Jason M Broderick

Consolidation tiragolumab plus Tecentriq does not improve progression-free survival in advanced lung cancer compared to Imfinzi.

Among patients locally advanced, unresectable, stage 3 non-small cell long cancer (NSCLC) that has not progressed after platinum-based concurrent chemoradiation (cCRT), consolidation therapy with tiragolumab plus Tecentriq (atezolizumab) did not improve independent review facility (IRF)-assessed progression-free survival (PFS) versus standard Imfinzi (durvalumab) therapy, study results have shown.

Findings from the phase 3 SKYSCRAPER-03 trial were presented at the 2025 ESMO Congress.

At a median follow-up of 30.7 months, the median IRF-PFS in the overall population was 14.2 months in patients receiving the combination versus 13.8 months in patients treated with Imfinzi. The 24-month PFS event-free rates were 39% and 38.5%, respectively. The median overall survival (OS) was 45.6 months versus 45.8 months, respectively. The 24-month OS event-free rates were 67% versus 66.3%, respectively.

Independent review facility (IRF)-assessed progression-free survival (PFS): the length of time a patient lives without their cancer growing or spreading, as determined by a group of expert doctors who review the scans independently from the study doctors.

Overall survival (OS): the percentage of people in a study who are still alive after a certain period of time.

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

The primary end point was also missed in PD-L1–positive patients with a median IRF-PFS of 19.4 months versus 16.6 months in patients treated with the combination versus Imfinzi, respectively. The median OS in these patients was not estimable versus 54.8 months, respectively. The 24-month PFS and OS event-free survival rates were 46.1% versus 42.9% and 72.2% versus 69.2%, respectively.

“SKYSCRAPER-03 did not meet its primary end point of IRF-PFS. There were no new or unexpected [safety] findings,” said first study author Dr. Rafal Dziadziuszko, department of oncology and radiotherapy of the Medical University of Gdansk, Poland.

What Was the Safety Profile of the Combination and Monotherapy Arms in the Trial?

“Tiragolumab plus [Tecentriq] demonstrated a tolerable safety profile, consistent with previous observations for the combination,” said Dziadziuszko.

Grade 3 (severe)/4 (life-threatening) treatment-related side effects occurred in 13.8% of patients in the combination arm, with serious treatment-related side effects experienced by 11.5%. There were two patient deaths considered to be related to the combination treatment. In the Imfinzi arm, grade 3/4 treatment-related side effects and serious treatment-related side effects each occurred in 10.7% of patients. There were seven patient deaths considered to be related to Imfinzi treatment.

What Was the Study Rationale and Design for the Trial?

Regarding the rationale for the study, Dziadziuszko explained, “Consolidation [Imfinzi] is the standard of care for patients with unresectable, stage 3 NSCLC that has not progressed following cCRT; however, disease recurrence [still] represents an unmet need.”

He added that the immune checkpoint target TIGIT has a role in cancer immune evasion and the study hypothesis was that tiragolumab, an anti-TIGIT monoclonal antibody, could potentially augment antitumor activity when used in combination with immunotherapies such as Tecentriq.

The open-label phase 3 trial was launched to test this hypothesis in patients with newly diagnosed, unresectable, stage 3 NSCLC whose disease has not progressed following at least two cycles of definitive platinum-based cCRT. Patients had to have known PD-L1 status and an ECOG performance status of 0 or 1. Patients with EGFR- or ALK-positive tumors were not eligible for enrollment.

At 1 to 42 days post cCRT, patients were randomized to combination therapy with tiragolumab (840 mg IV every four weeks) plus Tecentriq (1680 mg IV every four weeks) or single-agent Imfinzi (10 mg/kg IV every two weeks or 1500 mg IV every four weeks). Patient could receive up to 13 cycles of treatment (28-day cycles).

What Were the Patient Characteristics in the Trial?

