Silas Inman

The ADC zilovertamab vedotin plus Rituxan and chemo showed an ORR of 56.3% in relapsed/refractory DLBCL: © stock.adobe.com. 

Among patients with with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), zilovertamab vedotin, a ROR1-targeted antibody-drug conjugate, plus Rituxan (rituximab) and gemcitabine-oxaliplatin (R-GemOx) elicited an objective response rate of 56.3%, according to findings from the phase 2/3 waveLINE-003 study which were shared at the 

At the recommend phase 2 dose of 1.75 milligrams per kilogram (mg/kg) for zilovertamab vedotin plus standard R-GemOx, the complete response rate was 50% in the study. After a median of 9.9 months of follow-up, the median duration of response was 8.7 months, with 28.6% of patients continuing to respond at nine months. The median overall survival was not yet reached, with a 12-month estimated overall survival rate of 68.9% at the RP2D.

"This combination had a manageable safety profile, and the objective and complete response rate of 56% and 50% of the zilovertamab vedotin plus R-GemOx combination at the recommended phase 2 dose suggest improved activity in relapsed/refractory DLBCL," said principal investigator Dr. Philippe Armand, from Dana-Farber Cancer Institute. "The study is currently enrolling the phase 3 portion."

The phase 2 portion of the study enrolled 40 participants with relapsed/refractory DLBCL. R-GemOx was administered at standard doses in each group, with zilovertamab escalated across three dose levels. There were 17 patients who received 1.5 mg/kg, 16 receiving 1.75 mg/kg, and seven who received 2.0 mg/kg. Across all groups, the median number of prior therapies was two, with two specifically having received the CD79b-directed Polivy (polatuzumab vedotin). Armand noted this agent specifically, as it carries the same cytotoxic payload as zilovertamab vedotin; however, data were not shown for this subgroup during the presentation.

Across all patients enrolled, the median age was 66.5 years, with 55% being 65 years or older. ECOG performance status was zero (43%), one (48%), and two (10%) and nearly half of patients had Ann Arbor stage IV disease (53%). The DLBCL cell of origin was most commonly GCB (45%).

At the 1.5 mg/kg dose, the overall response rate was 26.7% with a complete response rate of 20.0%. The median duration of response in this group was 14.4 months, with a 9-month duration of response rate of 100%. The median overall survival was 11.5 months in this group, with a 12-month overall survival rate of 40.8%. The median follow-up for this dose level was 18.1 months.

In the 2.0 mg/kg group, the overall response rate was 57.1%, with a complete response rate of 42.9%. The median duration of response in this group was not yet reached. The median overall survival in this group was 7.4 months, with a 12-month overall survival rate that was not yet reached. The median follow-up in this cohort was 9.3 months.

"The obvious caveat here are the few patients and still limited duration of follow up. So, the estimates are not very stable," Armand cautioned regarding the response duration data.

There was a total of 7 dose limiting toxicities observed across the three dose levels. At the 2.0-mg/kg dose, there were four, compared with one in the 1.5-mg/kg group and two at the recommended phase 2 dose group. In the 2.0-mg/kg dose level, there was one treatment-related death from sepsis.

Other dose limiting toxicities in this group included grade 3 diarrhea, grade 4 neutrophil count decrease, grade 4 thrombocytopenia, grade 3 febrile neutropenia, and grade 4 neutrophil count decrease. To address these side effects, midway through the trial the protocol was adapted to included mandatory prophylaxis with G-CSF. In the recommended phase 2 dose arm, the dose limiting toxicities were grade 3 alanine aminotransferase increase and intestinal obstruction.

This combination had a manageable safety profile, and the objective and complete response rate of 56% and 50% of the zilovertamab vedotin plus R-GemOx combination at the recommended phase 2 dose suggest improved activity in relapsed/refractory DLBCL.

