Chris Ryan

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 

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 Data

Findings 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.

The 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.

“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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Articles

Imdelltra (tarlatamab-dlle) demonstrated significant improvements in progression-free and overall survival compared to chemotherapy in small cell lung cancer patients, as shown in the phase 3 DeLLphi-304 trial. The median overall survival was 13.6 months with Imdelltra versus 8.3 months with chemotherapy. Imdelltra also showed better patient-reported outcomes and a favorable safety profile, despite higher rates of cytokine release syndrome. The trial supports Imdelltra as a preferable second-line therapy, establishing a new paradigm for bispecific T-cell engager immunotherapies in lung cancer treatment.

Imdelltra Shows Survival Benefit in Small Cell Lung Cancer

Adding Imfinzi to chemotherapy before and after surgery improved survival and response rates in resectable gastric and gastroesophageal junction cancer.

Adding Imfinzi (durvalumab) to FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy before and after surgery improved event-free survival compared to placebo plus FLOT for patients with resectable gastric or or gastroesophageal junction (GEJ) adenocarcinoma, according to data from the phase 3 MATTERHORN trial.

Findings presented in a press briefing at the 

 showed that at a median follow-up of 31.6 months for the Imfinzi arm (474 patients) and 31.4 months for the placebo arm (474 patients), Imfinzi plus FLOT generated a median EFS that was not reached compared with 32.8 months for placebo plus FLOT. In the Imfinzi arm, the 18- and 24-month EFS rates were 73% and 67%, respectively. These respective rates were 64% and 59% in the placebo arm.

“The [EFS] benefit was seen across prespecified [subgroup] cohorts. We did not see any new safety signals. [Therefore], this will change practice for our patients, which is exciting to see,” lead study author Dr. Yelena Y. Janjigian, said in the press briefing.

Janjigian is chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York.

Event-free survival (EFS): time during and after treatment that a patient lives without cancer progressing or surgery being delayed or canceled.

Overall survival (OS): time from treatment start or diagnosis until death from any cause.

Pathological complete response (pCR): no detectable cancer found in surgical tissue after treatment.

Disease-free survival (DFS): time after treatment during which a patient shows no signs of cancer.

R0 resection: surgery that removes all visible cancer with no cancer cells seen at the edges of the removed tissue.

PD-L1 (programmed death-ligand 1): a protein that helps cancer cells avoid being destroyed by the immune system.

ECOG performance status: scale used to measure how a patient's disease is affecting their daily living abilities.

Regarding safety, any-grade adverse effects (AEs; side effects) occurred in 99% of patients in both arms. The rates of AEs possibly related to study treatment were both 95%. The rates of grade 3/4 AEs were 72% for the Imfinzi arm versus 71% for the placebo arm. Grade 3 (severe)/4 (life-threatening) AEs possibly related to treatment occurred at rates of 60% and 59%, respectively. The rates of serious AEs were 48% for the Imfinzi arm versus 44% for the placebo arm.

AEs led to treatment discontinuation of any study treatment in 30% of patients in the experimental arm versus 23% of patients in the control arm. Ten percent of patients discontinued Imfinzi due to AEs, whereas 6% discontinued placebo. FLOT was discontinued due to AEs in 25% and 20% of patients, respectively.

AEs led to death in 5% of patients in the Imfinzi arm versus 4% of patients in the placebo arm. These AEs were deemed possibly related to Imfinzi or placebo in 1% and less than 1% of patients, respectively. AEs leading to death that were possibly related to FLOT occurred at respective rates of 1% and less than 1%.

Any-grade immune-mediated AEs (irAEs) were reported in 23% of patients in the Imfinzi group versus 7% of patients in the placebo arm. The rates of grade 3/4 irAEs were 7% and 4%, respectively.

Surgery was not performed due to AEs in 1% of patients in the experimental arm versus less than 1% of patients in the control arm. The rates of AEs leading to a delay in surgery were 2% and 3%, respectively.

Investigators of the global, double-blind, placebo-controlled trial enrolled patients with stage 2 to 4a gastric/GEJ adenocarcinoma who had no evidence of metastases and received no prior therapy. Patients also needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to the Imfinzi or placebo arm. Neoadjuvant therapy lasted two cycles, comprising Imfinzi at 1500 milligrams (mg) once every four weeks plus FLOT or placebo plus FLOT. Following surgery, patients received 2 additional cycles of Imfinzi at 1500 mg once every four weeks plus FLOT, or placebo plus FLOT. Patients then received Imfinzi at 1500 mg once every four weeks or placebo as monotherapy for 10 additional adjuvant cycles.

