Category: Hem/Onc Updates

Neoadjuvant Immunotherapy in Early Breast cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant chemotherapy is commonly used for patients with locally advanced Triple-Negative Breast Cancer (TNBC) and HER2-positive breast cancer. Alongside this standard treatment, there has been a push to develop new strategies aimed at increasing pathologic Complete Response (pCR) rates and improving survival outcomes. The introduction of Immune Checkpoint Inhibitors (ICIs) marked a major shift in cancer treatment, initially proving effective in melanoma and later showing promise in metastatic TNBC. This success led researchers to test ICIs in early-stage breast cancer as well.

Multiple randomized clinical trials have studied the impact of combining ICIs with chemotherapy in the neoadjuvant setting, some continuing ICI therapy as adjuvant treatment. These trials have gone beyond TNBC, exploring their use in other breast cancer subtypes like HER2-positive and Hormone Receptor-positive (HR-positive)/HER2-negative cancers. While some trials achieved their goals, the best way to integrate ICIs into early treatment remains debated, with concerns about cost and safety still under discussion.

In response to the need for clarity, a comprehensive systematic review and meta-analysis was conducted to assess the efficacy of neoadjuvant ICI therapy combined with chemotherapy in early-stage breast cancer. The analysis reviewed randomized controlled trials retrieved from the PubMed database up until December 2023. These trials focused on comparing ICIs plus chemotherapy versus chemotherapy alone in patients with early-stage breast cancer. The meta-analysis included 5114 patients from nine randomized controlled trials. These patients were subdivided into three major subgroups – TNBC (N=2097) patients, HR-positive/HER2-negative (N=1924) patients, and HER2-positive (N=1115) patients. The Primary outcomes evaluated were pathologic Complete Response (pCR) and Event-Free Survival (EFS) stratified by molecular phenotype and PD-L1 status. Secondary outcomes included incidence of Adverse Events (AEs), with a focus on immune-related toxicities.
The following are the Key Findings:
Pathologic Complete Response (pCR):
Triple-Negative Breast Cancer: Neoadjuvant ICIs improved the pCR rate significantly, with an increase from 46.6% to 59.9% (absolute improvement of 13.3%), regardless of PD-L1 status.
Hormone Receptor-Positive, HER2-Negative Tumors: There was a significant benefit of ICIs in PD-L1-positive tumors. The pCR rate increased from 14.8% to 24.6% in these cases (absolute improvement of 9.8%). However, there was no significant benefit in PD-L1-negative HR-positive/HER2-negative patients.
HER2-Positive Tumors: No significant pCR improvement was observed with the addition of ICIs in this subtype.

Event-Free Survival (EFS):
TNBC Patients with pCR: For those with TNBC who achieved a pCR, ICIs improved EFS (HR=0.65, 95% CI 0.42–1.00). The 5-year EFS was 92.0% for patients treated with ICIs compared to 88.0% without ICIs.
TNBC Patients with Residual Disease: ICIs also showed better EFS (HR=0.77, 95% CI 0.61–0.98) in patients who had residual disease after treatment, with a 5-year EFS of 63.3% compared to 56.1% without ICIs.
Adjuvant ICI in TNBC: No additional survival benefit was found with the use of adjuvant ICIs (after surgery) in TNBC patients, regardless of whether they achieved pCR or had residual disease.

Safety Profile:
Adverse Events (AEs): During neoadjuvant treatment, grade 3 or higher immune-related adverse events (AEs) were observed in 10.3% of patients treated with ICIs. The overall incidence of severe AEs (grade 3 or worse) was higher in ICI-treated patients (63.6%) compared to chemotherapy alone (54.1%). This reflects the toxicity costs associated with ICIs

Implications:
Neoadjuvant vs. Adjuvant ICI: The findings suggest that ICIs have greater efficacy when used in the neoadjuvant setting compared to adjuvant treatment. This is likely due to the tumor presence during neoadjuvant therapy, which allows for immune system priming through exposure to tumor antigens.
PD-L1 as a Biomarker: PD-L1 expression appears to be a more reliable biomarker of response to ICIs in HR-positive/HER2-negative tumors than in TNBC, where ICI benefit seems independent of PD-L1 status.
TNBC and Residual Disease: In patients with residual disease after neoadjuvant therapy, the benefit of continuing ICIs in the adjuvant setting is limited. This raises the question of whether continuing ICIs postoperatively is necessary or whether alternative strategies, like the use of other novel therapies, may be more effective.

