Roman Fabbricatore

Enhertu plus Perjeta improved progression-free survival versus THP in patients with HER2-positive advanced or metastatic breast cancer across subgroups.

A clinically meaningful progression-free survival (PFS) benefit was observed with Enhertu (fam-trastuzumab deruxtecan-nxki) plus Perjeta (pertuzumab), despite prior treatment, hormone receptor status, or PIK3CA mutations, when compared versus Taxol, trastuzumab and Perjeta (THP), for patients with HER2-positive advanced or metastatic breast cancer. The results were presented as a subgroup analysis for the phase 3 trial at the 

What was the DESTINY-Breast09 Study Prior Treatment Status?

The PFS assessment for prior treatment status looked at those with de novo disease or recurrent disease. The median PFS for patients with de novo disease and treated with Enhertu plus Perjeta was not calculable (NC) compared versus 31.2 months for patients treated with THP. The PFS for those with recurrent disease in the Enhertu plus Perjeta arm was 38 months and 22.5 months for those in the THP arm.

The confirmed objective response rate (cORR) for patients with de novo disease receiving Enhertu plus Perjeta (200 patients) was 90.5% with 16.5% of patients having a complete response (CR) and 74% having a partial response (PR) versus 82% in the THP arm (200 patients) and 6.5% having a CR and 75.5% having a PR. For those with recurrent disease, the cORR for those with de novo disease (183 versus 187) was 79.2% with 13.7% having a CR and 65.6% having a PR versus a cORR of 74.9% with 10.7% having a CR and 64.2% having a PR.

The median duration of response (DOR) for de novo disease in the Enhertu plus Perjeta arm was 39.2 months versus 31.3 months for those in the THP arm. For those with recurrent disease, the median DOR was 35.3 months versus 21.9 months in the THP arm.

Baseline characteristics for those with de novo disease in the Enhertu plus Perjeta arm compared versus the THP arm was an ECOG performance status of zero (68% versus 60.5%), brain metastases (5% versus 3.5%), visceral metastases (73% versus 68.5%), hormone receptor positive status (56% versus 53%), and PIK3CA mutations not detected (73% versus 72.5%). For those with recurrent disease, the characteristics included an ECOG performance status of zero (65.6% versus 66.8%), brain metastases (8.2% versus 8%), visceral metastases (73.8% versus 70.1%), hormone receptor positive status (51.9% versus 55.1%), and PIK3CA mutations not detected (65.6% versus 64.7%).

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

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

Confirmed objective response rate (cORR): percentage of patients with a confirmed partial or complete response to treatment.

Complete response (CR): disappearance of all signs of cancer after treatment.

Partial response (PR): decrease in the size of the tumor or extent of cancer in the body after treatment.

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

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

PFS-2: time from randomization until second disease progression or death, whichever occurs first.

For those with de novo or recurrent disease, any treatment-emergent side effects occurred in 100% versus 99.4% of patients in the Enhertu arm versus 99% versus 98.9% in the THP arm. Side effects of grade 3 or higher were noted in 57% versus 52.5% in the Enhertu arm and 51% versus 53.8% in the THP arm. Any side effects leading to discontinuation occurred in 23% versus 18.2% of patients in the Enhertu arm versus 33.3% versus 22.8% in the THP arm. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 14.5% versus 9.4% in the Enhertu arm and 1% versus 1.1% in the THP arm.

The median PFS for patients who were hormone receptor-positive was 38 months in the Enhertu plus Perjeta arm and 27.7 months for patients in the THP arm. For patients who were hormone receptor-negative, the median PFS in the Enhertu plus Perjeta arm was 40.7 months versus 22.6 months in the THP arm.

“Patients with [hormone receptor-positive disease] could receive concurrent [endocrine therapy] benefit after six cycles of Enhertu or discontinuation of Taxol [therapy], which occurred in 13.5% [of patients in the Enhertu plus Perjeta arm] versus 38.3% [in the THP arm],” Dr. Sibylle Loibl, chair of the German Breast Group and the Chief Executive Officer, and associate professor of obstetrics and gynecology at the Goethe University of Frankfurt, said in the presentation.

