The head-to-head trial of Kangfang's AK112 (Ivosidenib) versus K drugs has finally released its overall survival (OS) data.
Two years ago, the HARMONi-2 study had already achieved superior efficacy over K drug in terms of PFS endpoints, making AK112 famous in one battle. The biggest suspense left for the market is: having won PFS, can OS also be won?
Now, this issue has been partially resolved.
Kangfang Bio recently announced that the HARMONi-2 study has met the key secondary endpoint of overall survival, achieving statistically significant and clinically meaningful survival benefits. Detailed data will be formally disclosed at the WCLC on September 12.
For late-stage tumor treatment, PFS proves that a drug can delay disease progression, while OS more directly answers whether patients can live longer. When a new drug attempts to challenge standard treatments that have been established for many years, a favorable PFS is just the first step, and OS determines how far this advantage can go.
Thus, HARMONi-2 reaching its OS endpoint is undoubtedly a significant positive signal, but the capital market's response was not as enthusiastic as expected: on the day the news was released, Kangfang's stock price ultimately rose 3.47%.
The market's restraint is not hard to understand.
HARMONi-2 and the previously read-out HARMONi-6 are both single-region studies in China, and they are increasingly confirming the clinical value of AK112 in the Chinese market, but Kangfang's larger valuation imagination comes from overseas.
What remains to be seen is whether AK112 can replicate this advantage in the global patient population, particularly in the US market.
Several industry insiders have also been cautious in their assessment of HARMONi-2, noting that the success of the China regional Phase III trial does not necessarily mean that HARMONi-3, a global Phase III trial, will automatically replicate that success.
HARMONi-3, particularly its squamous cell carcinoma cohort, is one of the most important breakthroughs in AK112's global commercial value. Once it wins head-to-head against K drug in the global Phase III trial, AK112 will truly have the qualifications to challenge the "King of Pharmaceuticals".
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Are OS Concerns Fading?
At WCLC 2024, HARMONi-2 fired the first shot in a head-to-head comparison of K drugs.
This Chinese single-arm Phase III study directly compared tislelizumab with pembrolizumab monotherapy in PD-L1-positive (TPS≥1%) first-line advanced NSCLC patients.
At the time, the announced PFS results were impressive: the median PFS for the Iovance Biotherapeutics' group was 11.14 months, and 5.82 months for the K drug group, with an HR of 0.51, representing a reduction of approximately 49% in the risk of disease progression or death.
But one question arises: PFS is so good, can it ultimately translate into OS?
Merck's Chief Medical Officer Eliav Barr stated at the time that PFS benefits "don't necessarily translate into OS benefits." Based on past experience with PD-1/VEGF combinations, OS is a more difficult endpoint to achieve and may become a key challenge for AK112 to overcome in order to gain FDA approval.
In April 2025, an interim analysis of HARMONi-2 was conducted when the OS data maturity was approximately 39%, with an OS HR of 0.777 for tislelizumab compared to K drug, representing a 22.3% decrease in the risk of death. However, due to the extremely low alpha value allocated for this early analysis, the statistical significance threshold was very high and did not meet the predefined requirements.
After the news was announced, the stock price of Summit, Kangfang's overseas partner, plummeted by nearly 37% at one point, making OS one of the biggest uncertainties looming over AK112.
In June this year, HARMONi-6 alleviated these concerns, with an interim analysis of the OS showing an HR as low as 0.66, significantly restoring market confidence in the long-term survival benefits of AK112.
Now it's HARMONi-2's turn.
According to an industry insider, the mature OS HR of the treatment may ultimately fall in the range of 0.75-0.77. This figure, even if it does not match HARMONi-6's 0.66, is not unexpected - HARMONi-2 faced K drugs that already had mature survival evidence, making the challenge more difficult in itself.
Another industry insider predicts that as the data further matures, the HR may be slightly better than 0.777, at around 0.76.
Of course, this is just speculation, and the specific figures have not been officially announced yet.
What truly matters is that if mature OS continues to show clear benefits, it means the previously strong PFS results are starting to translate into long-term survival benefits. The clinical value of AK112 in China's first-line lung cancer market is thus further solidified.
However, there is still a threshold between "China value" and "global value".
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HARMONi-3: The Real Test
Currently, the AK112 has shown a significant positive signal by crossing this threshold.
In June this year, the global multi-center phase III HARMONi trial targeting EGFR-sensitive mutation non-squamous NSCLC released its latest OS analysis: the ITT population's OS HR reached 0.76, and the Western subgroup's OS HR was also 0.76.
The OS HR for the Western subgroup had previously improved from 0.98 to 0.84, and now further to 0.76. This does not prove that AK112 can replicate Chinese data in all indications and all Western patients, but at least alleviates a major concern: whether the efficacy of Iwucosan is mainly limited to Chinese or Asian patients.
Summit has submitted a BLA to the FDA based on HARMONi, with a PDUFA date of November 14 this year. If approved, ivosidenib will cross a major threshold for registration in the US.