Zilovertamab vedotin-related side effects of grade 3 (severe)/4 (life threatening) in severity were experienced by 63% of patients in the recommended phase 2 dose group. This compared with 86% of those in the largest dose and for 53% of those in the lowest dose. Two patients discontinued the drug in the highest dose group, related to sepsis and respiratory fatigue. There were no discontinuations at the other dose levels. Serious drug-related side effects were experienced by 24% of those in the low dose group, by 31% at the recommended phase 2 dose group, and for 57% of those at the 2.0 mg/kg dose.

Several studies continue to explore zilovertamab vedotin for patients with DLBCL, including the phase 3 portion of the waveLINE-003 study. Armand also drew attention to studies looking at zilovertamab vedotin as a first-line treatment for DLBCL in combination with chemotherapy compared with chemo alone. Additionally, waveLINE-011 is investigating zilovertamab vedotin with chemo as a first-line therapy for the GCB subtype of DLBCL compared with Polivy plus chemo.

“WaveLINE-003: Phase 2/3 trial of zilovertamab vedotin plus standard of care in relapsed/refractory diffuse large B-cell lymphoma” by Dr. Philippe Armand, et al., American Society of Clinical Oncology Annual Meeting.

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Zilovertamab vedotin, a ROR1-targeted antibody-drug conjugate, combined with Rituxan and gemcitabine-oxaliplatin, demonstrated a 56.3% objective response rate in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients. At the recommended phase 2 dose of 1.75 mg/kg, the complete response rate was 50%, with a median response duration of 8.7 months. The safety profile was manageable, though severe side effects were noted. The study is progressing to phase 3, with ongoing investigations into zilovertamab vedotin as a first-line treatment for DLBCL.

The antibody-drug conjugate zilovertamab vedotin plus Rituxan and chemotherapy showed an objective response rate of 56.3% in relapsed/refractory DLBCL.

Zilovertamab Vedotin Plus Chemo Combo Shows Responses in R/R DLBCL 

Akeega delayed progression and symptoms in patients with HRR-positive castration-sensitive prostate cancer.

A 37% reduction in the risk of radiographic progression or death was observed with Akeega (niraparib plus abiraterone acetate [Zytiga]) plus prednisone compared with Zytiga, prednisone, and placebo (AAP), in patients with metastatic castration-sensitive prostate cancer (mCSPC) who had homologous recombination repair (HRR) gene alterations and had previously received androgen deprivation therapy (ADT), according to results from the phase 3 AMPLITUDE trial presented at the 

After a median follow-up of 30.8 months, the median radiographic progression-free survival (rPFS) was not estimable in the Akeega group compared with 29.5 months in the placebo arm. Furthermore, Akeega significantly reduced the risk symptomatic progression by 50% compared with AAP and placebo. Overall survival (OS) was not statically significant at the analysis, with trends beginning to emerge showing improvement with Akeega.

“Improvements in rPFS are supported by a statistically significant benefit in time to symptomatic progression and a trend toward improved OS,” lead investigator Dr. Gerhardt Attard, Cancer Institute, University College London, said during a presentation of the findings. “In my opinion, AMPLITUDE supports [Akeega] as a treatment option for patients in this poor prognostic disease group.”

HRR gene alterations: changes in genes like BRCA1 or BRCA2 that affect the cell’s ability to repair DNA damage.

Radiographic progression-free survival (rPFS): time during and after treatment that a patient lives without cancer getting worse on scans.

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

PARP inhibitor: a type of drug that blocks a protein cancer cells use to repair DNA damage, making them more likely to die.

Androgen deprivation therapy (ADT): treatment that lowers testosterone to slow prostate cancer growth.

De novo M1: metastatic cancer present when the disease is first diagnosed.

High-volume metastatic disease: cancer that has spread widely, often to multiple bones or organs.

Patient Demographics and Additional Findings From AMPLITUDE

In the study, 696 patients were evenly randomized to receive Akeega (348 patients) or placebo plus AAP (348 patients). The median age of enrolled patients was 68 years. Overall, 78% of patients had high-volume metastatic disease (M1), of which 87% were de novo M1. All patients had received ADT for six months or less and 16% of patients had received prior docetaxel. All patients in the study had an alteration in genes associated with HRR, which included BRCA1/2 alterations for 55.6% of patients. Remaining alterations could have been in BRIP1, CDK12, CHEK2, FANCA, PALB2, RAD51B or RAD54L.

