New Class of ADC Drugs Proves Effective Against Resistant Small Cell Lung Cancer
Alongside the EMA approval, the scientific community is discussing the breakthrough of ADC drugs targeting DLL3 and B7-H3, which show high efficacy in patients with relapsed SCLC, bypassing the tumor's immune resistance mechanisms.
A New Era of ADC Therapy in Resistant Small Cell Lung Cancer: Analysis of the Breakthrough
[The Gist]: What's Really Happening
On May 31, 2026, the scientific community is discussing what is already becoming clear: the treatment paradigm for relapsed small cell lung cancer (SCLC) has been overturned. This is not about a single breakthrough drug, but about a whole class of antibody-drug conjugates (ADCs) targeting DLL3 and B7-H3, demonstrating unprecedented efficacy where traditional chemotherapy is powerless. This is not an improvement by percentages—it's a shift in treatment philosophy.
The essence of what's happening is much deeper than the headlines suggest. The problem with SCLC has always been its incredible ability to relapse and rapidly develop resistance to chemotherapy and immunotherapy. Traditional second-line options (topotecan, lurbinectedin) yield a meager 20-40% objective response rate and a median progression-free survival of about 3-5 months. Immunotherapy, which revolutionized non-small cell lung cancer treatment, faces the challenge of a "cold" tumor microenvironment and defects in antigen presentation in SCLC—SCLC finds ways to "hide" from the immune system.
ADCs solve this problem in a radically different way. They don't wait for the immune system to "see" the tumor. ADCs use surface antigens (DLL3, B7-H3) as a physical anchor, delivering a cytotoxic payload directly into the cancer cell, bypassing MHC-dependent presentation mechanisms. This is MHC-independent cytotoxicity—a key advantage that overcomes resistance that kills patients after first-line chemoimmunotherapy fails.
The numbers currently being discussed in the corridors of ASCO and other congresses are truly impressive. Early phase I/II ADCs against B7-H3, DLL3, and SEZ6 show objective response rates (ORR) in the range of 33-68% with median progression-free survival of 4-7.6 months. This is 2-3 times higher than topotecan. If these numbers are confirmed in large randomized trials, we will witness the biggest leap in SCLC treatment in the last 20 years.
Timeline and Context
The history of ADCs in SCLC is a story of ups and downs, and 2026 became a turning point. The first major failure was Rova-T (rovalpituzumab tesirine)—an ADC against DLL3 that was so toxic its development was halted. The industry learned its lesson: the problem was not the target, but the design—an incorrect linker and payload led to systemic toxicity.
By 2026, the situation had changed dramatically. In May 2024, the FDA granted accelerated approval to tarlatamab (Imdelltra)—a bispecific T-cell engager against DLL3—based on an ORR of 40% and a median duration of response of 9.7 months. But that was only the first step.
The real breakthrough came in November 2025, when the FDA granted full approval to tarlatamab based on phase III DeLLphi-304 data. The numbers speak for themselves: median overall survival (OS) of 13.6 months versus 8.3 months with standard chemotherapy—a 40% reduction in the risk of death (HR 0.60). This is no longer a surrogate endpoint but a real extension of life. Moreover, 44% of patients in the study had brain metastases—a group typically excluded from clinical trials—and tarlatamab worked in them as well.
Concurrently, the ADC race is unfolding. On April 13, 2026, the FDA granted priority review status to the application for ifinatamab deruxtecan (I-DXd)—an ADC against B7-H3 from Daiichi Sankyo—with a PDUFA target date of October 10, 2026. Phase II data from IDEATE-Lung01 showed a clinically meaningful response in patients who had already failed platinum-based chemotherapy. If the ADC is approved by the end of the year, oncologists will have a second powerful tool in their arsenal.
Who Wins and Who Loses
Winner #1: Amgen with tarlatamab. The company achieved the impossible—turning an experimental bispecific into the standard second-line treatment for SCLC. Sales forecasts for tarlatamab estimate peak sales of $1.5-2 billion. Amgen has a first-mover advantage and intends to use it. Given that tarlatamab's patent protection extends until the late 2030s, this is a long-term cash cow.
Winner #2: Daiichi Sankyo and their DXd platform. The company already revolutionized treatment with Enhertu (ADC against HER2) in breast and gastric cancer. Now I-DXd (B7-H3) and possibly other ADCs from the same platform are poised to conquer SCLC. Their technology—a unique linker and a highly potent topoisomerase inhibitor—allows for a wide therapeutic window. If I-DXd is approved in October 2026, Daiichi Sankyo will solidify its status as a leader in ADCs.
Winner #3: Patients with relapsed SCLC. This is the most important winner. Previously, after first-line failure, a patient had a choice between toxic chemotherapy with minimal chance of response and palliative care. Now there is tarlatamab with an OS of 13.6 months, soon I-DXd, and likely other ADCs in the pipeline. Patients have gained hope and time.