Key stratification factors included region (Asia versus non-Asia), clinical stage (N+ versus N–), and PD-L1 status (tumor area positivity [TAP] less than 1% versus TAP more than or equal to 1%).

EFS served as the trial’s primary end point. Overall survival (OS), pathological complete response (pCR) rate, and disease-free survival (DFS) were key secondary end points.

All patients in the Imfinzi arm received any neoadjuvant treatment compared with 99% of patients in the placebo arm. Neoadjuvant treatment with Imfinzi or placebo was completed in 97% and 95% of patients, respectively. The respective rates of patients who completed neoadjuvant FLOT were 96% and 95%.

Surgery was attempted in 91% of patients in the Imfinzi arm versus 90% of those in the placebo arm. Surgery was completed in 87% and 84% of patients, respectively. The rates of R0 resection were 92% in both arms. Any adjuvant therapy was given to 77% of patients in the Imfinzi group versus 74% of patients in the placebo group. Fifty-two percent of patients in both arms completed adjuvant Imfinzi or placebo; 61% and 64%, respectively, completed adjuvant FLOT. At the data cutoff, 68% of patients in the Imfinzi arm and 59% of patients in the placebo arm were actively in follow-up.

At baseline, the median age was 62 years in the Imfinzi arm versus 63 years in the placebo arm. The majority of patients in both groups were male (Imfinzi, 69%; placebo, 75%), from regions outside of Asia (81%; 81%), had an ECOG performance status of 0 (71%; 77%), had gastric tumors (68%; 67%), had non-T4 disease (75%; 75%), had node-positive disease (69%; 70%), had a PD-L1 TAP of at least 1% (90%; 90%), had an intestinal histology (52%; 50%), and did not have microsatellite instability–high disease (64%; 65%).

The median OS was NR in the Imfinzi arm versus 47.2 months in the placebo arm. The 18- and 24-month OS rates were 81% and 76%, respectively, in the Imfinzi arm. These respective rates were 77% and 70% in the placebo arm. The median follow-up for OS was 34.6 months in the Imfinzi group versus 34.6 months in the placebo group.

Patients in the Imfinzi arm achieved a pCR rate of 19% compared with 7% for those in the placebo arm, translating to a 12% difference.

The median DFS was NR in the Imfinzi arm versus 39.8 months in the placebo arm. The 18- and 24-month DFS rates were 79% and 75%, respectively, for Imfinzi plus FLOT versus 73% and 66%, respectively, for placebo plus FLOT.

Patients in both arms received a median of two neoadjuvant cycles of Imfinzi/placebo and FLOT. They received a median of 12 adjuvant cycles of Imfinzi/placebo and a median of two adjuvant cycles of FLOT. All patients received at least one neoadjuvant cycle of Imfinzi/placebo plus FLOT. Exactly two cycles of neoadjuvant Imfinzi and FLOT were each given to 97% of patients in the experimental arm; these rates were both 96% in the control arm.

In the experimental arm, at least one cycle of adjuvant Imfinzi and FLOT was given to 76% and 75% of patients, respectively. The rates of patients who received at least two cycles of each were 73% and 67%, respectively. Seventy-two percent of patients received at least three cycles of adjuvant Imfinzi, and 52% received 12 cycles. In the control arm, at least one cycle of adjuvant placebo and FLOT was given to 74% of patients each. Seventy-two percent received at least two placebo cycles, and 68% completed two adjuvant FLOT cycles. Seventy-one percent of patients completed at least three cycles of adjuvant placebo, and 51% completed the full 12-cycle adjuvant placebo course.

“Event-free survival in MATTERHORN” by Dr. Yelena Janjigian, et al., 

The addition of Imfinzi (durvalumab) to FLOT chemotherapy significantly improved event-free survival (EFS) in patients with resectable gastric or gastroesophageal junction adenocarcinoma, as demonstrated in the phase 3 MATTERHORN trial. The trial showed a notable EFS benefit across various subgroups without new safety concerns. Adverse effects were similar between the Imfinzi and placebo arms, with slightly higher rates of immune-mediated adverse effects in the Imfinzi group. Secondary endpoints, including overall survival and pathological complete response rates, also favored the Imfinzi arm, indicating a potential shift in treatment practice.

Adding Imfinzi to fluorouracil-based chemo improved event-free survival and response rates in resectable gastric and gastroesophageal junction cancer.