Patient characteristics were well balanced between the two study arms. The median age was 64 years in the combination arm versus 65 years in the Imfinzi arm. About half of patients in each arm were aged less than 65 years at 50.8% and 47.4%, respectively. About 80% of patients in each arm were male, about 60% were White and about 35% were Asian. Patients’ ECOG performance status was mostly split evenly between 0 and 1, with a slightly higher number of patients in each arm at ECOG 1 status. About 75% of patients in each arm were former tobacco users and about 20% were current tobacco users.

“SKYSCRAPER-03: Phase III, open-label, randomised study of atezolizumab (atezo) + tiragolumab (tira) vs durvalumab (durva) in locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation (cCRT),” Dr. Rafal Dziadziuszko et al, presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA69.

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Articles

Consolidation therapy with tiragolumab plus Tecentriq did not improve progression-free survival (PFS) compared to standard Imfinzi therapy in patients with locally advanced, unresectable stage 3 non-small cell lung cancer (NSCLC) post-platinum-based concurrent chemoradiation. The phase 3 SKYSCRAPER-03 trial showed similar median PFS and overall survival (OS) between the two groups. The safety profile of the combination therapy was consistent with previous observations, with slightly higher rates of severe side effects compared to Imfinzi. The study aimed to address disease recurrence by targeting the TIGIT immune checkpoint.

Tiragolumab Plus Tecentriq Doesn’t Improve NSCLC Outcomes

Sac-TMT improved progression-free survival in patients with HR+/HER2– breast cancer.

Patients with previously treated, locally advanced or metastatic hormone receptor (HR)-positive, HER2-negative breast cancer experienced superior progression-free survival when treated with the TROP2-targeted antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT; SKB264; MK-2870) compared with chemotherapy, clinical trial results have shown.

Updated findings from the phase 3 OptiTROP-Breast02 trial were presented at the 2025 ESMO Congress in Berlin.

Notably, sac-TMT elicited a 65% reduction in the risk of disease progression or death versus chemotherapy and showed a consistent benefit across subgroups. At a median follow-up of 7.4 months, the median PFS (mPFS) in patients receiving sac-TMT (8.3 months) was approximately twice that of patients receiving chemotherapy (4.1 months).

Progression-free survival (PFS): the length of time a person lives with cancer without the cancer getting worse.

Objective response rate (ORR): the percentage of patients in a study whose cancer shrinks or disappears after treatment.

Disease control rate (DCR): the percentage of patients in a study whose cancer either shrinks, disappears, or remains stable with treatment.

Duration of response (DOR): the length of time a patient continues to have a response to a treatment without the cancer progressing.

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

Neutropenia: 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.

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

Additionally, an interim analysis of overall survival (OS) revealed a positive trend among those receiving sac-TMT compared to those receiving chemotherapy.

“The current chemotherapy options [for HR-positive/HER2-negative breast cancer] show limited efficacy,” said Man Li, professor at the Second Affiliated Hospital of Dalian Medical University, during the presentation. “Sac-TMT has shown promising activity in pretreated patients with HR-positive/HER2-negative metastatic breast cancer in [a] phase 2 study.”

These new statistically significant and clinically meaningful efficacy data from OptiTROP-Breast02, along with an observed manageable safety profile, strengthen the case for sac-TMT as a potential new treatment option for this patient population who comprise a vast majority of global breast cancer cases.

“The OptiTROP-Breast02 study supports sac-TMT as a new treatment option for patients with HR+/HER2– breast cancer following endocrine-based therapy and chemotherapy,” said Li.

OptiTROP-Breast02 is a global randomized open-label study evaluating the efficacy and safety of sac-TMT versus investigator’s choice of chemotherapy (ICC) in adult patients with unresectable, locally advanced or metastatic HR-positive/HER2-negative breast cancer who had failed at least one line of systemic chemotherapy. The study is assessing the primary end point of PFS, along with secondary end points of investigator-assessed OS, objective response rate, disease control rate and duration of response.

Patients were eligible for participation if they had HR-positive/HER2-negative breast cancer, had between one and four lines of chemotherapy, and had at least one endocrine therapy, CDK 4/6 inhibitor and taxane in any setting. Of 399 patients randomized to either the investigational arm (200 patients) or control arm (199 patients), 200 received 5 mg/kg of intravenous sac-TMT every 2 weeks, while 196 received ICC including eribulin, capecitabine, gemcitabine and vinorelbine.