In conclusion, Neoadjuvant Immune Checkpoint Inhibitors improve pathologic Complete Response rates and Event-Free Survival in early-stage breast cancer, especially in TNBC and PD-L1-positive HR-positive/HER2-negative tumors. However, their use in the adjuvant setting does not appear to provide added benefit. Ongoing trials, like the OptimICE-PCR trial, are designed to answer this question definitively by randomizing patients who achieve pCR to either continued ICI therapy or observation. For patients with residual disease post-neoadjuvant therapy, novel treatment approaches like Antibody-Drug Conjugates such as Sacituzumab Govitecan combined with ICIs are being investigated, offering potential new treatment paradigms.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. 2024;10(10):1331-1341. doi:10.1001/jamaoncol.2024.3456.

FDA Approves VYLOY® with Chemotherapy for Biomarker Positive Gastric or GEJ Adenocarcinoma

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SUMMARY: The FDA on October 18, 2024, approved Zolbetuximab-clzb (VYLOY®), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. The FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with Gastric or GEJ adenocarcinoma who may be eligible for treatment with Zolbetuximab.

The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients with metastatic disease is approximately 6%. These patients frequently are treated with platinum containing chemotherapy along with a fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed on the surface of the cancer cells and accessible to targeted therapies with antibodies. CLDN18.2 is expressed in 30-40% of Gastric adenocarcinomas.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. This study met the Primary endpoint and the median Progression Free Survival (PFS) was 10.6 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The Overall Survival (OS) was also significantly improved (18.23 versus 15.54 months, HR=0.75; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population.

GLOW trial is a global, multi-center, double-blind, randomized Phase III study, conducted to assess the efficacy and safety of Zolbetuximab plus CAPOX (N=254) versus placebo plus CAPOX (N=253) as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. In this trial, 507 eligible patients were randomly assigned 1:1 to receive Zolbetuximab 800 mg/m2 IV as a loading dose on cycle 1, day 1, of the first 21-day cycle, followed by 600 mg/m2 IV on day 1 of subsequent cycles, along with CAPOX regimen consisting of Capecitabine 1000 mg/m2 orally twice daily on days 1-14 of each cycle and Oxaliplatin 130 mg/m2 IV on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both treatment groups and patients could continue beyond 8 cycles with Zolbetuximab or placebo plus Capecitabine at investigator’s decision, and treatment continued until disease progression or unacceptable toxicities. CLDN18.2 positive was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining and patients were stratified by region (Asia versus non-Asia), number of organs with metastases, and prior gastrectomy (yes versus no). The median patient age was 60 years, majority of patients were male from Asia, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1. Basline characteristics were similar in both treatment groups. The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

At a median follow up of 12.6 months, the combination of Zolbetuximab plus CAPOX significantly improved PFS, and the median PFS was 8.2 months, compared with 6.8 months for those given placebo plus CAPOX (HR=0.68; P=0.0007). The median OS was 14.4 months versus 12.2 months respectively (HR=0.77; P=0.01). The PFS and OS benefits were sustained at 24 months, and the benefits were observed across most subgroups. The most common side effects were nausea and vomiting and the authors recommended increasing the infusion duration time, or splitting the dose over a 2 day period, in addition to the administration of prophylactic antiemetics.

The researchers concluded that the addition of first-line Zolbetuximab to CAPOX significantly improved PFS and OS in patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. The authors added that Zolbetuximab plus CAPOX represents a potential new first-line therapy for this patient group. Taken together, both GLOW and SPOTLIGHT trials showed a similar reduction in the risk of disease progression or death and a similar reduction in the risk of death with the addition of Zolbetuximab to chemotherapy, when compared with placebo plus chemotherapy.

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Shah MA, Shitara K, Ajani JA, et al. Nature Medicine 2023; 29:2133–2141

Liquid Biopsy May Predict Survival in Metastatic Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention.

Metastatic prostate cancer remains a significant concern in the United States, being the second leading cause of cancer-related deaths among men. Over recent years, the incidence of metastatic prostate cancer has notably increased. For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Signaling Inhibitors (ARSIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. In previous studies, treatment intensification has been deemed justified based on tumor histology and radiographic disease burden, but these criteria have not consistently predicted outcomes, underscoring the urgent need for robust new, noninvasive, prognostic biomarkers.

