Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives
FDA Approves Taletrectinib For ROS1-Positive Non-Small Cell Lung Cancer
Taletrectinib gains FDA approval as a groundbreaking treatment for ROS1-positive non-small cell lung cancer, offering hope for patients with CNS involvement.
The FDA has granted approval for taletrectinib, a novel oral tyrosine kinase inhibitor (TKI), for the treatment of adult patients with locally advanced or metastatic ROS1-positive NSCLC.1
This approval addresses a critical unmet need for patients with this specific oncogenic driver, particularly those who have developed resistance to prior TKI therapies or present with central nervous system (CNS) metastases.
The approval of taletrectinib marks an important advancement in the therapeutic landscape for ROS1-positive NSCLC, a subset of lung cancer characterized by rearrangements in the ROS1 gene. These fusions lead to constitutive activation of the ROS1 kinase, driving uncontrolled cellular proliferation and tumor growth.
The FDA's approval is primarily supported by compelling data from a pooled analysis of 2 pivotal phase 2 clinical trials: TRUST-I and TRUST-II. These multicenter, single-arm, open-label studies evaluated taletrectinib at a dose of 600 mg orally once daily in patients with advanced ROS1-positive NSCLC.
The integrated analysis included 273 efficacy-evaluable patients, encompassing both TKI-naive and TKI-pretreated cohorts.2 The primary end point for both studies was confirmed objective response rate (cORR) as assessed by an independent review committee. Key secondary end points included intracranial cORR, duration of response (DOR), progression-free survival (PFS), and safety.
Taletrectinib demonstrated a cORR of 88.8% in the TKI-naive population (n = 160). The median DOR was 44.2 months, and the median PFS was 45.6 months. In patients with measurable baseline brain metastases, the intracranial cORR was 76.5%.
In the TKI-pretreated cohort, the cORR was 55.8%. The median DOR was 16.6 months, and the median PFS was 9.7 months. Notably, in patients with the ROS1 G2032R mutation, the cORR was 61.5%. Intracranial cORR in this group was 65.6%.
Lung cancer: © Crystal Light - stock.Adobe.Com
The safety analysis, based on 352 patients treated with 600 mg once daily, indicated that taletrectinib was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were primarily gastrointestinal events (88%), followed by elevated aspartate aminotransferase (72%) and alanine aminotransferase (68%), with most cases being grade 1. Neurologic TEAEs were infrequent, with dizziness reported in 21% and dysgeusia in 15% of patients, predominantly grade 1 in severity. Treatment discontinuations due to TEAEs occurred in 6.5% of patients.
"I think the unique characteristics of taletrectinib is [the] lower rate of neurological toxicity that might made it make it attractive for patients with newly diagnosed ROS1-mutant non–small cell lung cancer," said Lyudmila Bazhenova, MD, medical oncologist and professor of medicine at UC San Diego Health, in an interview with Targeted OncologyTM.
Bazhenova underscored the importance of taletrectinib's CNS penetration for these patients.
"The reported incidence [of brain metastases] is about 20 to 30%, so it's relatively common to see brain mets in the [ROS1-mutant] population," according to Bazhenova.
The favorable efficacy, durable responses, robust intracranial activity, and manageable safety profile underscore taletrectinib's potential as a significant therapeutic option for patients with ROS1-positive NSCLC, addressing both TKI-naive and TKI-pretreated populations, including those with CNS involvement. An ongoing phase 3 trial (NCT06564324) is comparing taletrectinib head-to-head with crizotinib (Xalkori) in TKI-naive patients to further elucidate its role in this patient population.3
Taletrectinib is a next-generation, oral, CNS-active TKI designed to selectively inhibit the activity of the aberrant ROS1fusion protein.2 Unlike some earlier generation ROS1 TKIs, taletrectinib demonstrates enhanced potency against acquired resistance mutations, including the common G2032R mutation, which can emerge following prior TKI treatment. Its design also contributes to superior penetration of the blood-brain barrier, offering robust intracranial activity and potentially mitigating neurological adverse events associated with less selective inhibitors.
Taletrectinib functions by binding to the ATP-binding site of the ROS1 kinase, thereby inhibiting its phosphorylation activity. This action prevents the activation of downstream signaling pathways, such as PI3K/AKT and MAPK/ERK, which are essential for cancer cell survival and proliferation. The drug's selectivity for ROS1 over other kinases, such as tropomyosin receptor kinase B (TRKB), is hypothesized to contribute to its favorable safety profile regarding neurologic adverse events.
