Tumor electric field treatment in the center of the storm: Nothing wrong, reflection and hope for the future

It is extremely difficult to promote an innovative therapy to the market. American star biotech Novocure may have learned more about this recently.

On June 6, US time, Novocure announced the latest research results of TTFields (Tumor Electric Field Therapy), a phase III clinical LUNAR for stage 4 non-small cell lung cancer.

Data show that TTFields has achieved the clinical endpoint of OS (overall survival), and is more effective in combination treatment with immunotherapy, achieving an unprecedented 8-month improvement.

However, the market did not buy it. On that day, Novocure's share price nearly halved, and its Chinese partner Zai Lab's share price also fell sharply.

Why did a clinical study that achieved positive results cause a negative reaction from the capital market? The root cause may lie in two points:

Firstly, due to changes in the clinical landscape, although the LUNAR study was successful, it still left a lot of suspense; secondly, the market had previously given this treatment method a "game" changer's exaggerated expectations.

TTFields are innovative medical devices that apply physical external force through multiple mechanisms to kill cancer cells. Because healthy cells have different properties than cancer cells (including division speed, morphology, and electrical properties), TTFields do not significantly affect healthy cells. Thanks to its multi-mechanism effect, TTFields can bring significant clinical benefits to patients as a new cancer therapy in approved indications, and has been combined with chemotherapy, radiotherapy, immune checkpoint inhibition or PARP inhibition in preclinical models. When used together, agents have shown enhanced effects in solid tumor types.

The LUNAR study is a key battle for TTFields to impact the field of lung cancer. However, the control therapy selected in this clinical trial was mainly chemotherapy, and immunotherapy only accounted for 31% of the patients. Now, with the popularity of PD-1, immunotherapy has become the frontline treatment for non-small cell lung cancer.

In other words, LUNAR does not have sufficient data to prove that it is better than the latest standard therapy as a combination treatment. This sparked concerns among investors.

However, this is not a problem caused by the company's "clinical capabilities".

The LUNAR study started in late 2016. At that time, the standard treatment for non-small cell lung cancer in the United States was chemotherapy; it was not until 2 years after its clinical launch that immunotherapy began to enter clinical practice.

Obviously, given the environment at the time, there was no problem with the design of the LUNAR study. But even so, LUNAR research is still worthy of our deep thought.

Essentially, in the era of innovative technology, the accelerated evolution of the treatment landscape has brought additional clinical challenges to drug companies. Not only Novocure and Zai Lab, but also domestic and foreign pharmaceutical companies such as Eli Lilly and Alphabet Pharma have also encountered this problem.

This also reminds us that in an era of accelerated research and development of innovative drugs, all pharmaceutical companies may face an unprecedentedly complex problem.

/ 01 / The unknown behind clinical success

Judging from the clinical results, the LUNAR study is undoubtedly very successful.

The LUNAR study reached the clinical endpoint of OS. As shown in the figure below, the median overall survival of TTFields+ standard therapy was 13.2 months, while the median overall survival of patients treated with standard therapy in the control group was 9.9 months.

Although oncology drugs have many clinical surrogate endpoints, their only purpose is to prolong patient survival. In recent years, the FDA has paid more and more attention to the "gold standard" of OS data.

Therefore, being able to reach the OS endpoint has proven the value of TTFields. However, due to changes in the clinical treatment landscape, there are unanswered questions in the LUNAR study.

As mentioned above, the biggest attraction of TTFields is that it can become a "supercharger" for standard therapies, that is, it can be used in conjunction with standard therapies to bring better treatment options to patients.

In the clinical design of LUNAR, Novocure and Zai Lab established two major trial control groups. One group is TTFields combined with immune checkpoint inhibitors versus immune checkpoint inhibitor monotherapy; the other group is TTFields combined with docetaxel versus docetaxel monotherapy.

In the controlled trial of docetaxel, although the conditions of the enrolled patients were consistent with reality, the data results were not outstanding. Specifically, 58% of patients in the experimental group and the control group respectively received immunotherapy. The final clinical data showed that the experimental group failed to bring significant survival benefit compared with the control group.