Liquid biopsy, a noninvasive method of analyzing blood-based biomarkers, has emerged as a promising tool for early cancer detection, prognosis, personalized treatment decisions, and disease monitoring. In particular, Circulating Tumor Cells (CTCs)-cancer cells shed from primary or metastatic tumors into the bloodstream-offer a dynamic snapshot of disease status and have shown promise as biomarkers for prognosis, disease monitoring, and personalized treatment decisions. While CTCs have been extensively studied in metastatic Castration-Resistant Prostate Cancer (mCRPC), their role in mHSPC remains underexplored.

The S1216 trial is a prospective, multicenter, Phase 3, randomized clinical trial, conducted by SWOG in collaboration with the National Cancer Institute (NCI) and other research groups, to determine whether incorporating baseline CTC enumeration could serve as a reliable biomarker for predicting long-term outcomes, aiding in the identification of patients who may benefit from treatment intensification or novel therapeutic regimens. The primary goal of this study is to evaluate the prognostic value of Circulating Tumor Cell (CTC) counts in men with mHSPC, particularly their association with Overall Survival (OS).

The S1216 trial included 1313 men with newly diagnosed mHSPC, randomized in a 1:1 ratio to receive Androgen Deprivation Therapy (ADT) combined with either Orteronel, a CYP17 inhibitor that blocks androgen biosynthesis, or Bicalutamide, a nonsteroidal anti-androgen. ADT was administered using a Luteinizing Hormone-Releasing Hormone agonist, and Bicalutamide was given at a dose of 50 mg once daily, while Orteronel was administered at 300 mg twice daily. Treatment allocation was stratified based on disease severity, timing of ADT initiation prior to or after enrollment, and Zubrod Performance Status.

A key component of the trial was the collection and analysis of liquid biopsy samples, particularly CTC enumeration, at baseline and at disease progression to mCRPC. These blood samples were processed using the CellSearch platform, the only FDA-cleared system for CTC enumeration. The platform employs immunomagnetic beads that bind to epithelial cell adhesion molecules (EpCAM) on the surface of CTCs, enriching the sample for CTCs. After isolation, the CTCs were stained with specific markers to distinguish them from non-tumor cells: Cytokeratins (CK) markers for epithelial cells, CD45, a leukocyte antigen, used to exclude non-cancerous white blood cells, and DAPI, a nuclear stain to identify cells with intact nuclei. CTC counts were categorized into three groups: 0, 1-4, and 5 or more CTCs per 7.5 mL of blood. This categorization was based on findings from prior research in mCRPC, where higher CTC counts were associated with worse clinical outcomes. The goal was to determine whether a similar association could be observed in men with mHSPC. The Primary outcome of the study was Overall Survival (OS), with secondary outcomes including Progression-Free Survival (PFS) and Prostate-Specific Antigen (PSA) levels at 7 months.

Of the 1313 trial participants, 503 men had evaluable blood samples for CTC analysis at baseline. The results of the study showed that higher baseline CTC counts were strongly associated with worse clinical outcomes. Patients with 5 or more CTCs had a median OS of 27.9 months, compared with 56.2 months for men with 1-4 CTCs, and median OS of more than 78 months for men with 0 CTCs (median not reached). A similar trend was observed for PFS, with men who had 5 or more CTCs showing a significantly higher risk of disease progression. After adjusting for baseline clinical covariates, men with 5 or more CTCs were 3.22 times more likely to die during the study period and 2.46 times more likely to have their cancer progress, and had a lower odds of achieving a complete PSA response, compared to men with 0 CTCs at baseline.

This study demonstrates that baseline CTC count is a powerful, independent prognostic biomarker for men with mHSPC. CTC enumeration at the start of therapy can help identify men at higher risk of poor survival, even before the disease progresses to mCRPC. This information is particularly valuable for selecting patients for clinical trials of more aggressive or novel therapies. By identifying high-risk patients early, clinicians can potentially intensify treatment upfront, before PSA levels or clinical symptoms worsen.

In summary, CTC count provides critical insights into the biological behavior of metastatic prostate cancer and offers a noninvasive method for stratifying patients based on their risk of poor outcomes. Future research may expand the role of liquid biopsy beyond CTC enumeration to include molecular profiling of CTCs and circulating tumor DNA (ctDNA), enabling even more precise and personalized treatment strategies.

Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer. Goldkorn A, Tangen C, Plets M, et al. JAMA Netw Open. 2024;7(10):e2437871. doi:10.1001/jamanetworkopen.2024.37871

Measuring Lymphocyte Count May Predict Response to CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median Progression-Free Survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with relapsed or refractory myeloma often have disease that is refractory to multiple drugs.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase III studies involving patients with relapsed or refractory myeloma.

The researchers conducted an insightful study aimed at identifying predictive biomarkers to enhance the efficacy of CAR T-cell therapy for patients with relapsed or refractory multiple myeloma (MM). While CAR T-cell therapy has revolutionized treatment for B-cell malignancies and other blood cancers, the high cost of therapy and variability in patient response highlight the need for precise biomarkers that could guide clinicians in selecting the best candidates for this therapy. This research delves into the factors that affect patient response, specifically focusing on the role of the Absolute Lymphocyte Count (ALC) in predicting treatment success and disease progression.

The researchers analyzed data from 156 patients with relapsed or refractory multiple myeloma, treated with two BCMA-targeting CAR T-cell therapies: Ciltacabtagene autoleucel (CARVYKTI®) and Idecabtagene vicleucel (ABECMA®). These patients, who were treated between 2017 and 2023, had previously undergone several lines of therapy, rendering them refractory to conventional treatments. The research team collected and analyzed Absolute Lymphocyte Counts (ALC), a key immune marker, from 5 days before the CAR-T infusion for up to 15 days post-infusion, to determine if ALC could be used as a predictive biomarker for patient outcomes. The focus on this early post-infusion window was based on the hypothesis that the expansion of T cells, which is critical for the effectiveness of CAR T-cell therapy, would be reflected in the ALC levels. This study sought to correlate early ALC levels with long-term outcomes such as depth of response, Progression-Free Survival (PFS), and overall Duration of Response (DoR).

The findings demonstrated that ALC is a strong predictor of response to CAR T-cell therapy, with higher ALC values correlating with deeper responses and longer PFS. Specifically, patients who had an ALC maximum (ALCmax) above 1.0 x 103/µL during the first 15 days after infusion experienced a significant improvement in PFS, more than five times greater, compared to those with lower ALC counts. Patients with ALCmax above 1.0 x 103/µL had a median PFS of 33.1 months, while those with counts at or below 0.5 x 103/µL had a significantly shorter PFS of 6 months. The high-risk group, with an ALCmax of 0.5 or less x 103/µL, showed over three times the likelihood of early disease progression compared to their counterparts with higher ALC counts, making them a vulnerable population within the study cohort. The analysis also took into account a variety of potential confounding factors, such as patient age, previous therapies, high-risk cytogenetics, and the specific CAR T-cell product used. Even when these factors were considered, ALC remained an independent prognostic indicator, making it a reliable marker for predicting the depth and duration of response in this setting.

The researchers also explored the biological mechanisms underlying this phenomenon. CAR T-cell therapy relies heavily on the expansion of the infused T cells within the patient’s body. ALC, which includes a count of lymphocytes such as T cells, may serve as a surrogate marker for this expansion. Patients with higher ALC are likely to experience more robust CAR T-cell proliferation, leading to deeper and more durable anti-tumor responses. This aligns with previous findings that T-cell expansion after infusion is closely linked to treatment success. Additionally, the study noted that patients with higher ALC levels were also more likely to experience Cytokine Release Syndrome (CRS), a common side effect of CAR T-cell therapy that results from the rapid activation and expansion of T cells. While CRS can be a challenging complication to manage, its occurrence might also be a marker of effective CAR T-cell therapy.

The identification of ALC as a biomarker has significant implications for clinical practice. Physicians can now use ALC levels measured within the first 15 days post-infusion to guide treatment decisions. For patients with low ALC counts, this early biomarker could signal the need for alternative treatment approaches or additional therapeutic interventions to manage potential relapse. Given the limited options for patients who relapse after CAR T-cell therapy, having this early warning could be vital for planning the next steps in their treatment journey. Conversely, patients with high ALC levels can be reassured that they are more likely to achieve a deep and sustained response, allowing clinicians to optimize follow-up care and monitoring accordingly.