Imfinzi Combo Boosts Survival in Resectable Gastric and GEJ Cancer

Trodelvy plus Keytruda, when given in the frontline, extended survival without progression versus chemo plus Keytruda in PD-L1+ metastatic TNBC: © stock.adobe.com.

Trodelvy (sacituzumab govitecan-hziy) and Keytruda (pembrolizumab), when given as a first-line treatment, significantly improved survival without progression versus chemo plus Keytruda among patients with PD-L1–positive, advanced or metastatic triple-negative breast cancer (TNBC).

These primary findings were generated from the phase 3 ASCENT-04/KEYNOTE-D19, which were shared during the 

At a data cutoff date of March 3, 2025, out of the 221 patients treated with Trodelvy plus Keytruda, there was a median progression-free survival of 11.2 months by blinded independent central review (BICR) versus 7.8 months in the 222 patients treated with chemotherapy plus Keytruda, translating to a 35% reduction in the risk of disease progression or death. The six- and 12-month progression-free survival rates in the Trodelvy arm were 72% and 48%, respectively; in the chemotherapy arm, these respective rates were 63% and 33%.

“Results from ASCENT-04/KEYNOTE-D19 support the use of Trodelvy plus Keytruda as a potential new standard of care for patients with previously untreated, PD-L1–positive, locally advanced unresectable or metastatic TNBC,” Dr. Sara M. Tolaney, chief of the division of Breast Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts, said in the briefing. She is also an associate professor of medicine at Harvard Medical School.

Data from previous studies showed that median progression-free survival achieved with chemotherapy with immune checkpoint inhibition ranges from 7.5 months to 9.7 months in patients with PD-L1–positive metastatic TNBC; however, most patients will experience progressive disease and approximately half of those treatment for metastatic TNBC in the first line do not go on to receive second-line treatment.

Trial Design: Eligibility, Treatment, Objectives

The global, randomized, phase 3 study enrolled patients with treatment-naive, locally advanced unresectable or metastatic TNBC who had PD-L1 positivity defined as a combined positive score of at least ten per the 22C3 assay. At least six months must have passed since treatment in the curative setting, where prior anti–PD-(L)1 inhibition was permitted.

A total of 443 participants were randomly assigned to receive either 10 milligrams per kilogram (mg/kg) of intravenous Trodelvy on days one and eight, plus 200 mg of Keytruda on day one of 21-day treatment cycles versus Keytruda at the same dose and schedule combined with chemotherapy. Treatment continued until progressive disease and intolerable toxicity. All patients who experienced disease progression by BICR were permitted to cross over to receive single-agent Trodelvy in the second line.

Stratification factors comprised region (US/Canada/Western Europe vs the rest of the world), previous exposure to PD-(L)1 inhibition (yes versus no), and curative treatment-free interval (de novo TNBC versus recurrence within six to 12 months from treatment completion in the curative setting versus recurrence longer than 12 months from completion of treatment in the curative setting).

The primary end point of the study was progression-free survival by BICR, and secondary end points included overall survival, objective response rate and duration of response by BICR, safety and quality of life.

All patients were female and had a PD-L1 combined positive score of 10 or higher. Most patients were White (Trodelvy arm, 63%; chemotherapy arm, 63%), from the rest of the world (62%; 62%) and had an ECOG performance status of 0 (71%; 69%). Regarding curative treatment-free interval, most patients were recurrent in over 12 months (48%; 48%), followed by de novo (34%; 34%) and recurrent within 6 to 12 months (18%; 18%). Metastatic sites included lymph nodes (72%; 69%), lung (50%; 43%), other (37%; 32%), bone (28%; 20%), liver (25%; 26%) and brain (4%; 3%).

The chemotherapy selected before randomization in the Trodelvy arm was taxane for 52% of patients and gemcitabine/carboplatin for 48% of patients; in the chemotherapy arm, these respective rates were 51% and 49%. Four percent of patients in the antibody-drug conjugate arm vs 5% of those in the chemotherapy arm had prior exposure to PD-(L)1 inhibition.

Although overall survival data were immature at the time of the report, with a maturity rate of only 26%, a positive improvement was observed for the Trodelvy plus Keytruda arm vs chemotherapy plus Keytruda arm — despite a high crossover rate. Specifically, 43% of those on the chemotherapy arm crossed over to receive the antibody-drug conjugate as a single agent in the second line, which accounted for 81% of those who were subsequently given treatment after chemotherapy/Keytruda was discontinued.