But TTFields still has potential expectations because of the excellent clinical data in controlled trials of immune checkpoint inhibitors. It can be seen that the addition of TTFields has greatly improved the survival benefit of patients. The median survival period of the experimental group reached 18.5 months, while that of the control group was only 10.8 months.

It’s just a pity that the status of TTFields’ joint immunotherapy cannot be known until Novocure and Zai Lab further advance clinical practice.

First, LUNAR clinical research needs to further detect the expression of PD-L1 in the enrolled population. Based on the results of this study, it is known that TTFields can "enhance" immunotherapy, but the results of the "enhancement" remain to be further observed. Because in the two experimental groups of TTFields + immunotherapy and immunotherapy monotherapy, 49% and 38% of patients respectively had unknown PD-L1 expression. Only when the expression levels of all patients are announced can the "enhancement results" brought by TTFields to immunotherapy be finally known. By then, investors will be able to determine the treatment status of the TTFields/immunotherapy partnership in lung cancer and even other cancer types.

Second, LUNAR clinical research needs to further include patients who have been treated with immunotherapy. Immunotherapy is currently the main anti-tumor method for prolonging advanced NSCLC. The Lunar study has released a strong scientific signal for doctors: TTFields may become a new partner of immunotherapy and improve patient survival benefits.

So, how to maximize the efficacy of this new local physical therapy method and benefit more patients requires more precise patient screening, especially for patients with disease progression after immunotherapy treatment. patient.

In general, although it was clinically successful, because the clinical design was not perfect, the LUNAR clinical research results gave people hope but also left a lot of suspense.

This also leads to the existence of poor market expectations. Before the complete results of LUNAR were released, the market had already given full expectations to this research. On April 13, 2021, after reviewing the interim analysis report of the study, the U.S. Independent Data Monitoring Committee (DMC) recommended that the study sample size be reduced by nearly half and the follow-up time be shortened to 12 months. On that day, Novocure rose 49% and made another comeback. Pharmaceuticals rose 22%; in January 2023, Novocure and Zai Lab jointly announced that the LUNAR study had reached the primary endpoint of survival, with a statistically significant and clinically meaningful improvement in OS data. Novocure rose 68% that day, and Zaiding rose 41%.

Greenham said, "The stock market is a weighing machine in the long term and a voting machine in the short term." The release of two major pieces of good news aroused the appetite of investors, and expectations were extremely high; but now, Wall Street investors have discovered that they still have to wait for the answer to be revealed, and there will inevitably be a gap, which has caused the stock prices of the two companies to drop. of decline.

/ 02 / Evolving Treatment Landscape and Challenges

Clinical research results have caused shock in the capital market, but this is not a simple story of flaws in the clinical capabilities of pharmaceutical companies leading to trials that did not meet expectations. . Essentially, this is a change brought about by the evolution of the treatment landscape.

Take time back to the starting point of LUNAR research: November 25, 2016.

At that time, the standard therapy in the treatment of non-small cell cancer was still chemotherapy, and PD-1 was not fully approved as a first-line therapy until 2 years later in 2018.

It would be unrealistic for Novocure to fully enroll PD-1-treated patients at this point.

On the one hand, it is unknown whether and when immunotherapy will become a first-line therapy; on the other hand, before immunotherapy reaches the top, the number of patients treated with first-line immunotherapy is even more limited.

In hindsight, Novocure has chosen an optimal solution: taking patients who have been treated with chemotherapy as the main enrollment targets, and also including some patients who have been treated with immunotherapy.

However, no one expected that the times were changing too fast, and the proportion of immunotherapy-experienced patients enrolled in Novocure was limited, leaving many suspense in the end.

Today, it is meaningless for us to use the "rearview mirror" to criticize the clinical design at that time. It is more about learning from lessons. After all, there are many examples of the evolution of the treatment landscape in recent years posing clinical challenges to drug companies.

Many star companies overseas, including Eli Lilly and EQRx, have experienced this problem; domestically, many star pharmaceutical companies have also been affected.