The researchers are further investigating the biological factors that influence ALC levels after CAR T-cell infusion. By analyzing patient samples and conducting deeper biological studies, they aim to uncover why some patients experience robust lymphocyte expansion while others do not. Understanding these underlying mechanisms could lead to new interventions that enhance CAR T-cell expansion, ultimately improving outcomes for a broader range of patients. Identifying potential pre-infusion markers that could predict whether a patient will have a favorable ALC response may be relevant. If such biomarkers can be identified, clinicians might be able to intervene even earlier, adjusting treatment plans before CAR T-cell therapy begins.

Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Saldarriaga MM, Pan D, Unkenholz C, et al. Blood Adv (2024) 8 (15): 3859–3869. https://doi.org/10.1182/bloodadvances.2023012470

ENHERTU® Effective Against Brain Metastases in Patients with HER2+ Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH positive) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases which result in a significantly worse prognosis compared to those without brain metastases. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. However, CNS progression usually occurs within 6-12 months post-treatment. Furthermore, Whole-Brain Radiation Therapy, while commonly used for multiple brain metastases, is linked with cognitive decline, which is a particular concern for HER2+ breast cancer patients who can live several years after their diagnosis.

With regards to systemic treatment options for brain metastases, various other HER2-directed therapies have been explored including Tucatinib (TUKYSA®), which can cross the blood brain barrier. Tucatinib combined with Trastuzumab and Capecitabine is currently the preferred systemic treatment for HER2+ metastatic breast cancer patients with active brain metastases. The HER2CLIMB study investigated this combination in patients who had been previously treated. In patients with measurable brain metastasis at baseline, those receiving Tucatinib combined with Capecitabine, and Trastuzumab showed a confirmed intracranial Objective Response Rate (ORR) of 47.3%. CNS Progression-Free Survival (PFS) was 9.9 months for all patients and 9.6 months for those with active brain metastases.

Trastuzumab Deruxtecan-T-DXd (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

T-DXd has also shown promising intracranial activity in several studies, such as DESTINY-Breast01, 02, and 03, as well as the ongoing DESTINY-Breast07 and the DEBBRAH study, among others. These studies reported encouraging responses in patients with active brain metastases, suggesting potential efficacy in this difficult-to-treat population.

DESTINY-Breast12 is an open-label, multicentre, Phase IIIb/IV 2-cohort, non-comparative clinical trial designed to evaluate the efficacy and safety of T-DXd 5.4 mg/kg in patients with previously treated advanced/metastatic HER2-positive breast cancer. This study included two cohorts – patients without brain metastases (Cohort 1) and patients with brain metastases (Cohort 2), who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline. A total of 504 eligible patients (N=504) were enrolled across multiple sites of whom 263 patients had baseline brain metastases, and 241 patients had no baseline brain metastases. All patients received T-DXd 5.4 mg per kg every three weeks until disease progression or unacceptable toxicity occurred. Notably, patients with leptomeningeal metastases were excluded, as well as those who had received Tucatinib in prior treatments, to avoid confounding effects from a drug known to affect CNS lesions. The study allowed the inclusion of patients with stable or active brain metastases (previously treated and progressing), though it excluded those with no clinical indication for immediate retreatment of their brain metastases. Tumor assessments were performed regularly using MRI or CT scans. The Primary endpoint of Cohort 1 (non-brain metastases cohort) was Objective Response Rate (ORR) as assessed by Independent Review and the Primary endpoint of Cohort 2 (brain metastases cohort) was Progression-Free Survival (PFS). Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and Safety.

Results showed a 12-month PFS rate of 61.6% for patients with brain metastases, with CNS-specific PFS of 58.9%. Those with stable brain metastases had a 12-month PFS of 62.9%, while patients with active brain metastases had a 12-month CNS PFS of 60.1%. For patients without brain metastases at baseline, the ORR was 62.7%, with a significant proportion achieving Partial or Complete Responses. A post-hoc analysis revealed a CNS ORR of 82.6% in patients with active brain metastases who had not undergone prior local CNS therapy and 50% in those who had progressed after prior local CNS treatments. Importantly, the safety profile of T-DXd was consistent with prior studies, though Interstitial Lung Disease (ILD) or pneumonitis occurred in approximately 13-16% of patients, with a small percentage experiencing Grade 5 (fatal) events.