For patients specifically with BRCA mutations, the improvements in rPFS were more pronounced. In this group, there was a 48% reduction in the risk of radiographic progression or death with the addition of the PARP inhibitor. The median for the Akeega arm was not estimable compared with 26 months with AAP.

“This was a really exciting result,” said Attard. “This is the first study to show efficacy for PARP inhibition and androgen receptor inhibition in CSPC, the benefit [of which] might be greatest in patients with BRCA mutations.”

Those with BRCA1/2 mutations also had a significant reduction in the risk of symptomatic progression. In this subgroup, there was a 56% reduction in the risk of symptom progression with the PARP inhibitor compared with the androgen synthesis inhibitor and placebo.

“This is a patient-centric end point, measuring the time to worsening of symptoms, which includes needing radiation or a procedure or intervention or further cancer treatment,” said Attard. “Very convincingly we show a clear benefit with [Akeega].”

OS was still immature across the study. At the analysis, the BRCA1/2 subgroup showed similar trends as in the full population of those with HRR gene alterations. In this group, there was an early 25% reduction in the risk of death observed with Akeega.

“Half the number of patients have died from the target number we would require for the final analysis, but in my view, there’s a clear trend for favoring survival in the patients randomized to [Akeega],” said Attard.

Diving Into the Safety and Possible Implications

Grade 3 (severe) or 4 (life-threatening) adverse effects (AEs; side effects) were observed in 75.2% of those receiving Akeega compared with 58.9% of those in the control arm. The most common AEs were anemia (29.1% with Akeega versus 4.6% with placebo) and hypertension (26.5% versus 18.4%). Of those with anemia, the majority required a transfusion.

Dose interruptions were required for 66.9% of patients in the Akeega arm compared with 42.4% for the control arm. Dose reductions were needed to address AEs for 21.9% of those in the Akeega arm compared with 6.9% of those in the placebo group. Treatment was discontinued for 14.7% of those in the Akeega arm compared with 10.3% of those in the placebo group. Treatment-emergent AEs led to death for 14 patients in the investigational arm compared with seven in the control group.

“We’re used to the side effect profile with these drugs, and we aren’t seeing any new side effects but clearly those randomized to [Akeega] have more AEs than those randomized to placebo,” said Attard. “But critically, I think, the proportion of patients who [were] required to discontinue treatment was fewer than 5% for those on [Akeega] versus placebo.”

In 2023, Akeega was approved by the FDA in combination with AAP for patients with deleterious or suspected deleterious BRCA-mutated castration-resistant prostate cancer, based on findings from the phase 3 MAGNITUDE study. Results from the AMPLITUDE study could expand this approval to those with castration-sensitive disease.

“This is really exciting news for our patients,” ASCO expert commentator Dr. Bradley McGregor, from Dana-Farber Cancer Institute, said of the results. “PARP inhibitors have been a mainstay in the treatment of metastatic castrate-resistant prostate cancer for those patients with HRR alterations, and this is the first time we’ve seen data for these in the hormone-sensitive setting. As you heard this is a very poor prognostic group, so I think this is incredibly exciting.”

“Phase 3 AMPLITUDE trial: Akeega for metastatic castration-sensitive prostate cancer with homologous recombination repair gene alterations” by Dr. Gerhardt Attard, et al., 

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The addition of the PARP inhibitor Zejula to Zytiga and prednisone significantly reduced the risk of radiographic progression or death by 37% in patients with metastatic castration-sensitive prostate cancer (mCSPC) with HRR gene alterations, as shown in the phase 3 AMPLITUDE trial. The trial demonstrated a 50% reduction in symptomatic progression risk and a trend towards improved overall survival. However, Zejula was associated with higher rates of severe adverse effects, including anemia and hypertension, necessitating dose adjustments and treatment discontinuations in some cases.

Akeega delayed cancer growth and symptoms in patients with castration-sensitive prostate cancer and HRR gene mutations.

