration treatment approach that included Lunsumio administered subcutaneously at 45 mg in 21-day cycles (5-mg step-up dosing occurred in cycle 1) for a total of 17 cycles; and intravenous Polivy administered at 1.8 mg/kg on day 1 of cycles 1 through 6. Hospitalization was not required. Patients received corticosteroid premedication before each dose in cycle 1.

What Were the Baseline Characteristics of Patients Included in the Trial?

Patients had a median age of 68 years and had received three prior lines of therapy. Prior therapies included BTK inhibition (100%), CAR T-cell therapy (26%) and autologous stem cell transplant (31%). In total, 93% of patients were refractory to their last prior therapy. TP53 mutations or deletions were present in 39% of patients, 38% of patients had blastoid or pleomorphic disease, and 43% of patients had bone marrow involvement. Ki-67 scores of at least 30% and at least 50% were reported in 76% and 67% of patients, respectively. Additionally, 48% of patients had a simplified International Prognostic Index for MCL score of at least 6. Overall, 71% of patients had at least three high-risk features.

“This is a high-risk, heavily treated population,” Wang contextualized.

What Additional Efficacy Data Were Observed With Lunsumio Plus Polivy?

The responses observed with this combination were early and durable, Wang noted. At a median follow-up of 15.9 months, among all responders (37 patients), the median time to first response was 2.7 months, the median DOR was not reached and the 12-month response rate was 66%. Among complete responders (33 patients), the median time to first CR was 2.8 months, the median duration of CR was not reached and the 12-month response rate was 71.9%.

Among all treated patients, the median progression-free survival (PFS) was 18.6 months, and the 12-month PFS rate was 74.8%. The median overall survival (OS) was 20.7 months and the 12-month OS rate was 83.1%.

What Was the Safety Profile of Lunsumio Plus Polivy in Patients With MCL?

All patients experienced side effects, and 93% of patients experienced treatment-related side effects. The rates of grade 3 (severe)/4 (life-threatening) side effects and treatment-related side effects were 69% and 60%, respectively. Serious side effects and treatment-related side effects were reported in 62% and 41% of patients, respectively. Grade 5 (fatal) side effects and treatment-related side effects occurred in 12% and 2% of patients, respectively; these included COVID-19 pneumonia (three patients), pneumonia (one patient) and West Nile virus encephalitis (one patient). Treatment discontinuation related to side effects and treatment-related side effects occurred in 24% and 12% of patients, respectively. Patients received a median of 15 Lunsumio cycles and six Polivy cycles.

Side effects and treatment-related side effects that occurred in at least 20% of patients included fatigue, injection site reaction, neutropenia/decreased neutrophil counts, diarrhea, cytokine release syndrome (CRS), nausea, dyspnea, constipation, cough, headache, pyrexia, thrombocytopenia/decreased platelet counts, COVID-19 and myalgia. Side effects of interest included injection site reaction (grade 1 (mild), 52%; grade 2 (moderate), 5%), peripheral neuropathy (grade 1, 29%; grade 2, 12%), immune effector cell–associated neurotoxicity syndrome (grade 2, 2%), infections (any grade, 71%; grade 3/4, 14%; grade 5, 12%), tumor flare (grade 1, 5%; grade 2, 7%), neutropenia/decreased neutrophil counts (any grade, 45%; grade 3/4, 41%), and febrile neutropenia (grade 3, 5%).

Notably, B-cell depletion occurred rapidly during treatment, and investigators observed recovery of B-cell counts following treatment.

Wang ML, Kamdar M, Assouline S, et al. Fixed-duration outpatient subcutaneous mosunetuzumab + polatuzumab vedotin shows robust efficacy in a phase II study of relapsed/refractory post-BTKi mantle cell lymphoma. Presented at: 2025 SOHO Annual Meeting. September 3-6, 2025; Houston, TX. Abstract MCL-1493.