In summary, the DESTINY-Breast12 study highlights the efficacy of Trastuzumab deruxtecan in treating HER2+ metastatic breast cancer, particularly in patients with brain metastases. These findings provide valuable insights into managing a challenging subset of breast cancer patients who often experience poor outcomes due to CNS progression. Further research is warranted to refine treatment strategies, especially for patients with ILD risk factors, and to explore potential combinatory regimens for long-term CNS control.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Harbeck, N., Ciruelos, E., Jerusalem, G. et al .for the the DESTINY-Breast12 study group. Nat Med (2024). https://doi.org/10.1038/s41591-024-03261-7

FDA Approves Perioperative OPDIVO® in Resectable Lung Cancer

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SUMMARY: The FDA on October 3, 2024, approved Nivolumab (OPDIVO®) with platinum-doublet chemotherapy as neoadjuvant treatment, followed by single-agent Nivolumab after surgery as adjuvant treatment, for adults with resectable (tumors 4 cm or more and/or node positive) Non-Small Cell Lung Cancer (NSCLC) and no known Epidermal Growth Factor Receptor (EGFR) mutations or Anaplastic Lymphoma Kinase (ALK) rearrangements.

Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 25% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Nivolumab is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor which is highly expressed on activated T cells, and blocks its interaction with PD-L1 or PD-L2 on tumor cells, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Combining cytotoxic chemotherapy with a PD-1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

In the CheckMate 816 Phase III trial, neoadjuvant Nivolumab plus platinum-doublet chemotherapy in earlier stage resectable NSCLC, resulted in a marked improvement in pathologic Complete Response rate, with a statistically significant improvement in the Event Free Survival, compared to those receiving chemotherapy alone.

The present FDA approval was based on CheckMate 77T, which is a multicenter, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of perioperative Nivolumab plus chemotherapy in patients with resectable NSCLC. In this study, 461 patients (N=461) with untreated, resectable Stage IIA (more than 4 cm)-IIIB (N2) NSCLC, were randomly assigned 1:1 to receive Nivolumab 360 mg IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery, and adjuvant Nivolumab 480 mg IV every 4 weeks for 1 year (N=229), or placebo IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery and adjuvant placebo IV every 4 weeks for 1 year (N=232). Enrolled patients had no prior systemic anticancer treatment and no EGFR or ALK mutations. Patients were stratified according to histology, disease stage, and tumor PD-L1 expression (less than 1% versus 1% or more), and patients with brain metastasis were excluded. The median age was 66 years, and both treatment groups were well balanced. Approximately two-thirds had Stage III disease, more than 50% of patients had tumor PD-L1 expression of 1% or more, and about 40% of patients had PD-L1 expression less than 1%. Approximately 90% were current or former smokers and majority of patients (75%) received Carboplatin-based chemotherapy. Surgery was performed within 6 weeks following the last dose of neoadjuvant therapy and radiologic restaging. The Primary endpoint of this study was Event Free Survival (EFS) according to Blinded Independent Central Review. Secondary endpoints included Overall Survival, pathologic Complete Response, Major Pathologic Response (10% or less of viable tumor cells remaining at time of surgery), and Safety. The researchers presented the data from the first interim prespecified analysis of Event-Free Survival.

At a median follow-up of 25.4 months, approximately 78% in the Nivolumab/chemotherapy group and 77% in the placebo/chemotherapy group were able to undergo definitive surgery. Lobectomy was the most common type of surgery performed and about 90% of patients had a complete resection. Nivolumab plus chemotherapy significantly improved Event-Free Survival, compared to placebo plus chemotherapy (median Not Reached versus 18.4 months respectively; HR=0.58; P=00025). This represented a 42% improvement in Event-Free Survival among those treated with Nivolumab plus chemotherapy. The 12-month Event-Free Survival rate was 73% versus 59%, respectively and the 18-month Event-Free Survival rate was 70% versus 50%. The pathologic Complete Response rates as well as Major Pathologic Response rates were significantly higher with Nivolumab plus chemotherapy, compared to placebo plus chemotherapy (25.3% versus 4.7% and 35.4% versus 12.1% repectively). Surgery related adverse events were similar in both treatment groups at 12%. At the prespecified interim analysis, Overall Survival was not formally tested for statistical significance, but a descriptive analysis revealed no detriment.

The researchers concluded that CheckMate 77T met its primary endpoint and is the first Phase III perioperative study that builds on the current standard of care, neoadjuvant Nivolumab plus chemotherapy. Patient with early stage resectable NSCLC now have three different treatment options: 1) Neoadjuvant therapy followed by surgery 2) Surgery followed by adjuvant therapy, and now 3) Perioperative therapy, which includes neoadjuvant therapy, surgery, and adjuvant therapy. Circulating tumor DNA and other biomarkers may identify patients who are cured with chemoimmunotherapy and in whom adjuvant therapy can be avoided.