Akeega Combo Delays Progression in HRR+ Castration-Sensitive Prostate Cancer

For patients with relapsed or refractory myeloma, Belamaf (belantamab mafodotin) plus bortezomib and dexamethasone — a regimen referred to as BVd — lengthened the time that patients lived before experiencing disease progression compared to those treated with Darzalex (daratumumab), bortezomib and dexamethasone (DVd), according to research presented at the 2024 

American Society of Clinical Oncology Annual Meeting

A new three-drug regimen, called BVd, was found to be more effective than the standard regimen, DVd, for patients with relapsed or refractory myeloma.

BVd increased progression-free survival (PFS) by 59% compared to DVd. PFS is the time patients live until their disease worsens.

More data is needed to confirm the overall survival benefit of BVd.

The researchers concluded that BVd is a potential new standard of care for relapsed/refractory myeloma patients.

The median progression-free survival (PFS; time patients live until disease worsening) with BVd was 36.6 months compared with 13.4 months for DVd, representing a 59% reduction in the risk of progression or death.

Data for overall survival (OS; time from treatment until death of any cause) were not ready at the time that the researchers collected data, meaning that not enough patients had died for them to calculate an average. At 18 months, 84% of patients remained alive in the BVd group compared with 73% in the DVd arm, indicating an early, but not yet statistically significant, reduction of 43% in the risk of death. When an outcome difference between two datapoints is not statistically significant, it means that the researchers could not be certain that one regimen performed better than the other.

“There was a statistically significant and clinically meaningful progression-free survival benefit, with a strong and clinically meaningful overall survival benefit favoring BVd over DVd. All the response as well as the different response categories were also in favor of BVd,” lead investigator Dr. María-Victoria Mateos, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Centro de Investigación del Cáncer (IBMCC-USAL, CSIC), said during a presentation of the results. “These trials support the potential for BVd as a potential new standard of care for relapsed/refractory myeloma patients.”

In the study, 494 patients were randomly assigned to receive BVd (243 patients) or DVd (251 patients).

The median age of patients in the BVd arm was 65 years and was 64 years in the DVd arm. The ECOG performance score was 1 or less for 96% of patients, meaning that the patients could independently perform all of their daily tasks. Most had stage 1 or 2 disease (95%). The median time from diagnosis in the BVd arm was 4.3 years compared with 3.9 years in the control group. Two-thirds of patients had standard cytogenetic risk, meaning that they did not have genetic mutations associated with poor prognosis (72% and 70% in the BVd and DVd arms, respectively). The most common high-risk cytogenetic characteristics was t(4;14), which was present in 17% of participants. This was followed by a deletion in 17p13 for 12% in the BVd group and for 14% in the DVd arm.

Extramedullary disease (myeloma located outside of the bone marrow) was present for 5% of those in the BVd arm compared with 10% of those in the DVd group. Half of patients had received one prior line of therapy, and 12% in the BVd arm and 11% in the DVd group had received four or more lines of therapy. Prior therapies were similar between groups and the time to relapse after the most recent therapy was the same for each group, with 20% having relapsed in 12 or less months. There were 2% of patents in the DVd arm who had received prior Darzalex. Rates of prior chemotherapy and autologous stem cell transplantation were similar.

In a pre-specified subgroup analysis, Mateos noted that BVd was superior to DVd across all subgroups, including those with disease that did not respond to prior Revlimid (lenalidomide) and those with high-risk cytogenetics.

Deeper responses were noted with BVd versus DVd, Mateos noted. The objective response rate (ORR; percentage of patients whose disease shrunk or disappeared) with BVd was 82.7%, which consisted of a stringent complete response (sCR; when there are no myeloma cells or proteins detected in the bone marrow or urine) rate of 14% and a complete response (CR; no disease detected in the bone marrow) rate of 20.6%, for a CR or better rate of 34.6%.