Regarding cORR for patients with hormone receptor-positive disease in the Enhertu plus Perjeta arm (207 patients) was 81.2%, with 14.5% of patients having a CR and 66.7% having a PR. In the THP arm (209 patients), the cORR was 77% with 7.2% of patients having a CR and 69.9% having a PR. For patients with hormone receptor-negative disease, the cORR in the Enhertu plus Perjeta arm (176 patients) was 89.8%, with 15.9% of patients having a CR and 73.9% having a PR. In the THP arm (178 patients), the cORR was 80.3% with 10.1% of patients having a CR and 70.2% having a PR.

The median DOR for patients with hormone receptor-positive disease receiving Enhertu plus Perjeta was 35.3 months versus 26.4 months for patients in the THP arm. For those with hormone receptor-negative disease, the median DOR in the Enhertu plus Perjeta arm was 39.2 months versus 26.3 months in the THP arm.

Baseline characteristics for patients who are hormone receptor-positive in the Enhertu plus Perjeta versus THP arms included an ECOG performance status of zero (68.1% versus 61.7%), brain metastases (4.8% versus 3.3%), visceral metastases 71% versus 67.5%), de novo disease (54.1% versus 50.7%), and PIK3CA mutations not detected (70.5% versus 69.4%). For patients who are hormone receptor-negative, the baseline characteristics included an ECOG performance score of zero (65.3% versus 65.7%), brain metastases (8.5% versus 8.4%), visceral metastases (76.1% versus 71.3%), de novo status (50% versus 52.8%), recurrent status (50% versus 47.2%), and PIK3CA mutations not detected (68.2% versus 68%).

Regarding safety for hormone receptor-positive and hormone receptor-negative status, any treatment-emergent side effects occurred in 100% versus 99.4% in the Enhertu arm and 98.1% versus 100% in the THP arm; and side effects of grade 3 or higher occurred in 52.4% versus 57.7% in the Enhertu arm and 52.7% versus 52% in the THP arm; serious treatment-emergent side effects were noted in 28.2% versus 25.7% compared versus 29% versus 20.6%; treatment-emergent side effects leading to discontinuation occurred in 17% versus 25.1% and 27.1% versus 29.7%; and adjudicated drug-related ILD/pneumonitis occurred in 9.7% versus 14.9% and 0.5% versus 1.7%, respectively.

PIK3CA Mutation Status of the DESTINY-Breast09 Study

The median PFS for patients with PIK3CA mutations was 36.0 months versus 18.1 months in both arms, respectively. For those with PIK3CA not detected, the median PFS was 40.7 months for patients in the Enhertu plus Perjeta arm and 32.7 months in the THP arm.

The cORR for patients with PIK3CA mutations in the Enhertu plus Perjeta arm (116 patients) was 81% with 14.7% of patients having a CR and 66.4% having a PR versus a cORR of 73.6% in the THP arm (121 patients) with 4.1% having a CR and 69.4% having a PR. For those who did not have PIK3CA mutations detected, the cORR was 87.2% with 15.4% having a CR and 71.8% having a PR in the Enhertu plus Perjeta arm (266 patients) versus 80.8% with 10.5% having a CR and 70.3% having a PR in the THP arm (266 patients).

The median DOR for patients with PIK3CA mutations was 34.8 months in the Enhertu plus Perjeta arm versus 18.4 months in the THP arm. For those with PIK3CA mutations not detected, the median DOR was 39.2 months versus NC.

Baseline characteristics for patients with PIK3CA mutations between either arm included an ECOG performance status of zero (61.2% versus 62.8%), brain metastases (6.9% versus 5%), visceral metastases (64.7% versus 63.6%), recurrent disease status (53.4% versus 54.5%), and hormone receptor positive status (52.6% versus 52.9%). For those with PIK3CA mutations not detected, characteristics included an ECOG performance status of zero (69.5% versus 63.9%), brain metastases (6.4% versus 6%), visceral metastases (77.1% versus 71.8%), de novo disease (54.9% versus 54.5%), and hormone receptor positive status (54.9% versus 54.5%).

