Sabrina Serani

Treatment with Herceptin (trastuzumab) and Perjeta (pertuzumab) with endocrine therapy but without chemotherapy has been shown to potentially be an effective treatment for patients with HER2-positive and hormone receptor (HR)-positive metastatic breast cancer. Furthermore, the addition of Kisqali (ribociclib) might improve patient outcomes even more.

These findings come from the second interim efficacy analysis of the phase 3 DETECT V trial presented at the 2024 ESMO Congress.

In the study, 270 patients with metastatic HR/HER2–positive breast cancer receiving a first to third line of treatment were randomized to one of two arms. In the chemotherapy arm, patients received physician’s choice of chemotherapy plus Herceptin/Perjeta followed by maintenance Herceptin/Perjeta and endocrine therapy. In the chemotherapy-free arm, patients received physician’s choice of endocrine therapy plus Herceptin/Perjeta. After 124 patients enrolled, the study was amended to add Kisqali to endocrine therapy in both arms. 

The combination of Herceptin, Perjeta, and endocrine therapy without chemotherapy showed promising results in patients with HR+/HER2+ metastatic breast cancer.

Adding Kisqali to the treatment regimen further improved patient outcomes, reducing the risk of disease progression or death.

The DETECT V trial suggests that a chemotherapy-free regimen with Herceptin, Perjeta, and endocrine therapy, potentially with the addition of Kisqali, may be a promising treatment option for patients with HR+/HER2+ metastatic breast cancer.

Overall survival (OS, the time a patient lives, regardless of disease status) and progression-free survival (PFS, the time a patient lives without their disease spreading or worsening) was similar between the arms. In the chemotherapy-free arm, the median OS was not reached (meaning more than half of the patients in that arm were still alive) versus 46.1 months in the chemotherapy arm. For PFS, the median was 19.1 months in the chemotherapy-free arm versus 22.4 months in the chemotherapy arm.

The addition of Kisqali improved PFS and OS, with patients treated with Kisqali being 48% less likely to experience disease progression or death and being 58% less likely to die of any cause.

Dr. Wolfgang Janni emphasized that this was a comparison of subsequent study cohorts, not a randomized comparison for the addition of Kisqali. Janni is a professor at the University of Ulm in Ulm, Germany.

Regarding safety of the chemotherapy versus chemotherapy-free arms, the most common side effect in both arms was diarrhea, with 100 all-grade incidences in the chemotherapy-free arm and 146 in the chemotherapy arm.

“We did observe a higher amount of diarrhea in the chemotherapy containing arm, while we saw more prolonged neutropenia [low count of neutrophils, a type of white blood cell] in the chemo[therapy]-free arm, possibly due to longer exposure to [Kisqali],” Janni explained. In the chemotherapy-free arm, there were 64 incidences of all-grade neutropenia and 48 grade 3 (severe) or higher.

For the safety analysis of Kisqali versus no Kisqali, 55 patients (37.4%) receiving Kisqali experienced at least one serious side effect versus 43 patients (34.7%) in the no Kisqali arm. Ninety-five patients (64.6%) and 62 patients (50%) in the Kisqali and no Kisqali arms, respectively, experienced at least one grade 3 or higher side effect.

“The tolerability comparison between the two cohorts did not show a difference in the overall incidence of serious [side effects], but in [side effects] with grade 3 or higher, which was mainly caused by the higher incidence of neutropenia and liver enzyme abnormalities in the [Kisqali] cohort. There were no treatment-associated deaths in this study,” Janni said.

The final results from this study are pending, as are longer-term findings from the Kisqali cohort, which had shorter follow-up due to its later addition into the study regimens.

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Among patients with HR+/HER2+ breast cancer, Herceptin and Perjeta plus endocrine therapy proved to be beneficial without chemotherapy.