Perioperative Nivolumab in Resectable Lung Cancer. Cascone T, Awad MM, Spicer JD, et al for the CheckMate 77T Investigators. N Engl J Med 2024;390:1756-1769.

Late Breaking Abstract – ESMO 2024: Adjuvant KISQALI® Shows Deepening Benefit in Patients with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant Endocrine Therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.

Ribociclib (KISQALI®) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6, preferentially inhibiting CDK4 and blocking the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. The MONALEESA trials of Ribociclib have shown a consistent Overall Survival benefit, regardless of accompanying Endocrine Therapy, line of therapy, or menopausal status, in advanced breast cancer.

NATALEE is a global, multi-center, randomized, open-label Phase III trial, conducted to evaluate the efficacy and safety of Ribociclib with Endocrine Therapy as adjuvant treatment versus Endocrine Therapy alone, in patients with HR+/HER2-negative early breast cancer, who were at risk for disease recurrence. This study conducted in collaboration with Translational Research In Oncology (TRIO), randomly assigned 5,101 eligible men and pre- or postmenopausal women 1:1 to receive either adjuvant Ribociclib 400 mg orally daily for 3 years along with Endocrine Therapy consisting of Letrozole 2.5 mg/day or Anastrozole 1 mg/day, for 5 yrs or more (N= 2,549) or Endocrine Therapy alone for at least 5 years (N = 2,552). This study explored a lower Ribociclib starting dose of 400 mg daily rather than the dose approved for treatment in metastatic breast cancer (600 mg), with the goal to minimize toxicities and disruptions to patient quality of life, without compromising efficacy. Men and premenopausal women also received Goserelin. Eligible patients had an ECOG PS of 0-1 with Stage IIA (either N0 with additional risk factors or N1 with 1-3 axillary lymph nodes), Stage IIB, or Stage III HR-positive, HER2-negative breast cancer who were at risk for disease recurrence. Prior adjuvant Endocrine Therapy was allowed if initiated no more than 1 year before randomization. Stratification factors were menopausal status, disease stage, prior neoadjuvanr/adjuvant chemotherapy, and geographic region. Approximately 44% were premenopausal and 40% had Stage II breast cancer. Majority of patients (88%) received prior chemotherapy. The Primary endpoint of NATALEE was invasive Disease Free Survival (iDFS) as defined by the Standardized Definitions for Efficacy End Points (STEEP) criteria. Secondary endpoints included Distant Disease-Free Survival (DDFS) and Overall Survival (OS).

The authors had previously reported that at a median follow up of 34 months, the addition of Ribociclib to Endocrine Therapy significantly improved in invasive DFS compared with Endocrine Therapy alone (HR=0.748; P=0.0014), reducing the risk of disease recurrence by 25%.
The researchers in this updated analysis of the NATALEE trial presented the efficacy and safety data at data cutoff (29 Apr 2024), with all patients in the Ribociclib plus Endocrine Therapy group (N=2549) off treatment with Ribociclib. This update provided a robust framework for understanding the long-term implications of this therapeutic approach.

The updated analysis revealed that invasive DFS significantly favored the Ribociclib plus Endocrine Therapy combination over Endocrine Therapy alone. At the three-year mark, iDFS rates were 90.8% for the Ribociclib plus Endocrine Therapy group compared to 88.1% for those on Endocrine Therapy alone, with an absolute improvement of 2.7%. By the four-year follow-up, this gap widened, with iDFS rates of 88.5% versus 83.6%, reflecting a 4.9% absolute benefit. This benefit was consistent across various subgroups. Patients with node-negative disease (N0) experienced a 5.1% absolute increase in iDFS at four years, while those with node-positive disease (N+) saw a 5.0% improvement. Similarly, patients in Stage II had an absolute benefit of 4.3%, and those in Stage III achieved a 5.9% increase in their iDFS rates.

The Distant DFS data was similar to the iDFS findings, with Ribociclib plus Endocrine Therapy showing a Hazard Ratio of 0.715 (95% CI, 0.604–0.847; P<0.0001), indicating a substantial reduction in the risk of distant recurrence. While Overall Survival data remains immature, trends suggest a favorable outcome for the Ribociclib group.