For those with PIK3CA status detected or not detected, any treatment-emergent side effects occurred in 100% versus 99.6% in the Enhertu arm and 99.2% versus 98.9% in the THP arm; grade 3 or higher treatment-emergent side effects occurred in 53% versus 55.8% and 45% versus 55.7%; treatment-emergent side effects leading to discontinuation in 17.4% versus 22.3% and 24.2% versus 30.2%; and adjudicated drug-related ILD/pneumonitis in 9.6% versus 13.2% and 2.5% versus 0.4%, respectively.

What was the DESTINY-Breast09 Study Design

Patients were randomly assigned one to one to one to either Enhertu plus placebo (blinded until the PFS analysis; 387 patients), Enhertu plus Perjeta (383 patients), or THP (387 patients). This analysis focused on the Enhertu plus Perjeta and THP arms.

The primary end point was PFS by blinded independent central review, with secondary end points including overall survival, PFS by investigator, objective response rate (ORR) by blinded independent central review/investigator, DOR, PFS-2 by investigator, and safety and tolerability.

The investigators noted that if patients discontinued Enhertu due to side effects except for higher than grade 2 interstitial lung disease, patients could switch to trastuzumab. For patients with hormone receptor-positive disease, concurrent use of endocrine therapy was allowed after six cycles of Enhertu or who discontinued Taxol.

Patients were enrolled if they had first-line HER2-positive advanced/metastatic breast cancer; a disease-free interval of six months or more from last neoadjuvant or adjuvant therapy; one prior line of endocrine therapy for advanced/metastatic breast cancer; and asymptomatic brain metastases were allowed.

“Enhertu (T-DXd) + Perjeta versus Taxol + trastuzumab + Perjeta (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast9 in key subgroups of interest,” by Loibl S, Jiang Z, Barroso-Sousa R, et al Presented at the European Society for Medical Oncology Congress 2025, October 17–21, 2025; Berlin, Germany. LBA18.

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Articles

Enhertu plus Perjeta demonstrated a significant progression-free survival (PFS) advantage over THP in HER2-positive advanced/metastatic breast cancer, regardless of prior treatment, hormone receptor status, or PIK3CA mutations. The study revealed higher objective response rates and longer duration of response for Enhertu plus Perjeta, with notable differences in safety profiles. Patients with hormone receptor-positive disease benefited from concurrent endocrine therapy. The study design included random assignment to treatment arms, with primary and secondary endpoints focusing on PFS, overall survival, and safety.

Enhertu plus Perjeta improved progression-free survival versus THP in patients with HER2-positive advanced or metastatic breast cancer across subgroups.


Enhertu Plus Perjeta Boosts Survival in HER2-Positive Breast Cancer

Sacituzumab tirumotecan cut risk of progression or death by 51% versus chemotherapy in EGFR-mutated NSCLC after tyrosine kinase inhibitor resistance.

Sacituzumab tirumotecan (sac-TMT) led to a 51% reduction in the risk of progression or death compared with chemotherapy in patients with nonsquamous epidermal growth factor receptor–mutated non–small cell lung cancer that developed epidermal growth factor receptor tyrosine kinase inhibitor resistance, according to phase 3 results of the OptiTROP-Lung04 study presented during the 

Results showed that, at a median follow-up of 18.9 months, the median progression-free survival assessed by blinded independent central review was 8.3 months with sac-TMT and 4.3 months with chemotherapy. The 12-month progression-free survival rates were 32% and 8%, respectively. The benefit with sac-TMT was observed across all prespecified subgroups.

The investigator-assessed median progression-free survival was 8.4 months with sac-TMT and 4.8 months with chemotherapy. The 12-month rates were 35% and 11%, respectively.