Loser #1: Traditional second-line chemotherapy (topotecan, lurbinectedin). Their era is ending. Topotecan has an ORR of about 20% and toxicity that often outweighs the benefit. Lurbinectedin is slightly better but incomparable to ADCs and TCEs. Sales of these drugs will plummet once ADCs and TCEs become widely available. Manufacturers of topotecan generics are losing out.
Loser #2: Researchers who spent decades trying to "fix" the immune system in SCLC. All approaches aimed at "heating up" the cold tumor—combinations with anti-CTLA-4, innate immunity stimulators, vaccines—have proven clinically ineffective or weakly effective. ADCs and TCEs won by simply bypassing the problem, not solving it. This is a bitter pill for an entire scientific field.
Unexpected winner—companies developing ADCs against SEZ6 and TROP-2. While all attention is on DLL3 and B7-H3, there is evidence that the expression of these targets correlates with SCLC molecular subtypes. SEZ6 is highly expressed in neuroendocrine subtypes (SCLC-A and SCLC-N), while TROP-2 is expressed in non-neuroendocrine subtypes (SCLC-P and SCLC-I/Y). This opens the door to personalized ADC therapy: first determine the tumor subtype via biopsy, then select the ADC against the corresponding target. Companies that first implement this approach (e.g., AbbVie with ABBV-706 or Pfizer) could gain an advantage.
What the Media Isn't Saying
First: The toxicity of ADCs and TCEs is a serious problem that doesn't make headlines. Tarlatamab carries an FDA black box warning for the risk of fatal cytokine release syndrome (CRS) and neurotoxicity, including ICANS—immune effector cell-associated neurotoxicity syndrome. The incidence of CRS in studies reaches 50%, and although most cases are grade 1-2, there have been fatalities. ADCs are not safe either: interstitial lung disease (pneumonitis), myelosuppression, hepatotoxicity are known risks of the DXd platform. This is not "easy" therapy—it's toxic treatment requiring hospitalization and intensive monitoring.
Second: No ADC has yet been officially approved for SCLC. Despite all the hype, as of June 1, 2026, the FDA has not approved any ADC for SCLC. Rova-T failed. I-DXd is under review with a decision date of October 10, 2026. YL201, ABBV-706, and others are still in early phases. All articles about the "ADC breakthrough" are discussing potential, not clinical reality. The gap between early phases (where ORR may be inflated due to patient selection) and real-world practice can be huge.
Third (most overlooked): Even tarlatamab is not a cure, but a delay. Median OS of 13.6 months is nearly double that of chemotherapy (8.3 months), but it's still far from a cure. Sooner or later, the tumor finds a way to bypass this mechanism—for example, through downregulation of DLL3 on the cell surface. There have already been reports of acquired resistance to tarlatamab via mutations in Notch pathway components or through switching to alternative surface markers. SCLC is a smart tumor, and the arms race continues.
Fourth: The issue of price and accessibility. Tarlatamab costs about $25,000-30,000 per course (though exact figures depend on insurance negotiations). I-DXd will likely be similarly priced or higher. For many healthcare systems—especially in developing countries where SCLC is particularly prevalent due to high smoking rates—these sums are unaffordable. Will tarlatamab be available through global access programs? There is no clarity yet.
Forecast: Next 30 Days and 90 Days
Next 30 days: At June congresses—especially EAACI in Istanbul (June 11-15) and upcoming oncology meetings—we will see additional safety data on I-DXd and possibly the first long-term real-world evidence for tarlatamab. If RWE confirms the DeLLphi-304 data, confidence in tarlatamab will strengthen, and it will begin to replace chemotherapy even in countries where the FDA has not yet granted full approval (e.g., some regions in Asia).
Next 90 days (by September 2026): Preparations will begin for the I-DXd PDUFA date on October 10, 2026. Daiichi Sankyo will publish more detailed IDEATE-Lung01 data, likely in NEJM or Lancet Oncology. If ORR >40% with acceptable toxicity, Daiichi Sankyo's stock will rise 15-20% in the week before the decision date. Also expect Merck and other companies with ADC platforms to announce acceleration of their SCLC programs—the race is just beginning.
Long-term trend (12 months): By mid-2027, we will either have an approved ADC (I-DXd) and a fully approved TCE (tarlatamab), or, if something goes wrong, a major disappointment. But I'm betting on success. The more interesting question is how to combine these agents. Can you give tarlatamab and then, upon progression, I-DXd? Or vice versa? Cross-resistance is unknown. Clinical trials of ADC + TCE combinations are already being planned—if they show synergy, SCLC could transform from a death sentence into a chronic disease. But that's a question for 2027-2028. For now, we celebrate the first real breakthrough in a decade.
— Editorial Team
