In recent days, good news has been continuously coming from the ADC (Antibody-Drug Conjugate) drug field.
On April 21st, AstraZeneca/DS-8201 announced that its combination of DS-8201 and pertuzumab defeated THP (paclitaxel, trastuzumab, and pertuzumab therapy) in the first-line treatment of HER2-positive breast cancer. This is a milestone event that pushes DS-8201 further into first-line treatment.
As for Gilead, there is also good news regarding Trodelvy. On April 21st, Gilead announced that Trodelvy combined with Keytruda achieved great success in first-line treatment for triple-negative breast cancer (TNBC), with the primary endpoint, mPFS, significantly extending compared to chemotherapy + PD-1 control. This is also a milestone event, marking the full breakout of IO + ADC therapy in solid tumors, entering the first-line treatment stage.
Looking at the recent events overall, the trend is clear: the combination of ADC drugs is advancing into first-line treatments. This will be the general trend in the future, where relatively low-toxic ADCs replace highly toxic chemotherapy, combined with PD-1 or other types of monoclonal antibodies, to capture a larger market.
From a broader perspective, this signifies an overall shift in the innovative drug market, and ADCs are bringing a new era to cancer treatment.
First, let's look at the news of DS-8201 combined with pertuzumab. Pertuzumab is a HER2 monoclonal antibody that was approved by the FDA in 2012. It can be considered an exploration of large molecule targeted therapies from the previous era. Its achievements in HER2-positive breast cancer are undeniable, with sales reaching $4.139 billion in 2020, mainly driven by the HER2-positive breast cancer indication.
Now, let's talk about this combination—THP. Let’s look at the real-world data literature for first-line treatment of breast cancer. As shown in the chart, for first-line treatment of breast cancer, the mOS reached 58.3 months, and the mPFS reached 19.1 months. This was the effect previously achieved by a three-drug combination—two HER2 antibodies plus a chemotherapy drug in breast cancer.
If DS-8201 combined with pertuzumab can defeat this data, it means that the data for DS-8201 combined with pertuzumab will significantly exceed the mPFS of the aforementioned THP. How much will it exceed? Currently, AstraZeneca is only reporting very good mid-term results, which indicate that the mPFS data is significantly meaningful and statistically significant. A conservative estimate for the hazard ratio (HR) would be 0.8, and the mPFS may need to reach 23 months. Of course, it might even be better than 0.8, because AstraZeneca's announcement mentioned that the results show highly differentiated statistical significance. We might even estimate the HR to be closer to 0.7.
Next, let’s talk about Trodelvy. Trodelvy is targeting TNBC and has been on the market for four to five years, but its sales have remained lukewarm. Aside from the relatively small TNBC market, the key reason is that it has been in the later treatment lines. Trodelvy is currently still in the $1.5 billion range.
To sell more, moving to the first-line treatment is a must.
Its control group—the combination of Keytruda and chemotherapy—has already had a phase III clinical trial. We can refer to the previous data. The baseline was CPS > 10 in TNBC patients. In the CPS-10 subgroup, chemotherapy + Keytruda achieved an mOS of 23 months (HR=0.73) and mPFS of 9.7 months (HR=0.66).
According to Gilead, statistical differences were made, and compared to chemotherapy + Keytruda, the difference in mPFS can be at least around 0.8, with a range of 0.75-0.85.
For ADCs, the path they must take is to continue pushing forward into the treatment lines. Unlike PD-1, especially for HER2 ADC, the types of cancers it can target are not numerous, so the primary strategy for expanding indications is to keep moving forward into earlier treatment lines and exploring new combination therapies for a single type of cancer.
Previously, T-DM1 made such an attempt, but the results were not very good. Based on the phase III clinical trial for T-DM1 in first-line treatment of breast cancer (MARIANNE), compared to trastuzumab plus paclitaxel treatment, T-DM1 monotherapy and T-DM1 + pertuzumab combination therapy did not show differentiated efficacy, with HR values of 0.91 and 0.87, respectively. This clinical trial, spanning from 2010 to 2012, cast a shadow on ADCs’ push into first-line treatment at the time.
For solid tumors, the ADC to consider next is Pfizer's Padcev. The combination of Padcev + Keytruda for first-line treatment of urothelial carcinoma has now been approved, though it was approved based on phase I/II trials, not phase III. Looking at the clinical results, even for first-line treatment, the results are quite impressive. In the ADC + chemotherapy treatment group, cORR reached 64.5%, compared to 45.2% in the control group. Additionally, the waterfall plot shows that 97.1% of patients had tumor shrinkage.
Based on this, the FDA accelerated the approval of the combination of Keytruda + Padcev for first-line treatment of urothelial carcinoma. The significance of this approval is not just for the advancement of ADC therapies but also for the combination of IO + ADCs.
Further on, we come to recent events in "contemporary history." DS-8201 has finally secured a ticket for first-line treatment in breast cancer. Trodelvy has also achieved its long-awaited qualification for entering first-line treatment for TNBC.
One of ADC’s visions—to move from later lines to earlier lines—is turning from an ideal into reality.
PD-1 type monoclonal antibodies are currently the cornerstone of cancer treatment. Keytruda is a versatile drug that can be used for most types of cancers. However, the types of cancers ADCs can target are still limited. But ultimately, ADCs are safer than chemotherapy in principle. ADCs replacing chemotherapy and combining with PD-1 will reshape the landscape of cancer treatment and become a new cornerstone for cancer therapy.
Recent events are merely corroborations of previous discussions. Trodelvy’s combination with Keytruda has achieved differentiated efficacy, and this is a bigger distinction compared to the Padcev + Keytruda combination because the former is based on phase III clinical trials, providing a definitive verdict by verifying the superiority of this therapy over chemotherapy + Keytruda in the final stages.
Whether it's ADC therapy advancing through treatment lines or the combination of IO + ADC, both trends are inevitable progress in the pharmaceutical epic, a force that cannot be stopped. What we look forward to is more HR values with significant results in the future, providing stronger validation. IO + ADC is bringing a new era to cancer treatment, and the flourishing development of ADCs is iterating on chemotherapy, the traditional cornerstone of cancer treatment. Innovative drugs are truly making strides in the "daring to change the heavens and earth" enterprise.