“sac-TMT demonstrated statistically significant and clinically meaningful improvements in progression-free and overall survival compared to platinum-based chemotherapy,” lead study author Dr. Li Zhang, professor of medical oncology at Sun Yat-sen University Cancer Center in Guangzhou, China, said in an oral presentation of the data. “The results of the OptiTROP-Lung04 study support sac-TMT as a promising new treatment option for patients with EGFR-mutated non–small cell lung cancer with epidermal growth factor receptor tyrosine kinase inhibitor resistance.”

Sac-TMT is a TROP2 antibody-drug conjugate with a unique biofunctional linker that maximizes delivery of a belotecan-derivative topoisomerase I inhibitor payload to tumor cells. TROP2 is highly expressed in patients with EGFR-mutated non–small cell lung cancer, and preclinical data have shown that sac-TMT internalization and uptake are enhanced by EGFR mutations.

Disease control rate (DCR): percentage of patients whose cancer shrinks, disappears, or remains stable after treatment.

Investigator-assessed PFS: progression-free survival measured by the trial’s treating investigators rather than an independent review.

Current standard options for patients who relapse on third-generation EGFR tyrosine kinase inhibitors remain platinum-based chemotherapy, but more options are needed.

In the multicenter, open-label, phase 3 OptiTROP-Lung04 trial, 376 patients with nonsquamous stage 3B/3C or 4 non–small cell lung cancer with EGFR-sensitive mutations were randomly assigned 1:1 to receive sac-TMT at five milligrams per kilogram intravenously every two weeks or Alimta at 500 milligrams per square meter plus carboplatin area under the curve 5 or cisplatin at 75 milligrams per square meter every three weeks for up to four cycles, followed by Alimta maintenance at 500 milligrams per square meter every three weeks. Treatment was given until disease progression, intolerable toxicity, or patient request to discontinue therapy.

To be eligible for enrollment, patients needed to have an Eastern Cooperative Oncology Group performance status of zero or one and progression after third-generation tyrosine kinase inhibitor therapy or progression after first- or second-generation tyrosine kinase inhibitors with T790M-negative mutations.

Stratification factors included prior EGFR tyrosine kinase inhibitor therapy (third-generation in frontline versus second line versus no third-generation) or brain metastases (yes versus no).

The primary end point was progression-free survival assessed by blinded independent central review; secondary end points were overall survival, investigator-assessed progression-free survival, objective response rate, disease control rate, duration of response, and safety.

A total 148 patients on sac-TMT discontinued treatment due to disease progression (125 patients), patient or guardian withdrawal (12 patients), death (6 patients), side effects (2 patients), or other (3 patients). In the chemotherapy arm, 179 patients discontinued treatment due to disease progression (140 patients), patient/guardian withdrawal (16 patients), death (9 patients), side effects (5 patients), protocol deviation (2 patients), or other (7 patients). A total 69 and 102 patients in each arm, respectively, discontinued from the study due to death (67 and 101 patients) or were lost to follow-up (2 and 1 patients).

Patient baseline characteristics were generally well balanced between the sac-TMT (188 patients) and chemotherapy arms (188 patients). The median age was 60 years and 59 years, and 31% and 27% were at least 65 years. Most had a performance status of 1 (81% and 77%), had no smoking history (77% and 72%), had stage 4 disease (97% and 98%), and at least three metastatic sites (68% and 67%). A total 18% and 19% had brain metastases, and 13% and 18% had liver metastases. The majority in each arm had exon 19 deletions (56% and 63%), had unknown T790M mutation status (59% and 60%), and received a prior third-generation EGFR tyrosine kinase inhibitor in the frontline setting (63% and 62%).

The interim analysis showed that for sac-TMT, the median overall survival was not reached compared with 17.4 months with chemotherapy, leading to a 40% reduction in the risk of death. The 18-month overall survival rates were 66% and 48%, respectively. Overall survival was improved with sac-TMT across all prespecified subgroups.