The most typical one is Alphamab. Its core pipeline PD-L1/CTLA-4 dual antibody KN046 was developed for lung cancer indications. The control group was not immunotherapy but chemotherapy. However, in the actual clinical advancement, it passively became a confrontation with immunotherapy, resulting in its OS data. Hard to read.

These examples all tell us that in the era of innovative drugs, the difficulty of clinical design for pharmaceutical companies continues to increase. If we cannot "advance with the times" or even "lead the times", changes in the pace of future listings will be inevitable.

Next, all innovative drug development processes must pay attention to this issue, including TTFields.

/ 03 / Every step must be done correctly and steadily

Despite the blow in the capital market, TTFields’ journey will continue.

It is undeniable that TTFields has left many unknowns in the field of lung cancer; but it must also be admitted that the LUNAR study has also brought many positive signals.

First of all, as mentioned above, LUNAR research has produced OS data that fully proves its effect. How to make "effectiveness" reflected in more patients is the answer that Novocure and Zai Lab need to find.

Secondly, although the LUNAR study is full of controversy, it is not completely inconsistent with clinical practice.

Even in the United States, due to PD(L)1 expression issues, 30% of first-line patients still use chemotherapy as the standard treatment. In China, this number may be even greater due to issues such as treatment concepts.

This clinical path is even more different in China. On the one hand, the main reason is that the number of patients with EGFR mutations in China is much higher than that in the United States. Therefore, patients are usually treated with TKIs in the first line, and more immunotherapy-naïve patients are treated in the second line. patients, on the other hand, the penetration rate of immunotherapy in China is much lower than that in the United States. Therefore, the LUNAR study is relatively more convincing from the perspective of clinical practice in China.

Next, Novocure and Zai Lab’s top priority is how to improve the therapeutic effect of TTFields for the above-mentioned patient groups based on LUNAR research.

In addition, the release of clinical data further confirms that TTFields has the potential to increase sensitivity to PD-1 treatment. As mentioned above, in the controlled trial of TTFields combined with immune checkpoint inhibitors and immune checkpoint inhibitors alone, the addition of TTFields significantly improved the survival of patients.

In fact, Merck, the biggest winner in the immunotherapy market, has long noticed this. As early as 2021, Merck launched the KeyNote-B36 study of K drug combined with TTFields for the first-line treatment of non-small cell cancer. If this study can produce positive results, it will be another bright spot for TTFields. In addition, the LUNAR2 study of TTFields combined with immunotherapy/chemotherapy for the first-line treatment of advanced driver gene-negative NSCLC is already planned to be launched. These studies may provide more answers in the future.

Various results indicate that TTFields still has the potential to enrich the comprehensive treatment of tumors. In the future, whether TTFields can join hands with more immune checkpoint inhibitors to bring better treatments to patients will be the direction Novocure and Zai Lab will explore.

Of course, the future of TTFields is not limited to lung cancer. Currently, its exploration also includes more solid tumors, such as pancreatic cancer, ovarian cancer, gastric cancer, and liver cancer. Among them, TTFields’ clinical data on ovarian cancer will also be read out in the second half of the year.

If the clinical data is excellent, it will basically prove that TTFields has the potential to become a "pan-cancer" treatment. This will also prompt Novocure and Zai Lab to accelerate the exploration of TTFields in other solid tumor fields.

As long as exploration continues, TTFields may not be able to regain market confidence. In the world of innovative drug research and development, reversals are a routine plot.

Just like TIGIT targets in the field of immunotherapy. Who could have expected that the TIGIT target, which has failed several times and has a confusing future, will now excite the market because of the liver cancer data released by Roche at ASCO.

As the medical community's understanding of targets continues to deepen, the facts are mastered, and the results unfold, the future of a target may flip many times, and the same will be true for TTFields.

Of course, in general, in the era of innovative drugs, it will only become more and more difficult to get ashore. This also requires pharmaceutical companies to constantly adapt to changes in the environment and take every step correctly and steadily.