Herceptin, Perjeta Regimen May Be Effective Without Chemo in Breast Cancer

A treatment combination of Imjudo (tremelimumab) and Imfinzi (durvalumab) demonstrated improved survival outcomes, including disease control and treatment responses in patients with unresectable (surgically unremovable) hepatocellular carcinoma (liver cancer), according to a presentation at the 

The presentation highlighted updated five-year data from the phase 3 HIMALAYA study. These results set new standards in unresectable liver cancer, with one in 5 patients alive at five years, Dr. Lorenza Rimassa said in the presentation. 

A combination treatment of Imjudo (tremelimumab) and Imfinzi (durvalumab) has shown improved survival outcomes in patients with unresectable liver cancer.

The phase 3 HIMALAYA study revealed that one in five patients treated with Imjudo plus Imfinzi were alive at five years, surpassing the 9.4% survival rate for those treated with Nexavar.

Patients in the Imjudo plus Imfinzi group experienced a median overall survival of 16.43 months compared to 13.77 months in the Nexavar group.

The Imjudo plus Imfinzi combination also demonstrated better disease control, with higher rates of complete and partial responses and lower rates of disease progression.

Rimassa is an associate professor of medical oncology at Humanitas University and head of the Hepatopancreatobiliary Oncology Department at Istituto di Ricovero e Cura a Carattere Scientifico Maugeri Humanitas Research Hospital in Milan, Italy.

“This five-year updated analysis of the HIMALAYA study presents the longest follow-up to date in phase 3 studies for [unresectable liver cancer],” Rimassa said. “[Imjudo plus Imfinzi] sustained an overall survival (OS; time patients live, regardless of disease status) benefit versus [Nexavar (Nexavar)] and demonstrated unprecedented long-term survival benefit at five years, with a five-year survival rate of 19.6% for [Imjudo plus Imfinzi] versus 9.4% for [Nexavar].”

Survival Benefits of Imjudo Plus Imfinzi Versus Nexavar in Unresectable Liver Cancer

A total of 1,171 patients were randomly assigned to three treatment groups. The Imjudo-Imfinzi combination group included 393 patients. There were 389 patients in the Imfinzi monotherapy group and patients 389 patients in the Nexavar group. In the study, 393 patients were treated with the Imjudo-Imfinzi combination and 389 patients received Nexavar.

Patients from the Imjudo-Imfinzi combination group compared with Nexavar sustained an OS benefit. Specifically, the median OS was 16.43 months in the combination group and 13.77 in the Nexavar group. The median follow-up duration was 62.49 versus 59.86 months, respectively.

For patients experiencing disease control, the OS was enhanced, showing rates of 28.7% in the Imjudo-Imfinzi combination group and 12.7% in the Nexavar group at five years and increasing over time. There were 12 patients (3.1%) in the Imjudo-Imfinzi combination group who achieved complete response (disappearance of cancer) versus no patients in the Nexavar group, and 67 patients (17.0%) experienced partial response (tumor shrinkage) versus 20 patients (5.1%), respectively. Stable disease was achieved by 157 (39.9%) in the Imjudo-Imfinzi combination group and 216 patients (55.5%) in the Nexavar group, and 141 patients (35.9%) versus 118 (30.3%), respectively, experienced disease progression.

“More patients treated with [Imjudo-Imfinzi combination] versus Nexavar were still alive, still on study treatment, and fewer received a subsequent therapy at five years,” Rimassa noted.

Patients receiving the Imjudo-Imfinzi combination also experienced deeper tumor responses, including over 50% shrinkage in 34 patients, which was associated with longer overall survival, compared with 12 patients receiving Nexavar. In addition, 80 patients in the Imjudo-Imfinzi combination group versus 114 patients in the Nexavar group experienced minor responses of less than 30% tumor shrinkage; however, this also led to a long-term survival benefit for those receiving Imjudo-Imfinzi combination. In the Imjudo-Imfinzi combination group, there were 168 patients who had no shrinkage or growth versus 169 patients in the Nexavar group.