The median overall survival was not reached in the Trodelvy arm, and it was also not reached in the chemotherapy arm; 53 and 61 events were reported in the arms, respectively. The hazard ratio for overall survival was 0.89.

Trodelvy plus Keytruda induced an objective response rate of 60% vs 53% with chemotherapy plus Keytruda. In the antibody-drug conjugate arm, 13% of patients achieved a complete response and 47% had a partial response; 32% had stable disease, 4% progressed and 5% were not response evaluable. In the chemotherapy arm, the complete response and partial response rates were 8% and 45%, respectively; 32% of patients had stable disease, 12% experienced disease progression and 4% were not evaluable.

The median time to response in the Trodelvy arm was 1.9 months (range, 1.0-9.3); it was also 1.9 months (range, 1.1-11.4) in the chemotherapy arm. Notably, the median duration of response was 16.5 months in the antibody-drug conjugate arm and 9.2 months in the chemotherapy arm.

Any-grade treatment-emergent side effects occurred in over 99% of those in the Trodelvy and chemotherapy arms; these effects were grade 3 or higher for 71% and 70% of patients, respectively. Treatment-emergent serious side effects were experienced by 38% of those who received the antibody-drug conjugate vs 31% of those given chemotherapy; 28% and 19% of cases, respectively, were treatment related.

In the Trodelvy plus Keytruda arm, treatment-emergent side effects led to dose reductions or interruptions in 35% and 77% of patients, respectively; treatment-emergent side effects led to treatment discontinuation for 12% of patients and proved fatal for 3% of patients. Three of the 7 treatment-emergent side effects that led to death were determined to be related to treatment. In the chemotherapy plus Keytruda arm, treatment-emergent side effects led to dose reductions and interruptions for 44% and 74% of patients, respectively; treatment-emergent side effects led to discontinuation for 31% of patients. treatment-emergent side effects led to death for 3% of those in this arm; 1 of these cases was related to treatment.

“Overall, the safety profile of Trodelvy plus Keytruda was consistent with the known safety profiles of each drug,” Tolaney said. “The rate of serious side effects was higher in the Trodelvy plus Keytruda group compared with the chemotherapy plus Keytruda group; however, the rate of treatment-emergent side effects leading to dose reduction or treatment discontinuation was lower.”

Dr. Jane L. Meisel, professor in the Departments of Hematology and Medical Oncology and Gynecology & Obstetrics, and codirector of Breast Medical Oncology at Emory University School of Medicine in Georgia, commented on the significance of the findings.

“I do think this is really such potentially practice-changing data. We've seen in previous studies how Trodelvy works so well for patients with metastatic TNBC later on in their treatment. And now, to see this combined with Keytruda and compared with chemotherapy plus Keytruda with such both statistically and clinically meaningful benefits for patients, I think it really does change the game for this subgroup,” she said. “This is very exciting, and I look forward to seeing this potentially make its way into clinical practice. I think the nice thing too, is that as clinicians, many of us have used both of these agents — Trodelvy and Keytruda — quite a bit, and so the fact that there were no additional toxicities seen [beyond what we have] seen before, will help people get used to using this and feel comfortable with it once it makes its way into the clinic.”

Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109

Trodelvy combined with Keytruda as a first-line treatment significantly improved progression-free survival in patients with PD-L1–positive, advanced or metastatic triple-negative breast cancer compared to chemotherapy plus Keytruda. The phase 3 ASCENT-04/KEYNOTE-D19 trial demonstrated a 35% reduction in disease progression or death risk. The study's primary endpoint was progression-free survival, with secondary endpoints including overall survival and response rates. Safety profiles were consistent with known data, though serious side effects were more frequent in the Trodelvy plus Keytruda group.

Trodelvy plus Keytruda, when given in the frontline, extended survival without progression versus chemo plus Keytruda in PD-L1+ metastatic TNBC.

Trodelvy/Keytruda Extends PFS Versus Chemo/Keytruda in PD -L1+ TNBC  

Braftovi and Erbitux plus chemo improved survival without progression over standard therapy in BRAF V600E-mutant mCRC in the first-line setting: © stock.adobe.com.

Updated data from the phase 3 BREAKWATER trial showed that combining Braftovi (encorafenib) and Erbitux (cetuximab) with mFOLFOX6 chemotherapy (modified fluorouracil, leucovorin and oxaliplatin) elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with metastatic colorectal cancer (mCRC) harboring BRAF V600E mutations.

