Global big pharmaceutical companies are again revealing the high barriers to new drug development, as anticancer new drug pipelines pursued as "game changers" have successively run aground in phase 3 trials.
Analysts say that as previously launched immuno-oncology and targeted therapies have greatly improved survival metrics, the difficulty of developing anticancer drugs with new mechanisms of action is rising.
According to the pharmaceutical and biotech industry on the 27th, Merck (MSD) on the 21st (local time) announced an interim analysis of its phase 3 trial (Litespark-012) involving 1,138 patients with advanced clear cell renal cell carcinoma (ccRCC).
The trial evaluated the effect of a triplet regimen that adds the HIF-2α inhibitor "Welireg (belzutifan)" or the anticancer new drug candidate "quavonlimab," under development by MSD, to the existing standard combination of Keytruda (pembrolizumab) and Lenvima (lenvatinib). HIF-2α is a protein that helps cancer cells grow under hypoxic conditions.
In the analysis, the Welireg arm failed to achieve statistical significance for both the primary endpoint of progression-free survival (PFS) and overall survival (OS) compared with the control. The quavonlimab arm likewise failed to demonstrate efficacy.
Keytruda plus Lenvima has already demonstrated strong efficacy in multiple tumor types and has become a standard therapy. Welireg is approved for some indications but has not yet expanded into the first-line setting. First-line therapy refers to the standard treatment used first when a disease is initially diagnosed.
This trial was significant as an attempt to extend treatment into an earlier line, but the inability to show a survival benefit in the key first-line market is seen as putting the brakes on the label expansion strategy.
U.S. big pharma Gilead Sciences and Arcus Biosciences said on the 20th (local time) in a U.S. Securities and Exchange Commission (SEC) filing that they would terminate the phase 3 trial (Star-221) of the immuno-oncology candidate "domvanalimab."
The study was designed to compare the combination of "domvanalimab + zimberelimab + chemotherapy" with Keytruda-based therapy in previously untreated metastatic non-small cell lung cancer (NSCLC) patients.
However, an interim analysis found a low probability of demonstrating superiority on survival endpoints, leading to termination. There were no safety issues, but the development strategy effectively ran aground due to insufficient efficacy. Along with this, Gilead relinquished rights to parts of the early pipeline, narrowing the scope of its collaboration with Arcus.
U.K. drugmaker AstraZeneca also faced similar hurdles in late-stage development. In December last year, it sought to demonstrate the efficacy of a combination of the immuno-oncology drug "Imfinzi" and the ATR inhibitor candidate ceralasertib in a phase 3 trial in lung cancer patients, but failed to improve overall survival (OS).
ATR inhibitors work by blocking the DNA damage response function of cancer cells. The company aimed to boost anticancer efficacy by combining with the immuno-oncology drug Imfinzi, but the phase 3 trial hit a roadblock.
These cases lay bare the high level of difficulty in late-stage development of next-generation cancer drugs. An industry official said, "Even if response rates are high in early trials, results are often diluted in large phase 3 studies due to patient heterogeneity and the effectiveness of existing therapies."
In particular, they show that, as current standard therapies combining already marketed drugs have greatly increased survival for cancer patients, new treatment strategies are struggling to deliver overwhelming data.
Cancer cells send a "brake signal" to prevent T cells (immune cells) from attacking them, and the PD-1 pathway plays that role. Blockbuster PD-1 inhibitors such as Keytruda and Opdivo block this brake signal, allowing T cells to attack cancer again normally without interference from cancer cells.
Domvanalimab, developed by Gilead and Arcus, works by blocking another immune inhibitory receptor called TIGIT. In other words, it is an approach to release additional inhibitory signals that remain after PD-1 inhibition to enhance anticancer efficacy.
Although the medical community had high hopes for the TIGIT inhibition strategy, failures have been mounting. Swiss drugmaker Roche and the U.K.'s GSK plc previously took early shots at developing TIGIT-class cancer drugs, but Roche failed to meet key endpoints in phase 3, and while GSK was assessed as having succeeded in phase 3, judgments that efficacy was limited versus initial expectations kept it from reaching commercialization.
Even so, the push into the oncology market is expected to continue. According to the pharmaceutical market research firm IQVIA, the global oncology market is projected to grow from about $252 billion (about 373 trillion won) in 2024 to about $441 billion (about 653 trillion won) in 2029. Double-digit growth of about 11% to 13% annually is expected to continue.
With an aging population increasing the number of cancer patients and advances in early diagnosis extending treatment durations, big pharma and biotech firms are steadily ramping up investment in a range of research and development (R&D) targeting new mechanisms and synergies among existing therapies. Industry officials say that because successful development has outsized impact, competition to develop next-generation cancer drugs will continue.