REFERENCES: 1. FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. US FDA. June 11, 2025. Accessed June 11, 2025. Https://tinyurl.Com/4v5bkvfh 2. Pérol M, et al. Taletrectinib in ROS1+ non–small cell lung cancer: TRUST. J Clin Oncol. Published online April 3, 2025. Doi:10.1200/JCO.25.00275. 3. A phase III study comparing taletrectinib with standard therapy in ROS1 positive locally advanced or metastatic non-small cell lung cancer patients. ClinicalTrials.Gov. Updated March 11, 2025. Accessed June 11, 2025. Https://www.Clinicaltrials.Gov/study/NCT06564324 NewsletterStay up to date on practice-changing data in community practice.
ASCO Data Shows New Therapy Extends Survival In Small Cell Lung Cancer
Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers, with a five-year survival rate of just five to 10 percent. Black Americans, in particular, face disproportionately worse outcomes. They experience higher incidence rates, are less likely to be diagnosed early, and often encounter systemic barriers to timely and effective treatment. These disparities persist even among non-smokers, pointing to deeper issues like healthcare access, socioeconomic status, and structural inequality.
Early detection and prompt treatment are key to survival, but they remain unevenly distributed. The need for more effective, accessible therapies that can bridge these gaps has never been more urgent.
At the 2025 ASCO Annual Meeting, that urgency met a potential breakthrough.
A Major Advance: Tarlatamab Shows 40% Reduction in Death RiskAmgen announced new interim results from the global Phase 3 DeLLphi-304 trial, showing that IMDELLTRA® (tarlatamab-dlle)—a first-in-class T-cell engager—reduced the risk of death by 40 percent and extended median overall survival by more than five months compared to standard chemotherapy in previously treated SCLC patients. These results were published simultaneously in The New England Journal of Medicine.
"This is typically a pretty lethal disease," Dr. Charles Rudin, chair of the study's steering committee and a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, tells BlackDoctor.Org. "Median survival with chemotherapy in this context is seven to nine months. So, there was a real need for a new therapy."
IMDELLTRA delivered.
Highlights from the DeLLphi-304 TrialUnlike traditional chemotherapy, which broadly attacks fast-dividing cells and causes widespread toxicity, tarlatamab is a bispecific T-cell engager. It binds to both the cancer cell and the patient's T-cells, bringing them together so the immune system can directly kill the tumor.
"It's an immune therapy," Dr. Rudin says. "It brings the immune cell into the tumor and activates it in a pretty tumor-specific way."
This mechanism not only improves efficacy but also drastically reduces harmful side effects—a major factor in long-term patient outcomes and quality of life.
Implications for Health EquityGiven the disproportionate burden of SCLC on Black communities, a therapy like IMDELLTRA could be game-changing. Black individuals are less likely to be diagnosed early, more likely to face treatment delays, and often receive substandard care—factors that worsen survival.
While smoking is a major risk factor, disparities persist even among non-smokers, indicating that structural and biological factors also contribute. Recent research suggests potential genetic differences, like variations in EGFR mutations, that may affect lung cancer development in Black patients.
Bringing forward therapies that are more tolerable, require less hospitalization, and deliver better outcomes can help close this gap.
What's Next?Amgen plans to submit the DeLLphi-304 data to the FDA to support converting IMDELLTRA's May 2024 accelerated approval into full approval.
"We're not done," Dr. Rudin cautions. "But this is a really important milestone."
Looking ahead, researchers hope to move IMDELLTRA earlier in the treatment process, including as a maintenance therapy following first-line chemo. If it can prevent relapse in this setting, its impact could be even more profound.
"We try to give our best drug first," Dr. Rudin says. "If we think this is really a transformative therapy, we should try to move it as early as possible."
The Breakthrough Drug That Took Me From Stage 4 To Cancer-Free
Photo courtesy of Lalisha When Lalisha was diagnosed with stage IV small cell lung cancer (SCLC), doctors didn't offer much hope. The cancer was aggressive. The odds were grim. And yet — they're here. Alive. In remission. And advocating for others to fight just as hard as they did.
Their story is one of pain, persistence, and one bold decision that changed everything: to seek better answers and push for a treatment no one had offered them before.
That treatment, tarlatamab, was just spotlighted at the 2025 ASCO Annual Meeting. It wasn't a guarantee. But for Lalisha, it worked. Just months later, a scan showed no evidence of cancer in their body.
Here's how they got there — and the advice they're sharing with anyone facing the same fight.