The CR or better rate with DVd was 17.1% and consisted of a sCR rate of 5.2% and a CR rate of 12%. The ORR in the DVd arm was 71.3%. Minimal residual disease (MRD)-negative (no cancer detected in the blood) CRs were experienced by 24.7% of those in the BVd arm versus 9.6% in the DVd arm. Very good partial responses (VGPR; 90% or more decrease in blood M protein, associated with myeloma) were seen in 31.3% of those treated with BVd and for 29.1% of those treated with DVd. MRD-negative VGPR or better rates were 38.7% and 17.1% for BVd and DVd, respectively.

“The CR rate or better was doubled with BVd and it is important to note the superiority of MRD negativity rate, which in myeloma is one of the most important factors predicting outcome,” Mateos said.

Side effects of any grade was experienced by all patients enrolled in the trial. Moderate to severe (grade 3/4) side effects that were related to treatment occurred in 90% of those enrolled in the BVd arm compared with 67% in the DVd group. Side effects led to treatment discontinuation for 31% of patients in the BVd arm compared with 19% in the DVd group. Side effects led to a dose reduction for 75% of patients in the BVd group compared with 59% in the DVd group. Treatment-related serious side effects were seen in 19% of those in the BVd group and for 12% in the DVd group. Fatal side effects related to study drug were experienced by seven patients in the BVd arm compared with two in the DVd arm.

Changes in baseline correct visual acuity were the most unique side effects, Mateos noted. Overall, 34% of patients experienced a worsening in visual acuity from 20/20 to 20/50, or blurred vision, Mateos said. There were 2% of patients who experienced a shift to 20/200 vision, or impaired vision.

“With dose adjustments and delays, a majority of patients resolved these ocular events, and only 9% of patients had to discontinue treatment due to ocular events,” said Mateos.

An analysis was conducted to examine whether dose interruptions and delays impacted PFS. For those with one or more dose delays that lasted 12 weeks or longer, the median PFS was 36.6 months, which matched the overall median for the trial. Moreover, quality was not different between groups, Mateos noted.

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Belamaf plus bortezomib and dexamethasone lengthened the time patients with relapsed or refractory myeloma lived before their disease got worse. 

Belamaf Regimen Improves Progression-Free Survival in Myeloma 

Neoadjuvant (primary cancer treatment) Opdivo (nivolumab) plus Yervoy (ipilimumab) followed by therapeutic lymph node dissection (surgical removal of the lymph nodes) and response-driven adjuvant therapy (additional cancer treatment after the primary treatment to reduce the risk for the cancer to return) reduced the risk of progression, recurrence or death by 68% compared with therapeutic lymph node dissection and adjuvant Opdivo alone for patients with macroscopic stage 3 node-positive melanoma, study findings demonstrated.

Findings from the phase 3 NADINA study were presented at the 2024 ASCO Annual Meeting.

The combination of neoadjuvant Opdivo (nivolumab) and Yervoy (ipilimumab) followed by response-driven adjuvant therapy significantly reduced the risk of progression, recurrence or death by 68% compared to therapeutic lymph node dissection and adjuvant Opdivo alone in patients with stage 3 node-positive melanoma.

The NADINA phase 3 study demonstrated that 12-month event-free survival (EFS) was 83.7% for patients receiving the combination therapy, versus 57.2% for those receiving adjuvant therapy alone, with consistent benefits across various subgroups and a correlation between pathologic complete response and EFS.

Subgroup analyses indicated improved EFS for both BRAF-mutant and BRAF wild-type melanoma patients with neoadjuvant Opdivo/Yervoy compared to adjuvant therapy alone, with significant pathologic complete response rates observed.

The neoadjuvant combination therapy was associated with higher rates of severe side effects, but overall quality of life was similar to that of the adjuvant therapy group, highlighting the benefit of immunotherapy prior to surgery as a new standard of care for stage 3 melanoma.

At an analysis conducted after a median 9.9 months’ of follow-up, the estimated 12-month event-free survival (the time after primary treatment ends when a patient is free from the complications or events that treatment was meant to delay or prevent; EFS) rate with the neoadjuvant combination of Opdivo and Yervoy plus response-drive adjuvant therapy was 83.7% compared with 57.2% for adjuvant therapy alone. This benefit remained consistent across key subgroups, and a correlation was seen between pathologic complete response rates (the lack of the signs of cancer in tissue samples that are removed during surgery or after treatment) and EFS.

