ADC drugs have taken a key step toward becoming a first-line treatment for breast cancer.

01
First breakthrough

On December 15, the FDA announced approval for the combination of Enhertu (trastuzumab deruxtecan), an antibody-drug conjugate jointly developed by AstraZeneca and Daiichi Sankyo, and Roche's Perjeta (pertuzumab) for first-line treatment of patients with HER2-positive advanced or metastatic breast cancer . The indication is for adult patients who are confirmed HER2-positive by an FDA-approved testing method and have not previously received chemotherapy for metastatic breast cancer.

This approval marks the first time that an ADC drug has been approved by the FDA for first-line treatment of breast cancer, a major solid tumor.

This approval is based on a randomized, controlled clinical trial that enrolled 1,157 patients with HER2-positive metastatic breast cancer. The study compared the efficacy of Enhertu in combination with Roche's HER2-targeted monoclonal antibody Perjeta (pertuzumab) as first-line treatment with the current standard of care. Results showed that the median progression-free survival of the new combination regimen was 40.7 months , compared to 26.9 months in the control group . Regarding tumor response, 87% of patients in the new regimen experienced tumor shrinkage or disappearance, compared to 81% in the control group .

At the time of this analysis, overall survival data were not yet mature. Studies showed that approximately 16% of patients in both groups died, which was insufficient to draw definitive conclusions about overall survival. The FDA clearly stated in its approval announcement that this decision was based on clinical endpoints such as progression-free survival and overall response rate, while also taking into account study size, patient population characteristics, and the stability of efficacy differences.

In addition, the FDA also approved two companion diagnostic tests to identify eligible HER2-positive breast cancer patients who can receive the combination therapy of Enhertu and Perjeta. This means that the use of this combination regimen is explicitly limited to a specific population confirmed by standardized testing.

02
The significance of ADC as a first-line treatment for breast cancer

In the field of HER2-positive breast cancer, where treatment pathways are highly rigid, the FDA's approval of Enhertu as first-line treatment is not a conventional expansion of indications, but rather a rearrangement of the treatment priorities themselves.

HER2-positive breast cancer is a subtype of solid tumor with a highly mature treatment system. The stability of its first-line treatment does not stem from a stagnation of innovation, but rather from the fact that existing protocols have formed a highly stable balance through long-term practice. Since the CLEOPATRA study established the dual anti-tumor combination regimen of trastuzumab + pertuzumab + chemotherapy, this therapy has been repeatedly validated globally, demonstrating not only stable survival but also accumulating a wealth of real-world experience in terms of safety and manageability.

In the following decade, the field of HER2 treatment was not without change. New targeted drugs, ADCs, and combinations of different mechanisms continued to enter second- and third-line treatments, constantly reshaping treatment options at these levels.

However, the core structure of first-line treatment has remained largely unchanged. This phenomenon is not uncommon; in most solid tumors, first-line treatment is often the slowest to change and the most conservatively regulated. This is because first-line treatment corresponds to the treatment phase with the largest number of patients, the longest treatment duration, and the lowest risk tolerance; any structural adjustments must be based on extremely strong evidence. It is against this backdrop that understanding why ADCs have long struggled to enter first-line treatment becomes particularly crucial.

ADCs are not a new technology, but for a considerable period of time, their clinical positioning has been biased towards later-line treatment. This positioning does not mean that ADCs are ineffective, but rather stems more from the competition between their risk-benefit performance and the requirements of first-line treatment.

First, there are uncertainties regarding safety and long-term use. The core advantage of ADCs lies in their efficient delivery of cytotoxic loads, which often leads to significant efficacy in patients with high disease burdens and limited treatment options. However, this efficiency also means more complex toxicity management and greater difficulty in fully controlling long-term cumulative risks in advance. First-line treatment requires long-term, stable, and predictable disease control.

Secondly, there are the risks associated with production complexity and consistency. The manufacture of ADCs involves multiple process controls for antibodies, linkers, and cytotoxic payloads. First-line treatment means a larger patient base and longer treatment cycles, which places higher demands on production consistency, quality systems, and supply stability.

Finally, there is the lack of real-world tolerability accumulation. Patients receiving later-line treatment tend to have a higher tolerance for toxicity and adverse reactions, and are more likely to experience the potential risks of drugs in the real world. In contrast, first-line treatment has much stricter tolerability requirements, which is a significant hurdle that ADCs struggle to overcome in their early stages.

Against this backdrop, Enhertu's approval as a first-line treatment was not a radical institutional breakthrough, but rather the result of a gradual process over many years . In 2019, Enhertu was first approved as a third-line treatment , with a very clear purpose: to provide patients with new possibilities for disease control after existing treatments have failed. At this point, Enhertu was more like a last line of defense, compensating for the lack of subsequent treatment options with its high efficacy.

