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Immunotherapy Plus Chemotherapy Before Lung Cancer Surgery Significantly Improves Long-term Survival, Analysis Finds
By Hub staff report
/ Published June 3, 2025Adding immunotherapy to chemotherapy before surgery for patients with operable non-small cell lung cancer—the leading cause of cancer deaths worldwide—improved long-term survival overall compared with chemotherapy alone, according to a landmark study published Monday in the New England Journal of Medicine and presented at the annual meeting of the American Society of Clinical Oncology, the world's leading professional organization for physicians and oncology professionals caring for patients with cancer.
The research, conducted at the Johns Hopkins Kimmel Cancer Center and led by clinicians at its Bloomberg~Kimmel Institute for Cancer Immunotherapy and international partners, is the first and only phase 3 clinical trial to show a survival advantage for immunotherapy in conjunction with chemotherapy before surgery, without additional immunotherapy after surgery.
Key Takeaways"Just three doses of immunotherapy and chemotherapy showing a survival advantage is a big step forward for patients," says Julie Brahmer, director of thoracic oncology at the Kimmel Cancer Center and co-director of the upper aerodigestive program for the Bloomberg~Kimmel Institute.
During the clinical trial, 358 patients with stage 1B to 3A resectable non-small cell lung cancer were randomly assigned to receive standard chemotherapy for three cycles, with or without the anti-PD-1 immunotherapy drug nivolumab, followed by surgery. The initial results from the trial, published in the New England Journal of Medicine in 2022, resulted in Food and Drug Administration approval of the first immunotherapy/chemotherapy combination treatment for patients with operable non-small cell lung cancer, which is now the standard of care.
The final analysis of the data, presented at the ASCO meeting by principal investigator Patrick Forde of Trinity College Dublin, who conducted the research while at the Kimmel Cancer Center, expands on the trial's results with data from patients followed for five years after surgery.
In the immunotherapy plus chemotherapy arm, 24% of patients achieved complete remission—meaning no residual tumor was detected in the lungs or lymph nodes after surgery. For those patients who had complete clearance of their cancers at the time of surgery, five-year survival was 95%.
This work was supported by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.
Imdelltra Shows Survival Benefit In Small Cell Lung Cancer
Imdelltra improved survival and quality of life versus chemotherapy as second-line treatment for small cell lung cancer, reinforcing it as a new SOC.
Imdelltra improved survival and quality of life versus chemotherapy as second-line treatment for small cell lung cancer, reinforcing it as a new SOC.
Among patients with small cell lung cancer, second-line treatment with Imdelltra (tarlatamab-dlle) led to statistically significant and clinically meaningful improvements in progression-free survival and overall survival versus chemotherapy, according to data from the primary analysis of the phase 3 DeLLphi-304 trial presented at the 2025 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.
Findings showed that at a median follow-up of 11.2 months for patients treated with Imdelltra (254 patients) and 11.7 months for those given chemotherapy (255 patients), Imdelltra led to a median overall survival of 13.6 months compared with 8.3 months for chemotherapy. In the Imdelltra arm, the 6- and 12-month overall survival rates were 76% and 53%, respectively. These respective rates were 62% and 37% in the chemotherapy arm.
"Taking the efficacy and safety data together, these data clearly support Imdelltra as a preferable therapy for patients in the second-line setting for small cell lung cancer," lead study author Dr. Charles M. Rudin said in a presentation of the data. "Beyond redefining the standard of care for these patients, this study also establishes a new paradigm for the use of bispecific, T-cell engager immunotherapies for our patients with lung cancer."
Rudin is deputy director of the Cancer Center, co-director of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York.
In May 2024, the FDA granted accelerated approval to Imdelltra for the treatment of patients with extensive-stage small cell lung cancer with disease progression on or after platinum-based chemotherapy. This regulatory decision was supported by data from the phase 2 DeLLphi-301 trial.
More Efficacy, Patient-Reported Outcomes and Safety DataFindings also demonstrated that the median progression-free survival was 4.2 months for the Imdelltra arm versus 3.7 months for the chemotherapy arm. The 6-month progression-free survival rates in the Imdelltra and chemotherapy arms were 31% and 23%, respectively; the respective rates at 12 months were 20% and 4%.
Patients in the Imdelltra arm achieved an objective response rate of 35% compared with 20% for those given chemotherapy. In the experimental arm, the rates of complete response, partial response, stable disease, and progressive disease were 1%, 34%, 33% and 22%, respectively. In the chemotherapy arm, these respective rates were 0%, 20%, 44% and 20%. Ten percent and 16% of patients in the Imdelltra and chemotherapy arms, respectively, were not evaluable for response.
The median duration of response was 6.9 months in the Imdelltra arm compared with 5.5 months in the chemotherapy arm. The respective 6- and 12-month duration of response rates were 56% and 41% for Imdelltra compared with 29% and 13% for chemotherapy. The median time to response was 1.5 months versus 1.4 months for Imdelltra and chemotherapy, respectively. At data cutoff, response was ongoing in 47% of patients in the experimental group versus 15% of the control group.