"This was at once the interim and the final analysis, because it was highly statistically significantly positive," lead investigator Dr. Christian U. Blank, Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands, said during a press briefing on the results. "I think NADINA defines now in melanoma that neoadjuvant immunotherapy is the new standard of care for macroscopic stage 3 melanoma. It is a new template for other malignancies implementing an immunotherapy regimen followed by response driven activities."

In the study, 423 patients were randomly assigned to the neoadjuvant arm (212 patients) or the standard-of-care adjuvant group (211 patients). Most patients in the study were male (65%), and ages were mixed between those over and under the age of 60. All patients had at least 1 PET-positive lymph node at diagnosis, with 19.6% having 2 to 3 nodes and 3.5% with more than 3 positive nodes. There were 11.3% of patients with metastases in transit (when cancer cells travel from the original tumor but may have gotten stuck in between the tumor and the lymph nodes).

For those with BRAF-mutant melanoma (which may lead to uncontrolled cell division and growth leading to cancer), the EFS rate was 83.5% with neoadjuvant Opdivo/ Yervoy compared with 52.1% for those treated with adjuvant therapy alone. In the BRAF wild-type group (when the BRAF gene is found in its natural, non-mutated state), the EFS with neoadjuvant Opdivo/Yervoy was 83.9% compared with 62.4% with adjuvant therapy alone.

By local assessment (the evaluation of a patient’s response to treatment by an oncologist directly involved in their care), the major pathologic response rate (how to measure how the disease has responded to treatment) with neoadjuvant Opdivo/Yervoy was 56.6% and by central review (independent of biopsies, scans, or other measurements typically performed during a trial), it was 59%. The pathological complete response rate (lack of all signs of cancer) was 45.8% by local assessment and 47.2% by central review. A minority of patients had a pathological partial response (decrease in tumor size or extent of cancer in the body) of 9.4% by local assessment and 8% by central review. For those with a pathological complete response, the probability of relapse-free survival (the time after treatment when a patient survives without symptoms or signs of that cancer; RFS) at 12 months was 95.4%. For those with a near-pathological complete response (minimal amount of cancer remaining), which was included in the major pathologic response criteria, the 12-month RFS rate was 94.1%. Those with a partial response had a 12-month RFS rate of 76.1%.

Subgroup analyses favored Opdivo and Yervoy across all subgroups.

"The study confirms and shows for the first time in a phase 3 study that giving immunotherapy before surgery results in superior outcomes to giving immunotherapy only after surgery," said ASCO commentator Dr. Michael Lowe, from Emory University in Atlanta. "The study also confirms that giving two immunotherapy drugs before surgery results in excellent responses."

The most observed grade 3 or higher (severe or worse) side effects in the neoadjuvant arm were infection, diarrhea, abnormal blood counts, rash, fever and fatigue. Overall, serious side effects were observed in 29.7% of patients in the neoadjuvant group compared with 14.7% in the standard therapy arm. There was one death in the adjuvant only arm related to pneumonitis (inflammation of the lungs). Surgery-related side effects were reported in 14.6% of patients in the neoadjuvant Opdivo/Yervoy arm and in 14.4% of the adjuvant group.

"The quality of life was equal for the neoadjuvant arm and for the adjuvant arm, despite the difference in grade 3 or 4 (severe or life-threatening) toxicities in these patients," said Blank. "The majority of toxicity or quality of life reduction for the patients comes from the surgery and not from the immunotherapy."

Opdivo plus Yervoy in the neoadjuvant setting reduced the risk for recurrence, progression or death, potentially offering patients with stage 3 melanoma a new standard of care. 

Silas Inman

Zilovertamab Vedotin Plus Chemo Combo Shows Responses in R/R DLBCL

Akeega Combo Delays Progression in HRR+ Castration-Sensitive Prostate Cancer

Belamaf Regimen Improves Progression-Free Survival in Myeloma

Neoadjuvant Opdivo Plus Yervoy Provides ‘Excellent Responses’ in Stage 3 Melanoma

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