However, HARMONi corresponds to EGFR sensitive mutations and NSCLC after TKI treatment. Summit estimates that there are over 14,000 patients in the US each year who fit this treatment scenario - it has commercial value, but it's still not the truly large market for AK112.
What truly changed its global commercialization ceiling was the HARMONi-3.
This global, multicenter Phase III study directly compared toripalimab plus chemotherapy with Keytruda plus chemotherapy, including two separate analysis cohorts for squamous and non-squamous NSCLC.
The highest expectations for success currently are for the HARMONi-3 squamous carcinoma cohort, as it has HARMONi-6 as a reference in China. HARMONi-6 also uses camrelizumab in combination with chemotherapy for first-line squamous carcinoma and has achieved success, with good PFS and OS data that looks promising, as presented at this year's ASCO Plenary. The most critical issue now is whether the global squamous carcinoma cohort of HARMONi-3 can replicate the advantages seen in HARMONi-6 in China.
If successful, AK112's product positioning will undergo a fundamental shift, transforming from an innovative drug that has already proven its value in China and is gradually entering specific overseas indications, to truly entering the global first-line lung cancer core market. A successful HARMONi-3 will have a huge market.
But the competition remains undecided for now.
In May this year, the interim analysis of early PFS in the HARMONi-3 squamous cell carcinoma cohort did not meet the preset statistical significance, due to the low α value allocated to this analysis and the high statistical threshold, the independent data monitoring committee recommended that the study continue.
Strictly speaking, this does not necessarily prove that HARMONi-3 is unable to replicate the results of HARMONi-6 in Western or global populations, as specific HR and subgroup data for Europe and the US have not been disclosed; however, at the very least, it has not shown the sufficiently strong PFS advantage, enough to clear this high hurdle, as was seen early on with HARMONi-6 in China.
This is also why the market is starting to worry: whether the promising PFS seen in China can be replicated in a global population. If the final PFS results are not good enough, it will also increase uncertainty about whether OS can produce strong enough results.
HARMONi-3 also has a non-squamous carcinoma cohort, which is a comparison of IBI305 combined with chemotherapy versus K drug combined with chemotherapy. For this cohort, an industry insider believes the probability of success may be lower than that of squamous carcinoma. One reason is that Innovent has not conducted a fully corresponding Phase III validation of "IBI305 + chemotherapy versus K drug + chemotherapy" for first-line non-squamous carcinoma in China. Therefore, from a development pathway perspective, this cohort itself has higher uncertainty. It is precisely for this reason that the market's primary expectation for HARMONi-3 currently lies with the squamous carcinoma cohort.
For Summit and AK112, the recent success with the highest expectations and the potential to truly open up a large market is the HARMONi-3 squamous cell carcinoma cohort, with results still pending.
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Winning in Clinics is Not Enough, Winning in the Market is Also Crucial
Even if HARMONi-3 ultimately succeeds, the story of the "King of Medicine" is far from over.
First, there is a very practical issue: whether doctors are willing to switch medications.
Data from China on HARMONi-6 showed that the overall safety of tislelizumab was controllable, but Julie Brahmer, an invited discussant at ASCO 2026, noted that the study excluded patients over 75 years old and those at high risk of bleeding, and that the benefit was also reduced in the subgroup of patients over 65 years old.
This will directly impact doctors' prescription choices. K drugs have been used for many years, with a mature safety management pathway, while Ivosidenib increases the risk of VEGF-related bleeding, high blood pressure, and other conditions. To convince doctors to switch from familiar K drug regimens, the therapeutic advantages must be sufficient to offset the new safety concerns. This is also a key reason why Brahmer believes HARMONi-6 is not enough to immediately change clinical practices outside of China.
Another question is: how long is the time window for AK112?
The PD-(L)1/VEGF bispecific antibody is no longer a track exclusive to Kangfang. Multinational pharmaceutical companies such as Merck and BMS have entered the field in droves, with products like LM-299 and BNT327 accelerating global development.
This means that AK112 not only needs to win, but also needs to win as soon as possible.
The HARMONi-2 OS has reached its endpoint, further solidifying the clinical value of AK112 in the Chinese market; HARMONi has released a positive signal with cross-regional replication in the EGFR mutation population, but in the EGFR wild-type first-line population with greater commercial value, evidence of OS in European and American patients is still lacking, and the answer will have to wait for HARMONi-3.
If HARMONi-3 and HARMONi-7 fail to establish sufficient clinical advantages in a timely manner, later entrants may quickly catch up by leveraging their mature global clinical and commercial networks, thereby compressing AK112's first-mover advantage.
And HARMONi-7 is an even tougher battle ahead.
This global Phase III study targets first-line NSCLC patients with high PD-L1 expression, directly comparing single-agent tislelizumab with single-agent K drug, essentially revalidating the core logic of HARMONi-2 in a global population. HARMONi-7 is currently ongoing, with results yet to be released. The aforementioned industry insider believes that the probability of HARMONi-7's success may be even lower than that of the squamous cell carcinoma cohort in HARMONi-3.
Ivabradine is still some distance away from being crowned the "king of medicines".