What Were the Patient Characteristics in the OptiTROP-Breast02 Trial?

Patient characteristics were well balanced between the study arms. Across both arms, the median age was 54 years, two-thirds had an ECOG performance status of 1, about 53% were HER2 zero and 47% were HER2 low. About 96% of patients had visceral metastases and over three-fourths had liver metastases. About three-fourths of patients had received neoadjuvant chemotherapy and all patients had received prior taxane, endocrine therapy and a CDK 4/6 inhibitor. About 56% of patients had received at least two lines of chemotherapy in the advanced/metastatic setting and a little over one-fourth of patients had primary endocrine resistance.

This most recent report of safety data revealed a manageable safety profile, with no new safety signals. In terms of treatment-related side effects, the incidence of all-grade and at least grade 3 (severe) treatment-related side effects was comparable between investigational and control arms. The most common treatment-related side effects for both sac-TMT and chemotherapy were hematologic toxicities, including decreased white blood cell count, anemia and neutropenia. While stomatitis was more frequent in patients receiving sac-TMT (63% versus 8%), Li noted that these side effects were primarily low-grade and manageable.

Treatment discontinuation occurred in 87 and 138 patients in the investigational and control arms, respectively. The most common reason for discontinuation was radiographic disease progression in both the investigational arm (80 patients) and control arm (122 patients).

Regarding next steps Li said, “Phase 3 studies of sac-TMT as a monotherapy and/or in combination with Keytruda (pembrolizumab) in patients with chemotherapy-naïve HR-positive/HER2-negative breast cancer are ongoing globally and in China.”

“Sacituzumab tirumotecan (sac-TMT) vs investigator's choice of chemotherapy (ICC) in previously treated locally advanced or metastatic hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer (BC): results from the randomized, multi-center phase 3 OptiTROP-Breast02 study” by Man Li, presented at: ESMO 2025 Congress; October 17–20, 2025; Berlin Germany. Abstract LBA23.

Sacituzumab tirumotecan (sac-TMT) demonstrated superior progression-free survival (PFS) compared to chemotherapy in patients with previously treated, locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer, according to the OptiTROP-Breast02 trial. Sac-TMT reduced the risk of disease progression or death by 65% and showed a positive trend in overall survival. The trial confirmed sac-TMT's manageable safety profile, with hematologic toxicities being the most common side effects. Ongoing phase 3 studies are evaluating sac-TMT as monotherapy and in combination with pembrolizumab.

HR+/HER2- Metastatic Breast Cancer Progression Improved With Sac-TMT

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

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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 

Aidixi plus BCG led to high early response rates and manageable side effects in patients with HER2-expressing non–muscle-invasive bladder cancer.

Aidixi (disitamab vedotin), an antibody-drug conjugate (ADC) combined with Bacillus Calmette-Guérin (BCG) led to positive efficacy with a manageable safety profile in patients with HER2-expressing, high-risk non–muscle-invasive blader cancer (HR-NMIBC), according to results from a small study shared during the 2025 American Urological Association (AUA) Annual Meeting.

Among patients who were unable to undergo complete tumor resection or had carcinoma in situ (CIS), the clinical complete response (cCR) rates were both 100% for 11 patients evaluable at three months and five patients evaluable at six months. Further, in the three evaluable patients who underwent complete tumor resection, the event-free survival (EFS) rate at six months was 100%.

Regarding safety, 65% (13 patients) of patients experienced any-grade treatment-related side effects (TRAEs). These included elevated aspartate aminotransferase/alanine aminotransferase (40%; 8 patients), alopecia (45%; 9 patients), peripheral sensory neuropathy (35%; 7 patients), anorexia (10%; 2 patients) and rash (5%; 1 patient). BCG-related side effects were experienced by 60% (12 patients) of patients and included bladder irritation, fever, arthralgia, conjunctivitis, and hematuria. Only two patients (10%) experienced grade 3 (severe) TRAEs: one patient had grade 3 peripheral sensory neuropathy related to Aidixi and one patient had grade 3 hematuria related to BCG.