Rimassa stated that there were no new serious treatment-related side effects after the primary analysis with a data cut-off on Aug. 27, 2023. At the five-year data cut-off of March 1, 2024, 17.5% of patients in the Imjudo-Imfinzi combination group had experienced serious treatment-related side effects, which was the same percentage reported at the primary analysis. Similarly, for the Nexavar group, at the five-year analysis at the data cut-off, there were 9.9% of patients who experienced serious treatment-related side effects versus 9.4% at the primary data cut-off.

There were also 24.8% of patients in the Imjudo-Imfinzi combination group that had serious non-treatment-related side effects at the five-year data cut-off versus 23% at the primary data cut-off, and in the Nexavar group, there were 20.3% of patients experiencing serious non- treatment-related side effects versus 20.3%, respectively.

“Overall survival benefit with [the Imjudo-Imfinzi combination] was enhanced in patients who achieved disease control. Any degree of tumor shrinkage was linked to long-term survival, with those experiencing deep responses showing the greatest benefit. These findings indicate that conventional response measures such as complete response or partial response … may not fully capture the benefits of [the Imjudo-Imfinzi combination],” Rimassa concluded.

In patients with unresectable liver cancer, treatment with Imjudo plus Imfinzi showed better survival outcomes compared with Nexavar.

Imjudo Plus Imfinzi Improve Survival Versus Nexavar in Liver Cancer

A treatment combination of Braftovi (encorafenib), Erbitux (cetuximab) and chemotherapy showed promising anti-tumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer who were previously treated with at least one line of systemic therapy, according to a presentation at the 

A presentation at the conference highlighted updated safety results from the phase 3 BREAKWATER study, which included three components: a safety portion, a phase 3 randomization and a second randomization labeled as cohort 3.

The safety portion included two cohorts: Braftovi plus Erbitux and FOLFIRI chemotherapy (cohort 1); and Braftovi plus Erbitux and mFOLFOX6 chemotherapy (cohort 2). The phase 3 component randomized patients to three treatment groups: Erbitux alone; Erbitux plus mFOLFOX6 chemotherapy; or the control group of three chemotherapy regimens: FOLFIRI, mFOLFOX6, or capecitabine and oxaliplatin (CAPOX) with or without Avastin (bevacizumab). Cohort 3 randomly assigned patients to either Erbitux/FOLFIRI chemotherapy or FOLFIRI chemotherapy with or without Avastin.

A treatment combination of Braftovi, Erbitux and chemotherapy showed promising anti-tumor activity in patients with BRAF V600E-mutant metastatic colorectal cancer.

Among previously treated patients receiving Braftovi, Erbitux and chemotherapy as a second-line therapy, the ORR was 44.4%.

In patients receiving Braftovi, Erbitux and chemotherapy as a second-line therapy, the median DOR was 12.5 months, the median PFS was 12.6 months, and the median OS was 19.7 months.

Patients must have confirmed stage 4 colorectal cancer and be ineligible if they have tumors that are microsatellite instability-high or mismatch repair-deficient.

Of note, the presentation of the BREAKWATER study at ESMO mainly focused on the safety portion, which included patients from cohort 1.

There were 30 patients enrolled in cohort 1. The median age was 56.5 years and 66.7% were men. The ECOG performance status was either 0 (ability to independently perform daily tasks; 73.3%) or 1 (ability to perform most daily tasks independently; 26.7%). Twelve patients had not received prior therapy, and 18 patients had one prior line of therapy.

In a presentation at the 2024 ESMO Congress, Dr. Josep Tabernero, head of the Department of Medical Oncology, Vall d’Hebron University Hospital and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, discussed findings from the trial. Tabernero reported that only one dose-limiting toxicity (DLT; side effects from drugs that prevent an increase in dose) occurred with the Erbitux/chemotherapy combination, which was grade 4 (life-threatening) neutropenia (lower levels of a white blood cell type) that lasted more than seven days.

Treatment-related side effects of any grade were experienced by 93.3% of patients, with 50% of patients experiencing grade 3 (severe)/4 treatment-related side effects, and 16.7% of patients experiencing a serious side effect related to study treatment. There were no deaths related to the study treatment.