Budde LE, Olszewski AJ, Assouline S, et al. Mosunetuzumab with polatuzumab vedotin in relapsed or refractory aggressive large B cell lymphoma: a phase 1b/2 trial. 

. 2024;30(1):229-239. doi:10.1038/s41591-023-02726-5

A study to evaluate the safety and efficacy of mosunetuzumab (BTCT4465A) in combination with polatuzumab vedotin in B-cell non-Hodgkin lymphoma. ClinicalTrials.gov. Updated November 29, 2024. Accessed September 6, 2025. https://www.clinicaltrials.gov/study/NCT03671018

Lunsumio (mosunetuzumab-axgb) combined with Polivy (polatuzumab vedotin-piiq) demonstrated significant efficacy and tolerability in patients with relapsed/refractory mantle cell lymphoma (MCL) previously treated with BTK inhibitors. The phase 2 trial showed an overall response rate of 88%, with complete and partial response rates of 79% and 9%, respectively. The combination was effective across high-risk subgroups, including those with prior CAR-T therapy and TP53 mutations. Despite a high incidence of side effects, the treatment was generally well-tolerated, with manageable safety profiles and durable responses.

For patients with relapsed/refractory mantle cell lymphoma Lunsumio plus Polivy was associated with durable responses.

Lunsumio plus Polivy Associated With Responses in MCL

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%.

Zidesamtinib Elicits Responses in ROS1-Positive NSCLC

In patients with EGFR-mutated NSCLC ivonescimab plus chemotherapy was associated with significant progression-free survival.

Among patients with EGFR-mutated non-small cell lung cancer (NSCLC) who experienced disease progression following a third-generation tyrosine kinase inhibitor, treatment with ivonescimab plus carboplatin/pemetrexed was associated with significant and clinically meaningful progression-free survival (PFS) versus placebo plus carboplatin/pemetrexed, study results have shown.

Data from the phase 3 HARMONi trial were presented at the International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer, and the findings revealed that at a median follow-up of 22.3 months, the median PFS was 6.8 months and 4.4 months in the ivonescimab plus carboplatin/pemetrexed (172 patients) and the placebo plus carboplatin/pemetrexed (173 patients) arms, respectively. Specifically, at six and 12 months in the ivonescimab arm, the PFS rates were 54.% and 25.4%, respectively; these rates were 34.7% and 8.3% in the placebo arm.

“The efficacy of [ivonescimab] was consistent across subgroups, with perhaps more benefit [in patients] with brain metastases,” Dr. Jonathan Goldman, a professor of medicine in the Division of Hematology/Oncology, the director of Clinical Trials in Thoracic Oncology, and the associate director of Early Drug Development at the University of California Los Angeles, said in a presentation of the data.

Objective response rate: patients who responded partially or completely to treatment.

Anemia: low count of healthy red blood cells.

Increased alanine aminotransferase levels: an indicator of liver damage.

Increased aspartate aminotransferase levels: an indicator of liver and heart damage.

What Was the Background and Design of the HARMONi Study?

Topline results from the HARMONi trial revealed that the study met the PFS primary end point and showed a positive trend in the other primary end point of overall survival (OS) with ivonescimab plus carboplatin/pemetrexed compared with placebo plus carboplatin/pemetrexed in patients with EGFR-mutated NSCLC who experienced disease progression after treatment with a third-generation TKI.

The double-blind, multicenter trial includes patients at least 18 years of age with histologically or cytologically confirmed unresectable locally advanced or metastatic non-squamous NSCLC with an EGFR-sensitizing mutation.

Patients included on the study are randomly evenly assigned to receive either ivonescimab plus carboplatin/pemetrexed (219 patients) or placebo plus carboplatin/pemetrexed (219 patients). Those included in the investigational arm are treated with 20 mg/kg of ivonescimab every three weeks plus carboplatin at area under the curve 5 every three weeks for four 21-day cycles and pemetrexed at 500 mg/m

 every three weeks. Patients included in the placebo arm were treated with carboplatin and pemetrexed at the same dosing levels as those in the investigational arm.

