BOSTON, Mass. -- By Lee Han-soo / Korea Biomedical Review correspondent -- In the rapidly evolving landscape of oncology, where scientific breakthroughs emerge at breakneck speed and competition intensifies daily, Merck KGaA stands at a pivotal moment. 

The German pharmaceutical giant, long celebrated for cornerstone therapies like Erbitux, Bavencio, and Tepmetko, all reimbursed across major markets including Korea, and is orchestrating a bold transformation that could reshape its role in cancer treatment for decades to come.

According to Paul Lyne, Head of Oncology Research, the company is shifting from a legacy-focused approach to a pipeline anchored in three revolutionary scientific pillars -- antibody-drug conjugates (ADCs), cancer cell signaling including DNA damage response, and tumor-selective immunotherapy.

While many pharmaceutical companies abandon older therapies in pursuit of novel targets, Merck KGaA is taking a different approach -- extracting maximum value from proven platforms through intelligent combination strategies. 

"Even within our legacy programs, such as Bavencio and Erbitux, there's substantial room for further development," Lyne explains. The company's approach to Erbitux exemplifies this philosophy. 

Rather than viewing it as a mature asset, Merck continues to support its potential across multiple tumor types, including groundbreaking combinations with KRAS and BRAF inhibitors.

The results speak for themselves. At the recent ASCO meeting, data from the BREAKWATER study, conducted by Pfizer, demonstrated how a first-line regimen combining a BRAF inhibitor, chemotherapy, and Erbitux doubled overall survival in colorectal cancer patients. 

As Lyne notes, this "underscores the power of rational combination strategies" and validates the company's approach to maximizing therapeutic potential.

The science behind the strategy

However, this does not mean that Merck is not focusing on newer modalities. According to Lyne, Merck's ADC portfolio features two programs in clinical studies, with several more in preclinical research. 

The first targets CEACAM5, a cell-surface antigen highly expressed in colorectal and other gastrointestinal tumors. By delivering cytotoxic agents directly to cancer cells while sparing healthy tissue, this approach addresses fundamental limitations of conventional chemotherapy, offering the promise of enhanced efficacy with reduced systemic toxicity.

The first targets CEACAM5, a cell-surface antigen highly expressed in colorectal and other gastrointestinal tumors. This anti-CEACAM5 ADC exemplifies the broader potential of ADCs, which deliver cytotoxic agents directly to cancer cells while sparing healthy tissue. By doing so, ADCs address the fundamental limitations of conventional chemotherapy and offer the promise of enhanced efficacy with reduced systemic toxicity.

The second ADC program focuses on GD2, an antigen prominently expressed in pediatric and adult sarcomas. Currently in phase I trials, the potential extends beyond sarcomas to neuroblastoma and certain other cancers, representing a platform technology that could transform treatment across multiple indications.

In the realm of DNA damage response, Merck is advancing a next-generation PARP inhibitor that represents a step change in selectivity. 

While four first-generation PARP inhibitors have achieved approval, they broadly inhibit both PARP1 and PARP2, often resulting in dose-limiting hematologic toxicities. 

"First-generation PARP inhibitors target both PARP1 and PARP2," Lyne explains. "By selectively inhibiting PARP1, we aim to reduce toxicity and improve the therapeutic window, making our candidate potentially best-in-class."

This refined selectivity could enable longer treatment durations and synergistic combinations without compromising patient safety -- a critical advantage in maintenance settings or when combined with DNA-damaging chemotherapies.

Perhaps most intriguingly, Merck is tackling one of immuno-oncology's most challenging targets: CD40. 

While CD40 has long been recognized as a promising immune-activating target, systemic CD40 agonism has been associated with severe toxicities, including potentially fatal cytokine release syndrome. 

Merck is looking to solve this problem with a CD40 agonist engineered to activate only in tumor cells expressing MUC1, a transmembrane protein commonly found in epithelial tumors.

"By linking CD40 activation to MUC1 expression, we hope to retain the immunostimulatory power of the target while reducing the off-tumor effects that have plagued earlier candidates," Lyne explains. 

This tumor-selective strategy exemplifies Merck's broader commitment to creating more precise, better-tolerated immunotherapies that could function as standalone treatments or in rational combinations with checkpoint inhibitors or ADCs.

Merck's current approach reflects hard-won lessons about balancing innovation with clinical feasibility. The portfolio is strategically weighted approximately 60-65 percent focused on precedented biology, with the remainder dedicated to novel mechanisms. 

"A few years ago, we leaned more into high-risk novelty, but many of those programs didn't translate clinically," Lyne candidly admits. "Now, we're innovating within validated pathways where we believe we can do better -- whether by improving selectivity, delivery, or combinations."

This disciplined approach extends to biomarker strategy. More than 80 percent of Merck's oncology programs now include defined patient selection strategies, leveraging both tissue assays and increasingly sophisticated liquid biopsy technologies. 

In programs like Tepmetko, liquid biopsy serves dual purposes -- clinical trial screening and potential monitoring through circulating tumor DNA (ctDNA). While tissue remains the gold standard, liquid-based diagnostics offer improved access and convenience -- particularly valuable for frail patients or those with difficult-to-biopsy lesions.

Global collaboration and future vision

Merck's organizational structure reflects a sophisticated understanding of translational medicine. While discovery and development teams operate separately, cross-functional collaboration is embedded at every governance level. 

"We have development leaders embedded in research committees and vice versa," Lyne explains. "It ensures that what we discover translates into real clinical value."

This model incorporates real-time clinical insights -- from unmet needs and toxicity profiles to competitive landscapes -- directly into discovery strategy. 

The questions driving research have evolved from simple efficacy queries to more nuanced assessments “Will it be usable? Will it stand out? Will it meet a clinical gap?” Lyne said. 

Notably, Merck's global strategy recognizes Asia not merely as a recruitment region but as a growing engine of innovation.

The company has forged strategic collaborations with companies like Hengrui and Abbisko while expanding early-phase trial activity across the continent. 

"The scientific infrastructure, trial quality, and translational capabilities are very strong," Lyne notes. "Asia is essential to delivering globally relevant therapies."

Beyond Asia, Merck maintains robust academic collaborations, particularly around its Boston headquarters. Partnerships with institutions like Dana-Farber and Harvard Medical School, combined with academic networks in Europe and the U.S. create a rich ecosystem for translational research. 

When evaluating potential partners, Lyne stressed that Merck applies three criteria — scientific originality, strategic fit, and execution capability. 

"We want collaborators who can push the science and deliver," Lyne states.

Despite intensifying competition, Lyne views the current moment as unprecedented in its potential, not just for companies, but for patients as well.

"This is a golden age for oncology," he said. "We're seeing breakthroughs in tumor types that used to have very limited options."

Future advances, he believes, will emerge from targeted, scientifically grounded innovations, not merely discovering new targets, but refining how we deliver and select them. 

The integration of artificial intelligence, advanced biomarker strategies, and sophisticated combination approaches promises to unlock therapeutic potential that seemed impossible just a decade ago.

"The science is moving quickly, but so is our ability to apply it meaningfully," Lyne reflects. "Cancer is still devastating, but today, we have more tools than ever to fight it and more reason than ever to believe that progress will continue."