Efficacy data showed an objective response rate (ORR; percentage of patients whose cancer shrunk or disappeared) of 83.3% in patients from cohort 1 receiving Braftovi, Erbitux plus chemotherapy in the first-line metastatic setting. There were two complete responses (CRs; disappearance of cancer), eight partial responses (PRs; cancer shrunk) and one patient with stable disease (SD; cancer did not improve or worsen). The median duration of response (DOR) was not estimable. The median progression-free survival (PFS; time patients are alive without their disease worsening) was not evaluable, meaning not enough patients had their disease worsened by the data collection date, and the median overall survival (OS; time patients live regardless of disease status) was not evaluable.

Among previously treated patients from cohort 1 receiving treatment as a second-line therapy, the ORR was 44.4%. There was one CR, seven PRs and seven patients with SD. The median DOR was 12.5 months. The median PFS was 12.6 months, and the median OS was 19.7 months.

“The combination of [Braftovi, Erbitux] plus chemotherapy was tolerable without new safety signals in patients with BRAF V600E-mutant metastatic colorectal cancer … [and] showed promising improvement in key efficacy measures,” said Tabernero.

The BREAKWATER trial assessed the combination of Braftovi and Erbitux with or without chemotherapy in patients with metastatic colorectal cancer. Patients must have confirmed stage 4 colorectal cancer harboring a BRAF V600E mutation. Patients were ineligible if they had tumors that are microsatellite instability-high or mismatch repair-deficient.

Safety Among Patients With Metastatic Colorectal Cancer

At the 2024 ESMO Congress, Tabernero shared data from cohort 1 of the safety portion, which evaluated the combination of Braftovi, Erbitux and chemotherapy. The primary goal of the safety portion of the trial was DLTs, with secondary goals including safety and antitumor activity. 

Additional safety data showed that all patients experienced treatment-emergent side effects, with 63.3% and 46.7% experiencing grade 3/4 treatment-emergent side effects and serious treatment-emergent side effects, respectively. Treatment-emergent side effects leading to dose reduction, dose interruption or permanent discontinuation of any drug occurred in 53.3%, 73.3% and 30% of patients, respectively. Treatment-emergent side effects were associated with two patient deaths.

Treatment-emergent side effects across all grades occurring in at least 30% of patients included nausea (50%), diarrhea (46.7%), constipation (43.3%), fatigue (43.3%), dermatitis acneiform (acne-like bumps; 40%), rash (33.3%) and skin hyperpigmentation (30%). Treatment-emergent side effects of grade 3 or worse included two cases of dermatitis acneiform and one case each of diarrhea, constipation and fatigue.

Erbitux combination is currently approved by the FDA

 for use in patients previously treated for BRAF V600E-mutated metastatic colorectal cancer.

“Currently, there are no specifically targeted first-line treatments for BRAF V600E-mutant metastatic colorectal cancer, which highlights the unmet need for novel treatment options for this patient population,” said Tabernero.

In his concluding remarks, Tabernero said, “These results support the continued evaluation of Erbitux plus chemotherapy as a treatment option for patients with BRAF V600E-mutated metastatic colorectal cancer in cohort 3 of the BREAKWATER study.”

In patients with BRAF V600E-mutant metastatic colorectal cancer, a combination of Braftovi, Erbitux and chemotherapy showed promising antitumor activity.

Braftovi Regimen Is Promising in Metastatic Colorectal Cancer

The Oncologic Drugs Advisory Committee (ODAC), a group of experts that advises the Food and Drug Administration (FDA) on cancer therapies, recently voted in favor of imetelstat for the treatment of patients with myelodysplastic syndrome and anemia (decreased red blood cells) who are dependent on blood transfusions and are unresponsive to or ineligible for treatment with erythropoiesis-stimulating agents (ESAs). 

More specifically, 12 panel members voted that the potential benefits outweigh the potential risks, while two members voted the opposite.“Transfusion independence is the quality metric here and why I think there’s efficacy and meaningfulness for patients here,” said Dr. Ashley Rosko, professor in the Division of Hematology at The Ohio State University in Columbus, OH, and member of the ODAC.

