The "King of Chinese Medicine" from an Overseas Perspective: Recognition, Caution and Nitpicking

Text: Amino Observations

In the past day, the whole world has been discussing China's innovative drugs.

On the evening of September 8, Beijing time, the results of the HARMONi-2 study of ivoneximab, the PD-1/VEGF bispecific antibody in Akeso's focus pipeline, were presented at the 2024 World Conference on Lung Cancer (WCLC).

As this study is the world's first and only successful Phase III registrational clinical study with head-to-head comparison between single agent and K drug, it is expected to completely change the landscape of PD-1 monoclonal antibody-based tumor immunotherapy.

As a result, the results of HARMONi-2 have not only received wide attention and recognition from the domestic industry, but also aroused extensive discussion overseas.

So, what is the king of Chinese medicine from an overseas perspective?

/ 01 / Expectation

China's medicine king has also received overseas recognition.

"If these benefits are confirmed, our therapeutic harmony in this frontline area may eventually come to an end, and I think this is the disharmony that we should all support," said John Heymach, MD, chair of the Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, as he discussed HARMONi-2 results at WCLC.

It's not hard to understand. Judging by the results of the primary endpoint PFS, Ivosi showed extremely strong combat effectiveness.

First of all, the benefits are significant. Compared with K, evoximab further reduced the risk of disease progression or death in 49% of patients (PFS benefit was significantly and substantially improved, HR 0.51), and no clinical PFS HR was lower than 0.6 in previous combos, and median PFS was 5.3 months higher than 11.14 months in history.

Secondly, ivosib is very "comprehensive" and the whole subgroup benefits. Regardless of PD-L1 1-49% or ≥50%, regardless of non-squamous cell carcinoma or squamous cell carcinoma, whether there are brain metastases and liver metastases at baseline, ivoximab has a strong positive benefit, which further supports the combat effectiveness and future expectations of ivoximab.

At the same time, the safety of ivozimab is very beneficial. The safety profile of treatment with ivoximab in patients with squamous cell carcinoma at high risk of bleeding is good, and the risk associated with bleeding is comparable to that of pembrolizumab. Bleeding occurred in 14.7% of patients treated with ivonicimab, including 1% with grade 3 bleeding, with no more severe cases, compared to 11.1% and 0.5% in the K group. And, the reported cases of ivonicimab grade 3 bleeding were actually in patients with non-squamous cell carcinoma.

With these data, HARMONi-2 has been recognized by overseas scholars, experts and Wall Street, and has further raised expectations for the final OS results of overseas head-to-head K+ chemotherapy.

From the stock price performance of Summit, Akeso's partner, we can see that Wall Street recognizes and expects this data. Before today's market, Summit's stock price rose sharply, rising by more than 56% at one point. As of press time, the pre-market increase was more than 40%.

At present, Summit's market capitalization is $8.89 billion, and if this rally is maintained, it means that Summit's market capitalization will exceed $12 billion in one fell swoop, approaching a market value of 90 billion yuan.

In other words, a domestic innovative drug, ivoneximab, supports Summit's market value of nearly 100 billion. This also makes overseas once again feel the qualitative leap in the strength of China's innovative drug self-development.

/ 02 / Be cautious

While acknowledging and expecting it, there are also some cautious voices overseas.

The most important of these is whether the primary endpoint OS can benefit. After all, drug K relies on OS improvement to establish its position in the field of lung cancer, and ivoneximab may need OS results to prove that it has truly beaten drug K and won the favor of the FDA and doctors.

There are market voices that no matter how impressive the alternative endpoint PFS and ORR look, they cannot paint a real picture, and only OS data can show the value of ivosim.

The core logic of the above sound is that Ivosi did win, but at the moment there are only alternative finishes PFS and ORR. In the past, quite a few experiments have shown that surrogate endpoints are not reliable. Even, the K drug itself has been confused by the surrogate endpoint many times.

For example, Merck's cola combination has repeatedly shown a PFS or ORR benefit, but ultimately no benefit in terms of OS; In addition, the Keynote-042 study showed that K-drug clearly failed to beat chemotherapy in terms of PFS or ORR, but OS data showed benefit, supporting the approval of this indication.

Since at the WCLC conference, Ivosy did not announce any caliber about OS, so some overseas market participants maintained a cautious attitude.

Of course, there is also an affirmative answer. An analysis of previous studies conducted in July by Citi analyst Dr. Yigal Nochomovitz found that a more than 30% improvement in PFS in immuno-oncology trials in non-small cell lung cancer (NSCLC) was "very likely" to translate into statistically significant OS benefits.

Another Citi analyst, Wangbin Zho, believes that a roughly 40% advantage in PFS could lead to a "clinical" OS benefit for ivonicimab, which is stronger than 20%.

/ 03 / Nitpicking

At the same time, overseas markets are also nitpicking.

For example, some market participants believe that if it is compared with the cross-test of Keynote-024, it may be believed that the combat effectiveness of Ivosimab still needs to be observed in the end.

Keynote-024 is an early trial of K-Pa in the first-line treatment of NSCLC expressing 50% PD-L1≥.

Based on this data, Drug K may not perform well in HARMONi-2. Because in Keynote-024, the progression-free survival of drug K was 10.3 months, which was close to the 11.2-month mPFS of ivoximab.

The above voice said that while the comparison is not fair, it serves as another cautionary note anyway.

In addition, some market participants believe that a broader question about ivoximab is not whether ivoximab is better than pembrolizumab, but whether it is better than the combination therapy of drug K plus VEGF inhibitor Avastin.

Because PD-1 and VEGF inhibitors have been used in non-small cell lung cancer. While Summit claims that ivonexib may be more effective than using two separate medications, so far there is no easy way to prove this, as there does not appear to be a clear cross-trial comparison.

One comparison was in EGFR-positive patients, where the HARMONi-A trial alone showed that ivoximab plus chemotherapy did not perform better than Innovent in its triple therapy registrational study, Orient-31, in terms of median progression-free survival.

In addition, there are also voices that it is doubtful that the excellent data of the Chinese market can be replicated overseas, and Ivonexil needs to verify these results through global phase III trials.

To a certain extent, the overseas nitpicking of HARMONi-2 also shows that the potential ceiling of domestic innovative drugs is extremely high.

It is expected that Akeso and its partners will finally be able to come up with brilliant OS data and correct the name of domestic innovative drugs.