Clinical complete response (cCR): when no signs of cancer are found on medical tests after treatment.

Duration of complete response: how long the cancer remains undetectable after a complete response is achieved.

Event-free survival (EFS): the length of time after treatment that a patient remains free from cancer-related problems like recurrence or progression.

Cancer-specific survival: the percentage of patients who have not died from their cancer over a certain period of time.

Overall survival: the percentage of patients who are still alive for a certain period of time after treatment, regardless of cause of death.

Peripheral sensory neuropathy: nerve damage that causes numbness, tingling or pain, often in the hands and feet.

Anorexia: a loss of appetite caused by illness or treatment, not the eating disorder.

“[Aidixi] plus BCG may potentially provide a new bladder-sparing therapy for very high-risk NMIBC patients with HER2 expression who refused radical cystectomy or did not meeting the requirements for radical cystectomy,” Dr. Yijun Shen, department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China, said when presenting the data at the AUA meeting.

Study Background and Patient Characteristics

Explaining the rationale for the study, Shen said, “Forty percent to 60% of patients with HR-NMIBC will relapse after BCG treatment. Moreover, there is a high incidence of postoperative complications and a negative impact on health-related quality of life after radical cystectomy.”

Overall, the study included 20 patients with HER2-expressing, high-risk NMIBC. Patients were stratified into two cohorts: cohort A consisted of 15 patients with residual tumor or CIS following transurethral resection of bladder tumor (TURBT) and cohort B comprised five patients without residual tumor following TURBT.

In cohort A, the patient age range was 55 to 83 years. There were 13 men and two women, and NMIBC was the primary tumor for 12 of the 15 patients. One patient had a tumor stage of Ta and all other patients had a tumor stage of T1. All patients had multiple lesions and 12 patients had CIS. HER2 expression scores per IHC comprised three patients who were 1+, eight who were 2+, and four who were 3+. Twelve patients had residual tumors at second transurethral resection (TUR).

Patients in cohort B had an age range of 62 to 78 years. There were three males and two females and NMIBC was the primary tumor for all five patients. Across all patients, NMIBC was the primary tumor, and the tumor stage was T1. Four patients had multiple lesions and none of the patients had concurrent CIS or residual tumors at second TUR. HER2 expression by IHC was 2+ for three patients and 3+ for two patients.

All patients were treated with Aidixi at 2 milligrams per kilogram every three weeks for up to 8 cycles. This was followed by one-year of BCG bladder instillation.

The primary end points were three-month CR rate for cohort A and six-month EFS rate for cohort B. Secondary end points for both cohorts were six- and 12-month CR rates, duration of CR, one- and two-year EFS rates, one- and two-year cancer-specific survival rates, overall survival and safety.

“Preliminary efficacy and safety of Aidixi (dv) combined with Bacillus Calmette-Guérin (BCG) in the treatment of high-risk non-muscle invasive bladder cancer with HER2 expression: a prospective, open label, single-center study,” by Dr. Shen Y, et al. 

Aidixi (disitamab vedotin), an antibody-drug conjugate, combined with Bacillus Calmette-Guérin (BCG) demonstrated promising efficacy and a manageable safety profile in patients with HER2-expressing, high-risk non–muscle-invasive bladder cancer. The study showed a 100% clinical complete response rate at three and six months for patients unable to undergo complete tumor resection or with carcinoma in situ. Event-free survival at six months was also 100% for patients who underwent complete tumor resection. Treatment-related adverse events were mostly mild, with only 10% experiencing severe side effects.

Aidixi plus BCG showed strong early efficacy and manageable safety in patients with high-risk, HER2-expressing non–muscle-invasive bladder cancer.

Jason M Broderick

Tiragolumab Plus Tecentriq Doesn’t Improve NSCLC Outcomes

HR+/HER2- Metastatic Breast Cancer Progression Improved With Sac-TMT

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

Aidixi Plus Bacillus Calmette-Guérin Effective in Bladder Cancer

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