Despite concerns, the Oncologic Drugs Advisory Committee favors imetelstat's approval, highlighting its potential benefits for certain patients with MDS.

The drug offers the potential benefit of transfusion independence, which could potentially improve patient outcomes.

The committee’s evaluation raised questions about the drug's efficacy, especially regarding disease-modifying effects and patient-reported outcomes.

The new drug application for imetelstat was supported by data from the IMerge/MDS3001 study. Findings were published in 

Patients were randomly assigned to one of two groups: Two-thirds received imetelstat while the other third received a placebo.

In the experimental imetelstat arm, 40% of patients (40 patients) achieved red blood cell (RBC) transfusion independence of at least eight weeks versus 15% of patients (nine patients) in the placebo arm, meeting the study’s primary endpoint.

Imetelstat Hits Transfusion Independence Goal in Low-Risk Myelodysplastic Syndrome

Regarding safety, 91% of patients in the imetelstat arm and 47% of patients in the placebo arm experienced grade 3 to 4 treatment-emergent side effects, including neutropenia (68% versus 3%) and thrombocytopenia (62% versus 8%) — which are both conditions involving a decrease in a specific type of white blood cell. However, these safety issues were quickly resolved, according to Dr. Amer Zeidan, associate professor at Yale School of Medicine. No treatment-related deaths were reported.

“In this trial, the drug…was associated with treatment-related neutropenia and thrombocytopenia, which were grade 3 and higher in around two-thirds of patients. However, most of those were reversible within two weeks of holding the dose or delaying the cycle or reducing the dose and did not lead to an increase in clinically significant adverse events such as bleeding and febrile neutropenia. I think overall, the efficacy and safety profiles are favorable,” Zeidan explained in an interview with CURE®’s sister brand, Targeted OncologyTM.

According to Geron, the manufacturer of imetelstat, approximately 80% to 85% of patients with lower-risk MDS have anemia at diagnosis, with most being highly symptomatic, and 40% of these patients have anemia that is dependent on red blood cell transfusions.Not only does the reliance on red blood cell transfusions strain medical resources, but chronic red blood cell transfusions are correlated with negative clinical outcomes, including risks of transfusion reactions, cardiovascular complications, infections and iron overload, and associated end-organ dysfunction.

For these reasons, transfusion independence should be a therapeutic goal for patients and physicians, according to Dr. Michael Savona, Beverly and George Rawlings Director of Hematology Research and professor of medicine and cancer biology at the Vanderbilt University School of Medicine, as well as author of the IMerge study published in 

The current landscape of care for this intent-to-treat population is limited, with only Reblozyl (luspatercept) and Revlimid (lenalidomide) approved for patients who are relapsed or refractory to ESAs. Further, these agents are only indicated in small subpopulations and do not show extended durability of transfusion independence, as presented by Savona.

The basis of many drug approvals in MDS, including Revlimid and Reblozyl, has been RBC transfusion independence, and only the approval for azacitidine in 2004 was supported by primary endpoint overall survival data.

Dr. Rami Komrokji, vice chair of the malignant hematology department and lead clinical investigator of the MDS program at Moffitt Cancer Center and Research Institute, provided the clinician’s perspective for the applicant’s presentation.

Komorokji concluded that achieving transfusion independence was a meaningful clinical benefit for transfusion-dependent anemia in patients with lower-risk MDS and that the duration of response was only clinically relevant in responders. Komorokji, who also served as an investigator on the IMerge study, noted that imetelstat provides long-term, continuous transfusion-free periods, and meaningful increases in hemoglobin and hematologic function were observed with imetelstat.

In delivering the FDA’s opening remarks, Dr. Lori Ehrlich, cross-disciplinary team leader in the Division of Hematology Malignancies I, stated, “For a new drug to be approved in the United States, the FDA must determine that the drug is safe and effective for use under the conditions prescribed, recommended, or suggested in the product labeling. The demonstration of effectiveness requires substantial evidence that the drug will have the effect it purports or is represented to have.”