In October 2023, Lalisha was diagnosed with stage IV small cell lung cancer. The news hit hard. "I went so quickly from limited-stage to extensive-stage," they tell BlackDoctor.Org. "The first thing that went through my mind was, how am I going to survive this?"
Small cell lung cancer is aggressive and fast-spreading. Lalisha's cancer continued to advance even after multiple rounds of chemotherapy. The physical toll was intense: bone pain, fatigue, weakness that made it difficult to even get out of bed or dress themself. Emotionally, they were navigating depression, grief, and the terrifying task of coming to terms with their mortality.
But they didn't stop fighting.
A Critical Turning PointWhen treatment at their initial care facility failed to provide the clarity or results they needed, Lalisha took matters into their own hands. Their decision to drive themselves to the Mayo Clinic stemmed from a deep-seated mistrust rooted in personal history; their mother had died at 39 due to inadequate healthcare. Additionally, unclear and inconsistent communication from their physician prompted them to seek a second opinion.
Upon arriving at Mayo, they were immediately informed that surgery needed to be performed swiftly and learned that their initial physician had unnecessarily delayed treatment for three months after suspecting a pre-cancerous nodule. A biopsy and left lower lung lobectomy at the Mayo Clinic revealed that the nodules were not pre-cancerous, but cancerous. At that point, Lalisha was diagnosed with limited-stage small cell lung cancer (SCLC).
Lalisha decided to complete treatment at Northwestern Memorial Hospital in downtown Chicago.
Photo courtesy of Lalisha A Breakthrough Treatment Lalisha's cancer had spread throughout their entire body. The care team acted quickly. Even before the next scan was completed, they were making arrangements to provide access to tarlatamab, a promising new treatment developed by Amgen. They were hospitalized for their first two doses, experiencing side effects like cytokine release syndrome (CRS), but by the third dose, something changed.
They started to feel better.
Two months later, a PET scan revealed a stunning result: no evidence of active cancer.
"It was the best news I've ever received," Lalisha says. "My mental health improved. My physical health improved. I could walk without fear of falling. I could play basketball again. I had my life back."
From Survivor to AdvocateLalisha didn't stop at survival. A retired social worker with 30 years of experience, they found renewed purpose in helping others navigate their own battles with cancer. They now facilitate a support group for small cell lung cancer survivors, speak at conferences, and answer questions from others weighing their treatment options.
"I look at myself as an example of what happens when researchers, medical providers, and scientists focus on truly helping patients live," they say.
Photo courtesy of Lalisha Calling for Systemic Change Their story is also a call to action, especially for healthcare providers. "Some doctors become pessimistic and say things like, 'This is going to take you out.' That kind of language kills hope. We need providers who treat us like survivors, not statistics," they add.
Lalisha wants to see better access to lifesaving medications like tarlatamab, especially in small or under-resourced hospitals, and for patients of color who often face disparities in care. Their journey underscores the power of second opinions, patient self-advocacy, and equitable access to innovation.
Hope for the FutureToday, Lalisha wakes up with joy and gratitude. "There will be storms in my life, but I have learned how to dance in the rain," they add.
They continue to advocate for a future where no one with small cell lung cancer feels overlooked or defeated — where treatment isn't just about survival, but about reclaiming life.
Their message is simple, but powerful:
"You are the chief navigator of your care. Speak up. Ask questions. Get the second opinion. It's your life — and you are in charge," they conclude.
Photo courtesy of Lalisha Tips for Those Facing Small Cell Lung Cancer Whether you're newly diagnosed or deep in treatment, here are some of Lalisha's takeaways that may help:
1. Get a Second OpinionIf something doesn't feel right, get another perspective. Your life is worth the extra effort.
2. Advocate RelentlesslyYou are the leader of your care team. If a treatment plan doesn't sit well with you, say something. Don't stay silent.
3. Don't Lose HopeEven with aggressive cancers like small cell, progress is being made. New drugs like tarlatamab are emerging — stay informed and open to clinical trials or experimental options.
4. Build a Care NetworkSurround yourself with people who will support and advocate with you: caregivers, family, friends, other patients, or support groups.
5. Address Mental HealthGrief, fear, and depression are real. Don't go through it alone — talk to a counselor or palliative care team about emotional support.
6. Push for EquityIf you're from a marginalized background, know that disparities in care exist, and push harder. Don't let the system overlook you.
7. Celebrate Every VictoryWhether it's walking down the hall or getting back on the basketball court, small wins are huge. Embrace joy where you can.
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