Findings were presented in a press briefing ahead of the 

. Of the 236 patients treated with Braftovi plus Erbitux and mFOLFOX6, the median PFS was 12.8 at a median follow-up of 16.8 months. This number was 7.1 months at a median follow-up of 9.8 months among the 243 patients given standard-of-care treatment.

Additionally, Braftovi plus Erbitux and mFOLFOX6 generated a median overall survival of 30.3 months versus 15.1 months with standard-of-care. The estimated 12- and 24-month overall survival rates in the experimental arm were 80.1% and 52.0%, respectively. These respective rates were 66.0% and 29.0% in the standard-of-care treatment arm.

“Braftovi [in combination with] Erbitux and mFOLFOX6 — the BREAKWATER regimen — is a practice-changing, new standard-of-care for [patients] with mCRC with a 

 V600E mutation,” lead study author Elena Elez, MD, PhD, said during the press briefing.

Elez is an attending physician in the Gastrointestinal Tumors Service of the Medical Oncology Service at Vall d’Hebron University Hospital and principal investigator of the Gastrointestinal Tumor Group and Endocrine of Vall d'Hebron Instituto de Oncología in Barcelona, Spain.

the FDA granted accelerated approval to Braftovi in combination with Erbitux and mFOLFOX6

 for patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test. The regulatory decision was based on previously reported data from BREAKWATER, which showed that among the first 110 patients treated in each arm, the overall response rate was 61% for the combination versus 40% for standard-of-care. The median duration of response was 13.9 months and 11.1 months, respectively.

The open-label, multicenter study enrolled patients at least 16 years of age (or at least 18 years of age, based on the country), with mCRC who had measurable disease per RECIST 1.1 criteria and had not received prior systemic therapy in the metastatic setting. The presence of a BRAF V600E mutation was required, per local or central testing. Patients also needed to have an ECOG performance status of 0 or 1, along with adequate bone marrow, hepatic and renal function.

Combining Braftovi and Erbitux with mFOLFOX6 elicited a statistically significant and clinically meaningful improvement in progression-free survival versus standard-of-care therapy in the first-line treatment for patients with  mCRC harboring BRAF V600E mutations.

Key exclusion criteria comprised prior exposure to BRAF or EGFR inhibitors; symptomatic brain metastases; microsatellite instability-high/mismatch repair-deficient tumors, unless patients were ineligible for immune checkpoint inhibitors; and RAS-mutated disease.

Investigators randomly assigned 637 patients fashion to receive Braftovi plus Erbitux alone (158 patients); Braftovi in combination with Erbitux and chemo (236 patients); or standard-of-care (243 patients). Enrollment to the Braftovi/Erbitux alone cohort was stopped following a protocol amendment and subsequently enrolled patients were randomly assigned between the other two arms.

Treatment in the standard-of-care arm included mFOLFOX6, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan), or CAPOX (capecitabine and oxaliplatin) with or without Avastin (bevacizumab).

Stratification factors included region (United States/Canada versus Europe versus rest of world) and ECOG performance status (0 versus 1).

Overall response rate and progression-free survival per blinded independent central review served as the trial’s dual primary end points. Overall survival was a key secondary end point.

Data from the cohort of patients who received Braftovi plus Erbitux without chemo showed that the median progression-free survival was 6.8 months and the median overall survival was 19.5 months.

Updated response data demonstrated that the overall response rate for Braftovi plus Erbitux and chemo was 65.7%; the rates of complete response, partial response, stable disease  and progressive disease in this arm were 4.7%, 61.0%, 21.2% and 3.4%, respectively. In the standard-of-care arm, the overall response rate was 37.4% (95% CI, 31.6%-43.7%) with a complete response rate of 3.3%, a partial response rate of 34.2%, a stable disease rate of 35.0% and a progressive disease rate of 8.6%. In the Braftovi/Erbitux alone arm, the ORR was 45.6% with complete, partial response, stable disease and progressive rates of 1.9%, 43.7%, 36.1% and 7.6%, respectively.

The median time to response was 7.0 weeks (range, 5.1-103.6) for Braftovi/Erbitux/mFOLFOX6, 7.3 weeks (range, 5.4-48.0) for standard-of-care and 6.6 weeks (range, 4.3-86.4) for Braftovi/Erbitux. The median duration of response was 13.9 months, 10.8 months and 7.0 months, respectively.