“For a single randomized trial to support an application, results must be sufficiently robust and compelling. Because all drugs have adverse effects, the demonstration of safety requires showing that the benefits of the drug outweigh its risks,” Ehrlich continued.

The FDA’s issues with efficacy included that the secondary endpoints were not supportive of a disease-modifying treatment effect and that the patient-reported outcomes did not corroborate a treatment effect. Dr. Nina Kim, clinical reviewer, presented on behalf of the FDA.

Kim noted that the clinical meaningfulness of an eight-week transfusion independence period in the context of lower-risk MDS is uncertain. Further, the association between a treatment-induced increased transfusion independence rate and an improvement in overall survival has not been demonstrated, and to support a marketing application, this connection should be present. However, no other trial has demonstrated a survival advantage in lower-risk MDS with transfusion-dependent anemia.

In lieu of these findings, the FDA held that patient-reported outcomes should demonstrate significant improvements. While the patient-reported outcome findings were only exploratory, the FDA did not find compelling evidence to support an improvement in anemia-related symptoms, primarily fatigue.

Most of the study sites of IMerge/MDS3001 were not conducted within the United States, and 93% of patients were enrolled in non-United States. sites. Kim noted that the primary efficacy results varied between United States and non-United States sites, indicating that imetelstat may not be an ideal applicant for approval in the United States population.Although the incidence of grade 3 to 4 side effects was noted to be higher in the imetelstat arm, additionally, a higher percentage of patient deaths was observed in the imetelstat arm compared with the placebo arm.

Kim also identified issues with the dosing of imetelstat.

“Although other dose levels of imetelstat have been explored in myelofibrosis and solid tumors, only one dose has been explored in lower-risk MDS. The question remains whether this is actually the optimal dose in MDS given the dose modification rate with imetelstat observed in the MDS3001 study when compared with the placebo group, combined with the fact that there were high rates and a positive dose exposure-response relationship for grade 3 to 4 thrombocytopenia,” Kim said.

“This data suggests that this may not, in fact, be the optimal dose,” Kim continued.

Members of the committee who specialize in hematologic malignancies were encouraged by the results that imetelstat produced, especially for a patient population with limited options.

“I think transfusion independence is the standard of what to look for in these low-risk MDS patients. I think looking at things like [complete response (disappearance of cancer)] and [partial response (dedcrease in cancer)] really are not applicable in this population…The transfusion independence is the benchmark that is used in these patients. It’s been the benchmark that's used for other therapies in this setting,” said Dr. Anthony Hunter, assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, GA.

“While [the cytopenias] are numerically important, it was really gratifying to see that they did not result in complications. When you take a look at the infections that were reported, it looked like nearly the majority were viral infections. It has been really hard for any of us to conduct and help our patients during the [COVID-19] pandemic, and for a lower-risk MDS, they're coming in frequently for transfusions. It was a laudable effort,” said Dr. Jacqueline Garcia, medical oncologist in the Adult Leukemia Program at the Dana-Farber Cancer Institute in Boston, MA

“One of the things particularly with the MDS population is fatigue. When I'm looking at this data in terms of being able to say what the applicant has presented here sufficiently robust. I think yes, I do,” said Rosko.

“This is a supportive drug….they did a trial and met their primary endpoint,” said Dr. Jorge Nieva, associate professor of clinical medicine and section head of solid tumors, University of Southern California Norris Comprehensive Cancer Center in Los Angeles, CA. “The data here I think are sufficient.”

The Oncologic Drug Advisory Committee voted that the benefits of imetelstat outweigh the risks for transfusion-dependent myelodysplastic syndrome and anemia. 

Sabrina Serani

Herceptin, Perjeta Regimen May Be Effective Without Chemo in Breast Cancer

Imjudo Plus Imfinzi Improve Survival Versus Nexavar in Liver Cancer

Braftovi Regimen Is Promising in Metastatic Colorectal Cancer

FDA Committee in Favor of Imetelstat for Transfusion-Dependent MDS

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