Dr. Zhang also reported on subsequent anticancer treatment from the trial; 72% of patients on sac-TMT and 86% of those on chemotherapy received at least one subsequent treatment. In the sac-TMT and chemotherapy groups, respectively, these included chemotherapy (42%; 54%), specifically Alimta-based chemotherapy (37%; 13%), an EGFR tyrosine kinase inhibitor (43%; 40%), an anti-angiogenic agent (35%; 48%), immunotherapy (17%; 25%), or an antibody-drug conjugate (1%; 20%).

When assessed via blinded independent central review, the objective response rate with sac-TMT was 61% compared with 43% with chemotherapy; the disease control rate was 87% and 80%, respectively. The median duration of response was 8.3 months with sac-TMT and 4.2 months with chemotherapy; the 12-month rates were 36% versus 8%, respectively.

Regarding safety, treatment-related side effects occurred in 100% and 98% of sac-TMT– and chemotherapy-treated patients, respectively. Grade 3 or higher side effects occurred in 58% and 54% of patients, and serious side effects occurred in 9% and 18% of patients, respectively. Side effects that led to dose reductions and interruptions occurred in 30% and 37% of patients on sac-TMT; there were no side effects that led to discontinuation or death. In the chemotherapy arm, these rates were 23% and 33%; one patient each experienced side effects leading to discontinuation or death.

The median duration of exposure was 9.6 months with sac-TMT and 4.9 months with chemotherapy. The most common side effects in both arms were hematologic; sac-TMT had higher incidence of stomatitis that were mostly grade 1 or 2 (any-grade 62%; grade ≥3 5%). Ocular surface toxicities also occurred in 10% of patients on sac-TMT, all grade 1 or 2. No cases of interstitial lung disease or pneumonitis were reported on the sac-TMT arm.

Phase 3 trials are currently exploring sac-TMT alone and in combination with Tagrisso in patients with EGFR-mutant non–small cell lung cancer.

“Sacituzumab tirumotecan versus platinum-based chemotherapy in EGFR-mutated non-small cell lung cancer following progression on EGFR-TKIs” by Dr. Zhang, et al., presented at the 2025 ESMO Congress.

“Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations” by Dr. Zhao, et al., Nat Med.

Sacituzumab tirumotecan (sac-TMT) demonstrated a significant 51% reduction in progression or death risk compared to chemotherapy in EGFR-mutated non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors. The OptiTROP-Lung04 study showed sac-TMT improved progression-free survival to 8.3 months versus 4.3 months with chemotherapy. Overall survival was also enhanced, with a 40% reduction in death risk. Sac-TMT's safety profile was favorable, with manageable side effects. These findings suggest sac-TMT as a promising treatment option for this patient population.

Sacituzumab Tirumotecan Improves Survival in EGFR-Mutated Non-Small Cell Lung Cancer

Adding Tecentriq to chemo resulted in survival outcomes comparable to placebo plus chemo in patients with advanced or recurrent endometrial cancer.

Adding Tecentriq to chemo resulted in survival outcomes comparable to placebo plus chemo in patients with advanced or recurrent endometrial cancer, according to results from the phase 3 AtTEnd/ENGOT-EN7 trial presented at the 2025 ESMO Congress.

Adding Tecentriq (atezolizumab) to chemotherapy resulted in survival outcomes comparable to placebo plus chemotherapy in patients with advanced or recurrent endometrial cancer, according to results from the phase 3 AtTEnd/ENGOT-EN7 trial presented at the 2025 ESMO Congress.

After a median follow-up of 48.9 months, overall survival (OS) did not significantly differ between patients treated with Tecentriq versus placebo, with a median of 36 months versus 30.5 months, respectively. The respective 12- and 24-month OS rates were 80.1% versus 73.8% and 61.1% versus 58.4%. Additionally, 12.1% of patients in the Tecentriq arm versus 29.2% in the placebo arm received subsequent immunotherapy.

