ESMO breast cancer data: iza-bren doubles PFS over chemo, BioNTech and DualityBio flag limited benefit for their drug

The European Society for Medical Oncology congress in Madrid has produced a run of breast cancer results. Some are strong, some are small, and one came with its own sponsors saying the benefit looks limited.

Iza-bren beats chemo, with a toxicity bill

The headline trial is PANKU-Breast01, a randomized study from China of izalontamab brengitecan, or iza-bren, in relapsed HR-positive, HER2-negative advanced breast cancer. Patients had already received at least one prior line of chemotherapy.

Median progression-free survival was 8.2 months with iza-bren versus 4.0 months with physician's-choice chemotherapy. That is a 59% reduction in the risk of progression or death. The confirmed objective response rate was 40.5% versus 20.2%, and disease control was 86.3% versus 63.7%. The advantage held across all prespecified subgroups. Results were published simultaneously in The Lancet.

Overall survival is immature and showed no significant difference between the arms at this interim look.

The drug is harder on patients. Grade 3 or higher treatment-related adverse events and serious events were substantially more common with iza-bren, according to presenter Bo Lan, MD, of Peking Union Medical College in Beijing. Discontinuations because of side effects were similar in both arms.

"The results support iza-bren as a potential new standard-of-care option in this population," Lan said.

The caveats from the discussant

Fumikata Hara, MD, of Aichi Cancer Center in Nagoya, Japan, was the invited ESMO discussant. He called the efficacy "impressive" but pointed to the comparator. The control arm was chemotherapy, not another antibody-drug conjugate such as trastuzumab deruxtecan.

"Therefore, [iza-bren's] relative efficacy and its optimal position in ADC sequencing remains unknown," Hara said. He also raised cross-resistance to the same topoisomerase-1 payload as an important open question.

Hara added that hematologic toxicity was substantial, with frequent dose reductions. Only about 12% of patients were 65 or older, so safety in older patients is unknown.

What is riding on it for Bristol Myers Squibb

Iza-bren is an EGFR x HER3 bispecific antibody-drug conjugate, formerly BL-B01D1, developed by China-based SystImmune. Bristol Myers Squibb paid $800 million upfront for rights to it. The deal could reach $8.4 billion if regulatory and commercial targets are met.

Bristol has said the drug will be a cornerstone of its oncology business after Opdivo, a roughly $10 billion-a-year PD-1 inhibitor, loses patent protection around 2028. Analysts have projected peak annual iza-bren sales of $3 billion to $5 billion or more, depending on how many cancers end up on the label.

China's National Medical Products Administration approved iza-bren earlier this year for recurrent or metastatic nasopharyngeal carcinoma and recurrent or metastatic esophageal squamous cell carcinoma. The drug also carries FDA breakthrough therapy designation in non-small cell lung cancer. Positive phase 3 data in triple-negative breast cancer and esophageal cancer came out at this year's ASCO, and first PANKU-Lung01 data in EGFR-mutated lung cancer are slated for ESMO.

Kisqali reports a six-year survival signal

Novartis announced on October 23 six-year follow-up from the phase 3 NATALEE trial of Kisqali (ribociclib) plus endocrine therapy in stage II and III HR-positive, HER2-negative early breast cancer at high risk of recurrence. Kisqali plus endocrine therapy reduced the risk of death by 19.1% versus endocrine therapy alone (HR 0.809; 95% CI 0.661 to 0.989).

In absolute terms, the survival difference grew from 1.2 percentage points at five years to 2.1 points at six. Invasive disease-free survival benefit rose from 4.1 to 5.3 points. Breast-cancer-specific survival showed a roughly 30% lower risk of cancer death (HR 0.709).

Patients had been off Kisqali for a median of 38 months. Dennis J. Slamon, MD, of UCLA called the findings important "for patients as well as health care providers worldwide." Novartis's Andrea Myers described Kisqali as a standard of care for eligible patients.

A different ADC, a much weaker read

BioNTech and DualityBio announced today, October 26, that their phase 3 DYNASTY-Breast02 trial of trastuzumab pamirtecan met its primary endpoint. The gain in progression-free survival over investigator's-choice chemotherapy was, in the companies' own words, "statistically significant, yet modest." Patients had HR-positive, HER2-low metastatic breast cancer, were chemotherapy-naive and had progressed on endocrine therapy.

Interstitial lung disease occurred more often than in earlier trials of the drug. Most cases were Grade 1 or 2, but a small share of patients had Grade 3 to 5 events, which includes deaths. Overall survival data are immature.

The companies said the available data "suggest limited potential patient benefit in this treatment setting." They said they will discuss the data and determine next steps. BioNTech trades on Nasdaq as BNTX. DualityBio trades in Hong Kong as 9606.HK.

Atirmociclib adds a mixed subgroup picture

A separate trial of the oral CDK4 inhibitor atirmociclib plus fulvestrant in patients previously treated with a CDK4/6 inhibitor also reported improved progression-free survival. The comparator was investigator's choice: fulvestrant alone (58%) or everolimus plus exemestane (42%).

Confirmed response rate was 19.3% versus 11.3%, with a nominal P value of .0901. Clinical benefit rate was 61.9% versus 46.0%. The subgroup hazard ratios diverge. Against fulvestrant the HR was 0.51, while against everolimus plus exemestane it was 0.80 with a confidence interval of 0.504 to 1.284. In patients 65 and older the HR was 1.05, versus 0.49 in younger patients. Liver metastases were more common in the atirmociclib arm, 44% versus 29%.

What comes next

For iza-bren, the pending questions are overall survival and head-to-head performance against other ADCs. Neither is answered by a chemotherapy-controlled trial with immature survival data. BioNTech and DualityBio have yet to say what they will do with trastuzumab pamirtecan in this setting.