What Were the Additional Efficacy and Safety Findings From the HARMONi Study?

At an overall median follow-up of 29.7 months, the median OS was 16.8 months and 14 months in the ivonescimab and placebo arms, respectively. Furthermore, the objective response rate (ORR) was 45% in the ivonescimab arm compared with 34% in the placebo arm. The disease control rate (DCR) was 84% vs 73% in the respective arms. Notably, the median duration of response (DOR) in the ivonescimab (98 patients) and placebo (75 patients) arms were 7.6 months and 4.2 months, respectively.

Regarding safety, any-grade treatment-related side effects were observed in 95% and 93.1% of patients from the ivonescimab and placebo arms, respectively. In the ivonescimab arm, grade 3 (severe) or greater side effects and serious side effects occurred in 50% and 28% of patients, respectively; these occurred in 42.2% and 15.1% of patients in the placebo arm. Treatment-related side effects that led to discontinuation of ivonescimab or placebo, respectively, were observed in 7.3% and 5% of patients. Moreover, treatment-related side effects that led to death were reported in 1.8% and 2.3% of patients, respectively.

In the ivonescimab arm, the most common treatment-related side effects observed included anemia (any grade, 49.1%; grade 3 or higher, 10.1%), decreased white blood cell count (45%; 12.8%), decreased neutrophil count (42.7%; 19.3%) and decreased platelet count (32.6%; 12.4%). The most common treatment-related side effects reported in the placebo arm included anemia (56.4%; 12.4%), decreased white blood cell count (44%; 11%), decreased neutrophil count (42.2%; 16.5%) and decreased platelet count (28.0%; 6.4%).

Of note, grade 3 or higher immune-related side effects occurred in 9.6% and 6% of patients in the ivonescimab and placebo arms, respectively; grade 3 or higher VEGF-related treatment-related side effects occurred in 7.3% and 3.2% of patients. In particular, the most common irAEs occurring in at least five patients in the ivonescimab arm included hypothyroidism (any grade, 8.3%; grade 3 or higher, 0.5%), hyperthyroidism (any grade, 4.1%), increased alanine aminotransferase levels (2.8; 0.9%), and increased aspartate aminotransferase levels (any grade, 3.2%). Additionally, the most common VEGF-related treatment-related side effects occurring in the ivonescimab arm included proteinuria (13.8%; 0.9%), hypertension (13.3%; 3.7%) and hemorrhage (10.6%; 0.9%).

Goldman JW, Passaro A, Laskin J, et al. Ivonescimab vs placebo plus chemo, phase 3 in patients with EGFR+ NSCLC progressed with 3rd gen EGFR-TKI treatment: HARMONi. Presented at: International Association for the Study of Lung Cancer 2025 World Conference on Lung Cancer; September 6-9, 2025; Barcelona, Spain. Abstract 4808.

Ivonescimab plus chemotherapy demonstrates statistically significant and clinically meaningful improvement in progression-free survival in patients with EGFR-mutant non-small cell lung cancer after EGFR TKI therapy in global study. News release. Summit Therapeutics. May 30, 2025. Accessed September 7, 2025. https://www.smmttx.com/wp-content/uploads/2025/05/2025_PR_0530-_-HARMONi-Data-_-FINAL.docx.pdf

Phase III study of AK112 for NSCLC patients. ClincialTrials.gov. Updated October 8, 2024. Accessed September 7, 2025. https://clinicaltrials.gov/study/NCT06396065

Ivonescimab combined with carboplatin/pemetrexed significantly improved progression-free survival (PFS) in patients with EGFR-mutated NSCLC who progressed after third-generation TKI therapy, compared to placebo. The phase 3 HARMONi trial showed a median PFS of 6.8 months for ivonescimab versus 4.4 months for placebo. The study also indicated a positive trend in overall survival (OS) and higher objective response and disease control rates with ivonescimab. Safety profiles were comparable, with common side effects including anemia and decreased blood cell counts.

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