In a planned subgroup analysis based on mismatch repair deficient (dMMR) status, patients with dMMR disease experienced significantly improved OS with Tecentriq. Median OS was not evaluable in the Tecentriq arm versus 31.8 months with placebo; 12- and 24-month rates were 86.8% versus 66.8% and 74.8% versus 54.8%. Subsequent immunotherapy was received by 7.4% versus 45.5% of patients in each respective arm.

Among patients with non-dMMR status, survival outcomes did not significantly differ. Median OS was 30 months with Tecentriq versus 30.2 months with placebo; 12- and 24-month rates were 77.8% versus 75.8% and 55.9% versus 58.8%. Subsequent immunotherapy was received by 13.8% versus 24.3% of patients, respectively.

Progression-free survival (PFS) outcomes numerically favored Tecentriq across all patients. Median PFS was 9.9 months versus 8.9 months, with 12- and 24-month rates of 44.7% versus 28.9% and 28.7% versus 16.8%. Among patients with dMMR disease, median PFS was not evaluable versus 6.9 months, with 12- and 24-month rates of 62.7% versus 23.3% and 52.1% versus 16.3%. In non-dMMR patients, median PFS was 9.5 months versus 9.2 months, with 12- and 24-month rates of 39.1% versus 30.2% and 21.7% versus 16.0%.

Overall survival (OS): The length of time patients are still alive after starting treatment.

Progression-free survival (PFS): The length of time patients live without cancer getting worse.

Mismatch repair deficient (dMMR): A genetic feature of some cancers where cells cannot fix DNA errors properly, making tumors more responsive to immunotherapy.

Objective response rate (ORR): The percentage of patients whose tumors shrink or disappear after treatment.

Complete response (CR): The disappearance of all signs of cancer.
Partial response (PR): A significant reduction in tumor size but not complete disappearance.

Duration of response (DOR): How long a patient’s tumor remains reduced or gone after treatment.

ECOG performance status: A scale (0-5) that measures a patient’s daily functioning and ability to care for themselves.


Objective response rate (ORR) and duration of response (DOR) in dMMR patients numerically favored Tecentriq. ORR was 82.4% with a complete response (CR) rate of 26.5% and a partial response (PR) rate of 55.9%, versus 75.7% with a CR rate of 18.9% and a PR rate of 56.8% with placebo. Median DOR was not evaluable versus 4.9 months, with 12- and 24-month rates of 66.9% versus 22.3% and 57.6% versus 14.8%. In non-dMMR patients, ORR was 75.6% versus 74.6%, with CR and PR rates of 15.1% and 60.5% versus 10.5% and 64.0%. Median DOR was 7.8 months versus 7 months, with 12- and 24-month rates of 35.1% versus 29.8% and 19.9% versus 15.0%.

“The addition of Tecentriq to chemotherapy did not demonstrate a statistically significant survival benefit in patients with advanced or recurrent endometrial carcinoma,” said Dr. Maria Pilar Barretina Ginesta. “In the pre-planned subgroup analysis based on mismatch repair status, substantial survival improvement was observed in patients with dMMR carcinomas.”

The study enrolled patients with advanced newly diagnosed or recurrent endometrial carcinoma or carcinosarcoma and randomly assigned them to receive paclitaxel and carboplatin area with Tecentriq or matching placebo. Following chemotherapy, patients received Tecentriq as maintenance or matching placebo.

Patients were stratified by country, histology, recurrent status, and dMMR status. Dual primary end points were PFS and OS.

Among all patients in the Tecentriq (360) and placebo (189) arms, 22.5% versus 23.3% had dMMR status. Recurrent disease status was 67.5% versus 66.7%, and 70.6% versus 68.2% had not received prior chemotherapy. In newly diagnosed disease, 75.2% versus 85.7% had measurable disease. Median age was 67 versus 65 years, and most patients were Caucasian (80.3% versus 75.7%), PD-L1–negative (68.6% versus 68.2%), and had intact ARID1A expression (68.9% versus 69.3%).

