"Efficacy Is Not Everything": GSK's ADC Cautionary Tale

"The efficacy data is strong, but the toxicity data is also very strong."

On July 17, the FDA Oncology Drugs Advisory Committee (ODAC) rejected the approval of GSK's BCMA ADC drug Blenrep for second-line combination therapy for relapsed or refractory multiple myeloma. The most attention-grabbing issue was its toxicity.

Although the ODAC's opinion cannot completely dictate the FDA's decision, Blenrep's future is now filled with new uncertainties. Originally, it was highly likely to become a celebrated success story in the ADC field.

In November 2022, Blenrep was withdrawn from the market due to the failure of a confirmatory Phase III trial.

But just two and a half years later, Blenrep made a comeback with a head-to-head victory over the standard triplet therapy through combination therapy. The success of two pivotal Phase III trials (DREAMM-7 and DREAMM-8) has once again demonstrated its clinical value.

Given the promising clinical results, GSK is highly confident. In April this year, Uke Miels, the company’s Chief Commercial Officer, projected that Blenrep’s peak sales would exceed $3.8 billion and even stated its goal to replace daratumumab, which boasts annual sales of over $10 billion.

If all goes well, the FDA will make a final decision on the potential approval of the drug by July 23, 2025. But the new variables at present are undoubtedly reminding GSK: reality is always crueler than ideals.

This also serves as a reminder to the booming ADC field: efficacy is not everything.

/ 01 / GSK's Confidence

Originally, the two Phase III clinical trials, DREAMM-7 and DREAMM-8, made GSK extremely optimistic.

Specifically, in the DREAMM-7 trial, compared with daratumumab plus bortezomib and dexamethasone (BVd), the median PFS of Blenrep plus BVd nearly tripled (36.6 months vs 13.4 months). This combination therapy reduced the risk of death by 42%, with a three-year survival rate of 74% in the treatment group versus 60% in the control group.

In the DREAMM-8 trial, the OS endpoint was missed, but Blenrep in combination with pomalidomide and dexamethasone (BPd), compared to bortezomib combined with BPd, showed a median PFS (not reached) in the Blenrep combination group superior to the control group (12.7 months) over a median follow-up of approximately 21.8 months.

Based on the results of DREAMM-7 and DREAMM-8, GSK believes that Blenrep is not only nearing approval but may also become a blockbuster drug in the short term, and in the long term, redefine the treatment of r/rMM.

This points to a more ambitious goal, which is to replace Johnson & Johnson's daratumumab. After the success of the DREAMM-7 and DREAMM-8 trials, GSK launched the DREAMM-10 study in November 2024, pitting Blenrep in combination with lenalidomide and dexamethasone against the gold-standard regimen of daratumumab + lenalidomide + dexamethasone.

GSK is confident, "There, we only need to determine the dosage and design of the dosing cycle," said Luke Miels.

But for ADC drugs, efficacy is clearly not the only concern.

/ 02 / "The efficacy data is strong, but the toxicity data is also very strong"

The attitude of ODAC is in stark contrast to that of GSK, a result that is likely to come as a surprise to everyone.

Previously, in the eyes of the market, the only potential concern was the DREAMM-8 trial (due to missing the overall survival endpoint), while the recognition of DREAMM-7 was almost a foregone conclusion.

However, the final voting results of ODAC showed that the trial results of DREAMM-7 and DREAMM-8 were not fully recognized. On the one hand, this is related to the composition of the patient population enrolled —— the proportion of American subjects in both clinical trials did not exceed 5%, which was heavily questioned.

But the more critical reason still lies in safety issues.

The toxicity issues of Blenrep have long been a known risk, particularly ocular toxicity, which was especially prominent in the DREAMM-7 and DREAMM-8 trials.

The incidence of Keratitis-Vasculitis Anterior (KVA) events is not only high, but the severity is also concerning: In DREAMM-7 and DREAMM-8, 77% and 78% of patients, respectively, experienced Grade 3-4 KVA events.

Moreover, although ocular toxicity can theoretically be managed by extending the infusion interval or reducing the dosage, the actual recovery outcomes are not satisfactory — the recurrence rate of KVA events is high, and the recovery period is prolonged.

Overall, patients in DREAMM-7 and DREAMM-8 showed poor tolerance to the pre-set doses: by the third treatment cycle, more than half of the patients in both trials were unable to receive treatment at the predetermined dose.

As one committee member specifically pointed out: although the efficacy data provided by GSK was "very strong," the toxicity data was "equally very strong," which led him to cast a vote against it.

/ 03 / Efficacy Is Not Everything

Although ODAC cannot completely determine the FDA's final decision, it has sounded an alarm for the ADC field: efficacy is not the only criterion; finding a precise balance between efficacy and safety is the core logic of drug development.

Specifically, for Blenrep, its toxicity issues are deeply tied to the drug's characteristics. Although the BCMA target is not expressed in the human eye, studies have confirmed that Blenrep can be taken up by corneal epithelial cells through macropinocytosis, thereby inducing ocular toxicity — and since corneal epithelial cells have a fast renewal rate, they are inherently more sensitive to drug toxicity.

In fact, GSK had an opportunity to avoid this risk. According to the FDA, the two sides had long-standing disagreements: the FDA had suggested allowing more patients to receive a lower dose of Blenrep, believing that a lower dose might alleviate ocular toxicity issues.

However, GSK does not agree with this approach, believing that the safety benefits brought by a low dose are relatively limited. GSK insists that "a high starting dose is key to inducing deep remission" and advocates reducing the dose later if necessary to minimize toxicity. This is because GSK considers these ocular toxicity events to be manageable and not necessarily leading to long-term vision loss.

It is precisely this侥幸心理 towards risk that caused GSK to miss the opportunity to test a lower dose, and possibly as a result, lost a key chance to turn the tide. Although the final fate of Blenrep remains uncertain, this incident alone is enough to serve as a wake-up call for the entire industry.

After all, excessive toxicity is a common problem with ADC drugs. Due to factors such as target-mediated delivery characteristics, the cytotoxic intensity of the payload, and insufficient linker stability, ADC drugs are highly prone to fall into the dilemma of uncontrollable toxicity.

Currently, in the midst of the ADC research and development boom, some pharmaceutical companies, in order to cater to market hype, may overly pursue impressive efficacy data while neglecting the balance between safety and efficacy.

In the short term, this tendency may create a hot spot, but in the long run, it undoubtedly plants hidden dangers.

       Title: "Efficacy Is Not Everything," A Cautionary Tale from GSK's ADC