As more data accumulated, Enhertu's role in second-line treatment gradually became clearer, establishing a systemic advantage compared to T-DM1. The key to this stage was not merely improved efficacy figures, but rather the regulatory authorities' growing familiarity with its toxicity profile, management methods, and patient selection criteria. It was during this process that Enhertu gradually transformed from a rear-line tool responsible for containment into a vanguard in the attack.

The FDA approved the combination of Enhertu and Perjeta, rather than monotherapy, which demonstrates that regulators have not rejected existing treatment systems but rather are embedding new therapies into their core structure . Enhertu's entry into first-line treatment is not a radical move, but rather the result of the FDA's gradual confirmation of its long-term safety and efficacy stability. This path cannot be replicated by all ADCs.

03
Why did the FDA intervene before OS was mature?
Should the front line still be allowed to pass?

A key factor in this approval is that overall survival data was not yet mature at the time of analysis. However, this does not mean that the FDA has lowered its evidence requirements for first-line treatments, but rather reflects a comprehensive trade-off in the weighting of endpoints in specific disease scenarios.

In metastatic HER2-positive breast cancer, progression-free survival (PFS) has long been considered an important endpoint reflecting disease control, especially given sufficient sample size, clear study design, and well-defined population. This study included over 1100 patients who had not received chemotherapy for metastatic disease, ensuring strong statistical stability and clinical interpretability of the PFS data.

Furthermore, the simultaneous approval of companion diagnostics allows for more precise definition of the treatment population, which to some extent reduces the risk of unnecessary exposure. From a regulatory perspective, the FDA has essentially accepted the premise that, under specific conditions, ADCs can serve as long-term treatment tools, not just second-line eradication therapies. This judgment echoes, in a subtle way, the cautious adjustment of the evidence pathways demonstrated in recent years in areas such as CAR-T and PI3K.

The approval of Enhertu as a first-line treatment inevitably puts pressure on the dominant players in the traditional HER2 treatment system. However, this change has not unfolded in a direct confrontational manner. In the FDA-approved regimen, Perjeta remains a core component of the combination therapy. This choice means that Enhertu's entry has not overturned the existing system, but rather chosen a collaborative model of harmony in diversity: retaining key nodes within the new technological structure to maintain the continuity of the treatment pathway. This transitional adjustment is often more readily accepted by clinical practice and the real world than a complete replacement.

04
What does the ADC becoming a one-line unit mean?

Enhertu's approval for front-line testing does not equate to ADCs fully entering the front-line era. The signal it sends is very specific: when ADCs are pushed to the front-line, the challenge is no longer just about technological breakthroughs, but a concentrated test of systems engineering capabilities.

In first-line treatment scenarios, safety profiles must demonstrate a stable and predictable risk profile over the long term. This includes not only the incidence of serious adverse events, but also their type, timing, and controllability of intervention. First-line treatment typically targets earlier-stage patients in better overall condition, who generally have lower tolerance for toxicity. This dictates that regulatory authorities place significantly higher safety requirements on ADCs compared to later-line treatments when assessing their suitability for earlier intervention.

More importantly, the placement of ADCs as first-line treatment inherently shifts the responsibility for real-world monitoring forward. When ADCs are used as first-line treatment, they are no longer merely a supplementary measure but rather part of long-term disease management. Any potential cumulative toxicity or rare risks will be amplified in a larger population and are more likely to trigger ongoing regulatory evaluation.

Therefore, Enhertu's first-line approval did not lower the standard for ADCs to enter the first-line treatment sequence, but rather made the standard more specific: only when the efficacy advantage is clear, the safety profile is clear, the manufacturing capability can withstand long-term large-scale testing, and trust can be continuously built within the regulatory framework, can ADCs truly stand at the forefront of the treatment sequence.

In fact, Enhertu is not the only ADC drug with the potential to be used as a first-line treatment. In fact, in several solid tumor areas, a number of ADCs are already attempting to move to earlier treatment lines, and the clinical designs of some of these projects are clearly aimed at first-line or near-first-line treatment scenarios.

In the field of non-small cell lung cancer, the exploration of ADCs as first-line treatment is more direct, but also more cautious. Dato-DXd has been used in clinical practice to compare with standard chemotherapy or immunotherapy regimens, and some study designs have explicitly covered the first-line treatment population.

However, unlike breast cancer, the biggest constraint on ADCs in lung cancer is not entirely due to efficacy, but rather to safety , especially potential risks such as interstitial lung disease. In first-line treatment scenarios, the tolerance for such adverse events is extremely small. Therefore, even if an ADC shows activity in later lines of treatment, its suitability for earlier intervention still highly depends on the accumulation of long-term safety data.

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