There is no accident, let alone fluke, in the research and development of innovative drugs. Even if a star product has proven itself in many indications, it cannot guarantee victory in the development of the next indication, even if ideal data have been obtained in early clinical trials.
The highly anticipated combination therapy Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has staged a scene of high opening and low walking and big diving in the first-line treatment of advanced liver cancer: its phase Ib clinical trial The data “exploded” and made people full of confidence; but the phase III clinical trial proved that it was only an oolong. Compared with monotherapy, Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) did not There’s nothing special about it, it’s embarrassing. In addition to sigh, the failure of Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) is also a warning to us: the early clinical success of an innovative drug only proves its success to the next stage. It’s just a clinical ticket.
For a long time, Merck’s Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has been a high-profile presence in PD-1 combination therapy. In theory, the two are a perfect match.
We know that the wanton growth of tumors is inseparable from blood vessels attacking nutrients. As a multi-targeted receptor tyrosine kinase (RTK) inhibitor, lenvatinib can inhibit the RTK associated with pathological neovascularization, tumor growth and cancer progression, cutting off the tumor’s forage from the rear. At the same time, inhibiting the formation of abnormal blood vessels can improve the tumor microenvironment, enhance the PD-1 response rate, and truly achieve the effect of 1+1>2.
The theory has also been proved in practice. Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has shown good clinical data in early clinical trials. At the 2018 ASCO meeting, Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) made a blockbuster in the field of liver cancer treatment. According to its Phase Ib study KEYNOTE-524 for the first-line treatment of advanced liver cancer, among the 30 patients recruited, the objective response rate was 42.3%, and the progression-free survival was 9.7 months. At the 2019 AACR meeting, Merck’s updated clinical data showed that the combination allowed the patient’s overall survival to reach 20.4 months. This far exceeds the efficacy of the first-line therapy lenvatinib. In a clinical trial called REFLECT, the objective response rate of lenvatinib alone in patients with advanced unresectable hepatocellular carcinoma was 24%, and the overall survival was 13.6 months. That said, Keytruda (pembrolizumab) in combination with Lenvima (lenvatinib) has the potential to extend the survival of liver cancer patients by nearly seven months. In view of this, on July 25, 2019, the U.S. FDA granted Keytruda (pembrolizumab) in combination with Lenvima (lenvatinib) breakthrough therapy designation for the first-line treatment of patients with advanced unresectable liver cancer who cannot be treated locally. Since then, the data of KEYNOTE-524 has been continuously updated, but the results have never been disappointing. In addition to Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) in the field of liver cancer, it has also won breakthrough therapy designations by the US FDA in the fields of kidney cancer and endometrial cancer.
However, the combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib) in the development of liver cancer indications has been disappointing.
On August 3, Merck and Eisai announced that the Phase III LEAP-002 study of K drug combined with lenvatinib as first-line treatment for patients with advanced unresectable hepatocellular carcinoma failed to meet the dual primary endpoints of overall survival and progression-free survival : Although there is an improvement trend, the results are not statistically significant. The highly anticipated Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has turned over in the first-line treatment of advanced liver cancer indications . This also means that it has lost the most important battle in the field of liver cancer. In this regard, Merck threw the pot to Lenvatinib. Indicates that lenvatinib has achieved better overall survival data in the LEAP-002 study than before. This is not uncommon in the field of liver cancer, but it still cannot get rid of the fact that Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) is not insurance.
In fact, this is not the first time that Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has overturned in phase III clinical trials.
In 2021, “Keytruda (pembrolizumab) combined with Lenvima (lenvatinib), the phase III clinical trial of LEAP-007 ended in failure, and in the first-line treatment of non-small cell lung cancer, it also failed to show that it surpassed the K drug alone. The effect of the medicine, the first attempt failed.
At this year’s ASCO conference, Merck announced a Phase 3 clinical trial called LEAP-011, which showed that Keytruda (Pabola), compared with K-drug monotherapy, was effective in patients with advanced urothelial cancer who were not suitable for platinum-based chemotherapy. Zombizumab) in combination with Lenvima (lenvatinib) also did not significantly improve progression-free survival and overall survival.
The series of failures of Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) tell us a cruel reality: even if the data in the early stage is brilliant, everything may be overturned and reconstructed in the later clinical stage.
The combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib) in the liver cancer indication “rolled over” is not the first example of clinical data reversal in the field of innovative drug research and development, nor will it be the last. After all, the success of early clinical data is not easy to replicate in subsequent clinical trials. According to a study data, even after the death valley of Phase I and II clinical trials, the failure rate of Phase III clinical trials is still as high as 42.2%. It is not difficult to foresee that the story of “nine deaths and one life” will only be played over and over again in the field of innovative drug research and development. This point, domestic investors may have been deeply touched. The most typical example is the closely watched TIGIT monoclonal antibody, which became popular because of Roche’s early clinical trials, and is now being questioned because of Roche’s successive losses. This also tells us that we must maintain absolute objective rationality at all times.
In recent years, the prosperity and development of innovative drugs and the fuelling of capital have made many innovative drug companies’ innovative achievements begin to emerge. However, some innovative pharmaceutical companies, relying only on early clinical single-arm trials, have launched the slogans of “First in class” and “Best in class” and “rush forward”, which obviously does not conform to the law of innovative drug research and development. The failure of Keytruda (pembrolizumab) combined with Lenvima (lenvatinib) has once again sounded the alarm for us. Whether it is an investor or an innovative pharmaceutical company, the way to survive is to treat early clinical trials cautiously and reduce the cost of trial and error.