Any-grade side effects occurred in 98.6% versus 100%, with 75.8% versus 63.8% related to Tecentriq versus placebo. Grade 3 or higher side effects were observed in 26.4% versus 14.1%, with fatal side effects in 0.3% versus 0.5%. The most common side effects in the Tecentriq versus placebo arms were anemia (41.3% versus 35.1%), fatigue (39% versus 41.1%), neutropenia (40.7% versus 39.5%), peripheral sensory neuropathy (38.8% versus 39.5%), nausea (34% versus 37.3%), and hair loss (31.5% versus 36.2%).

"Final overall survival (OS) results from the randomized double-blind phase III AtTEnd/ENGOT-EN7 trial evaluating atezolizumab in combination with paclitaxel and carboplatin in women with advanced/recurrent endometrial cancer," by Dr. Maria Pilar Barretina Ginesta. Presented at the European Society for Medical Oncology (ESMO) Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA39.

The phase 3 AtTEnd/ENGOT-EN7 trial evaluated the addition of Tecentriq (atezolizumab) to chemotherapy in patients with advanced or recurrent endometrial cancer. Results showed no significant overall survival (OS) benefit compared to placebo, except in patients with mismatch repair deficient (dMMR) disease, who experienced improved OS. Progression-free survival (PFS) outcomes favored Tecentriq across all patients. Objective response rate (ORR) and duration of response (DOR) were better in dMMR patients with Tecentriq. Side effects were common, with higher grade 3 or higher side effects in the Tecentriq arm.

Tecentriq Plus Chemo Shows Comparable Survival in Endometrial Cancer

Data from the AQUILA study support the use of fixed-duration subcutaneous Darzalex Faspro as an early treatment option in high-risk smoldering myeloma: © stock.adobe.com.

A poster presented at the 2025 Society of Hematologic Oncology Annual Meeting showed that subcutaneous Darzalex Faspro (daratumumab and hyaluronidase-fihj) significantly lowered the risk of disease progression or death compared with active monitoring in patients with high-risk smoldering multiple myeloma.

With a median follow-up of 65.2 months, the median progression-free survival (PFS) was not reached with Darzalex Faspro versus 41.5 months with monitoring, correlating with a 51% reduction in the risk of progressive disease or death. Per International Myeloma Working Group SLiM diagnostic criteria, investigators noted progression to multiple myeloma in 25.8% (50 of 194 patients) and 33.2% (65 of 196 patients) of each respective arm. Progression to multiple myeloma occurred in 6.2% (12 of 194 patients) and 17.3% (34 of 196 patients) of patients in each arm.

Investigators highlighted a PFS benefit with Darzalex Faspro across all pre-specified subgroups. An especially pronounced benefit occurred among patients with high-risk status; the median PFS was not reached with Darzalex Faspro versus 22.1 months with monitoring in this group.

“Darzalex Faspro demonstrated a favorable safety profile, with a low rate (5.7%) of treatment discontinuation due to treatment-emergent side effects. Patients maintained their health-related quality of life during Darzalex Faspro treatment compared with active monitoring,” lead study author, Dr. Meletios Athanasios Dimopoulos, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine in Greece, wrote in the poster with coauthors. “Results from the phase 3 AQUILA study strongly support early intervention with subcutaneous Darzalex Faspro monotherapy for a fixed duration in patients with high-risk smoldering multiple myeloma, representing an opportunity to delay or avoid end-organ damage and progression to multiple myeloma although preserving quality of life and extending survival.”

In the open-label, multicenter phase 3 AQUILA study, 390 patients were randomly assigned to receive subcutaneous Darzalex Faspro at 1800 milligrams every week on cycles 1 and 2, every two weeks on cycles 3 to 6, and every four weeks thereafter for a maximum of 36 months (194 patients) or active monitoring, which consisted of no disease-specific therapy with side effect monitoring for up to 36 months (196 patients). During the study’s follow-up phase, investigators evaluated efficacy until progression and assessed survival every 6 months until the study’s conclusion.