Regarding patient-reported outcomes, the mean improvement in dyspnea score from baseline to week 18 was 1.94 in the Imdelltra arm versus –7.20 in the chemotherapy arm. At week 18, cough score improvements were reported in 16.1% of patients in the Imdelltra group versus 9% of patients in the control group. Improvements in chest pain at week 18 were reported in 8.7% and 3.5% of patients, respectively.
The median treatment duration was 4.2 months in the Imdelltra arm (252 patients) versus 2.5 months in the chemotherapy arm (244 patients). Any-grade treatment-emergent adverse effects occurred in 99% of patients in the experimental arm versus all patients in the chemotherapy arm. The rates of any-grade treatment-related adverse effects were 93% and 91%, respectively.
Grade 3 (severe) treatment-related adverse effects were reported in 27% of patients in the Imdelltra group compared with 62% of patients in the chemotherapy group. The respective rates of serious treatment-related adverse effects were 28% and 31%. These effects led to dose interruption and/or reduction in 19% of patients treated with Imdelltra versus 55% given chemotherapy, and led to treatment discontinuation in 3% and 6% of patients, respectively. One patient experienced a grade 5 (death) treatment-related adverse effect in the Imdelltra arm compared with four patients in the chemotherapy arm.
In the experimental arm, treatment-emergent cytokine release syndrome occurred during the first 2 cycles of Imdelltra in 60% of patients who were monitored for 48 hours (209 patients) at grade 1 (45%), grade 2 (13%), and grade 3 (1%). Nineteen percent of patients had serious cytokine release syndrome, and it led to treatment discontinuation in 0.5% of patients. The median time to intervention was 27 hours from the last Imdelltra dose.
In patients who were monitored for cytokine release syndrome for at least six to eight hours during the first 2 cycles of treatment with Imdelltra (43 patients), cytokine release syndrome was reported in 37% of patients at grade 1 (28%) and in 9% of patients at grade 2. Seven percent of instances in this group were serious, although none led to treatment discontinuation. The median time to intervention was 17 hours.
Although treatment-emergent adverse effects such as cytokine release syndrome, dysgeusia, fever, and decreased appetite were more common with Imdelltra, chemotherapy was associated with increased incidence of anemia, neutropenia, thrombocytopenia, and decreased platelet counts. The rates of grade 3 or higher adverse effects such as anemia, neutropenia, leukopenia, thrombocytopenia, febrile neutropenia, decreased platelet count, decreased neutrophil count, fatigue, pneumonia and low sodium levels were all higher with chemotherapy versus Imdelltra.
DeLLphi-304 BackgroundThe open-label, randomized, controlled study enrolled patients at least 18 years of age with histologically or cytologically confirmed small cell lung cancer who experienced disease progression following a first-line, platinum-based regimen with or without an immune checkpoint inhibitor. Patients were required to have an ECOG performance status of 0 or 1. Patients with asymptomatic, previously treated or untreated brain metastases were allowed to enroll.
Investigators randomly assigned patients in a 1:1 fashion to receive Imdelltra or chemotherapy comprising lurbinectedin (47 patients), topotecan (185 patients), or amrubicin (23 patients). Stratification factors included prior treatment with a PD-(L)1 inhibitor (yes versus no), chemotherapy-free interval (less than 90 days versus at least 90 days to less than 180 days versus at least 180 days), brain metastases (yes versus no), and intended chemotherapy (topotecan/amrubicin versus lurbinectedin).
Overall survival served as the trial's primary end point. Progression-free survival and patient-reported outcomes were key secondary end points. Other secondary objectives included objective response rate, duration of response, disease control rate and safety.
At baseline, the median age was 64 years in the Imdelltra arm versus 66 years (range, 26-84) in the chemotherapy arm. The majority of patients in both arms were male (Imdelltra, 72%; chemotherapy, 66%), were White (60%; 55%), were current or former smokers (91%; 88%), had an ECOG performance status of 1 (67%; 68%), received prior anti–PD-(L)1 therapy (71%; 71%), and received prior radiotherapy (63%; 63%). A chemotherapy-free interval of less than 90 days was most common in both arms (43%; 45%), followed by at least 90 days and less than 180 days (33%; 31%) and at least 180 days (24%; 25%).
Brain metastases were present in 44% of patients in the Imdelltra arm versus 45% of patients in the chemotherapy arm. The rates of patients with liver metastases were 33% and 37%, respectively. Among evaluable patients, 95% in the Imdelltra arm (217 patients) and 93% in the chemotherapy arm (214 patients) were positive for DLL3 expression.
Reference:
"Tarlatamab versus chemotherapy as second-line treatment for small cell lung cancer: primary analysis" by Dr. Charles M. Rudin, et al., 2025 ASCO Annual Meeting.
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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.
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