In the Braftovi/Erbitux/chemo arm, the 6- and 12-month duration of response rates were 71.0% and 34.8%, respectively. These respective rates were 41.8% and 17.6% in the standard-of-care arm; they were 40.3% and 20.8%, respectively, for Braftovi/Erbitux alone.

At data cutoff, 28.4% of patients in the Braftovi/Erbitux/chemo arm remained on treatment compared with 6.6% in the standard-of-care arm and 7.6% of patients in the Braftovi/Erbitux arm. Subsequent therapy was administered to 63.9% of patients in the Braftovi/Erbitux/chemo group versus 61.2% in the standard-of-care group and 73.3% in the Braftovi/Erbitux group. A BRAF inhibitor–based regimen was given as subsequent therapy to 71.9% of the 139 patients in the standard-of-care arm who received additional treatment.

The median time to second disease progression or death was 20.7 months in the Braftovi/Erbitux/chemo arm, 12.7 months in the standard-of-care arm and 14.3 months in the Braftovi/Erbitux arm.

Regarding safety, the Braftovi plus Erbitux and chemo regimen was generally tolerable with a consistent safety profile. No substantial increases in chemotherapy dose reductions or discontinuation were observed compared with the standard-of-care arm.

Any-grade side effects were reported in all patients in the Braftovi/Erbitux/chemo arm, 99.1% of patients in the standard-of-care arm and 97.4% of patients in the Braftovi/Erbitux arm. The rates of grade 3 (severe) or grade 4 (life-threatening) side effects were 81.5%, 66.8% and 42.5%, respectively. The respective rates of grade 5 (death) events were 4.3%, 4.4% and 2.6%. One grade 5 side effect in the standard-of-care arm was deemed treatment related.

The most common grade 1/2 side effects included nausea (combination, 51%; standard-of-care, 46%), anemia (31%; 21%), diarrhea (41%; 46%), decreased appetite (35%; 26%), vomiting (32%; 20%), decreased neutrophil count (15%; 12%), arthralgia (29%; 5%), rash (29%; 4%), asthenia (24%; 14%), pyrexia (27%; 15%), peripheral neuropathy (20%; 20%), constipation (27%; 22%), peripheral sensory neuropathy (20%; 20%) and fatigue (24%; 24%).

The most frequently reported grade 3/4 side effects included nausea (combination, 3%; standard-of-care, 4%), anemia (15%; 4%), diarrhea (1%; 5%), decreased appetite (2%; 1%), vomiting (4%; 2%), decreased neutrophil count (19%; 17%), arthralgia (3%; <1%), rash (1%; 0%), asthenia (5%; 1%), pyrexia (2%; <1%), peripheral neuropathy (8%; 4%), constipation (<1%; <1%), peripheral sensory neuropathy (7%; 4%) and fatigue (3%; 4%).

Side effects led to permanent discontinuation of any study treatment in 26.7% of patients in the Braftovi/Erbitux/chemo arm, 17.5% of patients in the standard-of-care arm and 13.1% of patients in the Braftovi/Erbitux arm. Side effects led to dose reductions of any treatment in 65.5%, 54.1% and 10.5% of patients, respectively. The rates of side effects leading to dose reductions were 59.9% in the Braftovi/Erbitux/chemo arm and 54.1% in the standard-of-care arm. Side effects led to the discontinuation of chemotherapy (with or without Avastin) in 20.7% of the patients in the Braftovi/Erbitux/chemo group versus 17.5% in the standard-of-care group.

Elez E, Yoshino T, Shen L, et al. First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): progression-free survival and updated overall survival analyses. 

. 2025;43(suppl 17):LBA3500. doi:10.1200/JCO.2025.43.17_suppl.LBA3500

Elez E, Yoshino T, Shen L, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer. 

. Published online May 30, 2025. doi:10.1056/NEJMoa2501912

The phase 3 BREAKWATER trial demonstrated that combining Braftovi (encorafenib) and Erbitux (cetuximab) with mFOLFOX6 chemotherapy significantly improved progression-free survival in patients with metastatic colorectal cancer (mCRC) with BRAF V600E mutations compared to standard-of-care. The combination also showed a median overall survival of 30.3 months versus 15.1 months for standard treatment. The regimen was well-tolerated, with manageable side effects. The FDA granted accelerated approval for this combination in December 2024, establishing it as a new standard-of-care for this patient population.

Braftovi and Erbitux plus chemotherapy improved survival without progression over standard therapy in BRAF V600E-mutant mCRC in the first-line setting.

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