The trial’s primary end point was independent review committee. Key secondary end points included objective response rate (ORR), time to first-line treatment for multiple myeloma, PFS on first-line treatment, and overall survival (OS).

Patients 18 years and older with a confirmed smoldering multiple myeloma diagnosis per International Myeloma Working Group criteria for no longer than 5 years, and an ECOG performance status of 0 or 1 were eligible for enrollment on the trial.

The median age was 63 years in the Darzalex Faspro arm and 64.5 years in the active monitoring arm, and most from each respective arm were women (51% versus 52.6%). In each arm, most patients had an ECOG performance status of 0 (85.1% versus 81.6%), fewer than thre risk factors for progression to multiple myeloma (79.4% versus 79.6%), and intermediate-risk (39.7% versus 38.8%) or high-risk status (37.1% versus 43.9%).

Data showed an ORR of 63.4% with Darzalex Faspro versus 2% with active monitoring. Among patients who received Darzalex Faspro, a very good partial response or better occurred in 29.9%, and 8.8% had a complete response or better.

The median time to initiating subsequent frontline therapy was not reached in the Darzalex Faspro arm and 50.2 months in the monitoring arm. The 60-month PFS rate on frontline therapy was 85.9% and 78% in each respective arm. The 60-month OS rates were 93% and 86.9%, respectively; data showed a strong positive trend toward longer OS with Darzalex Faspro.

Investigators noted no new safety signals among those who received Darzalex Faspro. In the Darzalex Faspro and monitoring arms, 96.9% versus 82.7% had side effects of any grade, 40.4% versus 30.1% had grade 3 or higher side effects, 29% versus 19.4% had serious side effects, and 1% versus 2% had grade 5 side effects. The most common grade 3 or higher side effect in each arm was hypertension (5.7% versus 4.6%), and the incidence of second primary malignancies was comparable between arms (9.3% versus 10.2%).

Health-related quality of life outcomes with Darzalex Faspro appeared to be consistent across multiple measures and domains. Similar mean changes between baseline and week 112 occurred in both treatment arms.

The European Commission approved subcutaneous Darzalex Faspro for this smoldering multiple myeloma population in July 2025 based on findings from the AQUILA trial. Additionally, the FDA’s Oncologic Advisory Drug Committee voted in favor of Darzalex Faspro’s benefit/risk profile for those with high-risk smoldering multiple myeloma in May 2025. 

“Phase 3 AQUILA study of daratumumab monotherapy versus active monitoring in patients with high-risk smoldering multiple myeloma,” by Dr. Meletios Athanasios Dimopoulos. Presented at the 2025 Society of Hematologic Oncology Annual Meeting (SOHO); Sept. 3-6, 2025; Houston, TX. MM-691.

“European Commission approves DARZALEX (daratumumab) as the first licensed treatment for patients with high-risk smouldering multiple myeloma,” by Johnson & Johnson. News release; July 23, 2025.

“May 20-21, 2025 Meeting of the Oncologic Drugs Advisory Committee (ODAC) - Day 1. Streamed live May 20, 2025,” by U.S. Food and Drug Administration. https://www.youtube.com/live/iSGFdhMgh1E

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Subcutaneous Darzalex Faspro (daratumumab and hyaluronidase-fihj) significantly reduced the risk of disease progression or death in high-risk smoldering multiple myeloma patients compared to active monitoring. The phase 3 AQUILA study demonstrated a 51% reduction in progression risk, with a median progression-free survival not reached in the treatment arm. Darzalex Faspro showed a favorable safety profile and maintained patients' quality of life. The European Commission approved its use in July 2025, and the FDA's advisory committee endorsed its benefit/risk profile for high-risk patients.

Data from the AQUILA study support the use of fixed-duration subcutaneous Darzalex Faspro as an early treatment option in high-risk smoldering myeloma. 

Roman Fabbricatore

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