Safety data revealed that Ribociclib was well tolerated, and remained consistent with previous analyses. The adverse events of special interest, particularly those Grade 3 or higher, included neutropenia (44.4%), liver-related issues (8.6%), and QT interval prolongation (1.0%).

The researchers concluded that in this 4-year landmark analysis, Ribociclib plus Endocrine Therapy reduced the risk of Invasive and Distant disease recurrence by 28.5% compared with Endocrine Therapy alone. Further, this benefit was maintained even after the end of planned 3-year Ribociclib treatment, for both node-positive and node-negative patients. This deepening efficacy, particularly evident in node-negative and high-risk early breast cancer patients, underscores the necessity of evolving treatment strategies in the fight against breast cancer.

Adjuvant ribociclib (RIB) plus nonsteroidal aromatase inhibitor (NSAI) in patients (Pts) with HR+/HER2− early breast cancer (EBC): 4-year outcomes from the NATALEE trial. Fasching PA, Stroyakovskiy D, Yardley D, et al. DOI: 10.1016/j.annonc.2024.08.2251

Late Breaking Abstract – ESMO Congress 2024: IMFINZI® Along with Neoadjuvant Chemotherapy Improves Survival in Muscle Invasive Bladder Cancer

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. Perioperative immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in improving these outcomes. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Durvalumab (IMFINZI®) is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. A preceding single-group, Phase 2 trial indicated that perioperative Durvalumab, combined with neoadjuvant Gemcitabine plus Cisplatin chemotherapy followed by radical surgery, was both safe and effective. Building on these findings, the Phase 3 NIAGARA trial aimed to evaluate the efficacy and safety of perioperative Durvalumab combined with neoadjuvant chemotherapy (Gemcitabine plus Cisplatin), followed by radical cystectomy, compared with neoadjuvant chemotherapy alone followed by radical cystectomy, in Cisplatin-eligible MIBC patients.

The NIAGARA trial was an open-label, randomized, multicenter, Phase 3 study, enrolling 1,063 (N=1063) Cisplatin-eligible patients with MIBC (clinical stage cT2–T4aN0/1M0). Patients were randomized in a 1:1 ratio to receive one of two treatment regimens. The experimental arm (Durvalumab group) included neoadjuvant Durvalumab 1500 mg IV alongside Gemcitabine plus Cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant Durvalumab monotherapy 1500 mg IV every 4 weeks for up to 8 cycles (N=533). The comparison arm consisted of neoadjuvant Gemcitabine plus Cisplatin followed by radical cystectomy alone, without the addition of Durvalumab (N=530). Patients were stratified by clinical tumor stage (cT2N0 vs more than cT2N0), renal function (CrCl 60 mL/min or more vs 40 or more to less than 60 mL/min), and PD-L1 status (high vs low/negative). The dual Primary endpoints of the trial were Event-Free Survival (EFS) and pathological Complete Response (pCR), with Overall Survival (OS) as a key Secondary endpoint. Event-Free Survival was defined as the time from randomization until progression that precluded surgery, failure to undergo surgery, recurrence after cystectomy, or death from any cause.

In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group. The Hazard Ratio (HR) for EFS in the Durvalumab arm was 0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates. Treatment-related adverse events of Grade 3 or 4 severity occurred in 40.6% of patients in the Durvalumab arm and 40.9% in the comparison arm, with treatment-related deaths reported in 0.6% of patients in both groups.

In conclusion, the addition of perioperative Durvalumab to neoadjuvant chemotherapy significantly improved both EFS and OS compared to chemotherapy alone, without compromising the ability to perform radical cystectomy. These results are practice-changing, marking a major advancement in the treatment of MIBC. The findings support the hypothesis that perioperative immune checkpoint inhibitors, by priming the immune system before surgery and targeting residual micrometastatic disease post-surgery, improve long-term clinical outcomes. Biomarkers like circulating tumor DNA (ctDNA) could be pivotal in guiding treatment decisions, as emerging data suggests that negative ctDNA status post-neoadjuvant therapy correlates with reduced relapse risk.

Perioperative Durvalumab with Neoadjuvant Chemotherapy in Operable Bladder Cancer. Powles T, Catto J, Galsky MD, for the NIAGARA Investigators. Published September 15, 2024. DOI: 10.1056/NEJMoa2408154

FDA Approves RYBREVANT® plus Chemotherapy for EGFR-Mutated NSCLC

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SUMMARY: The FDA on September 19, 2024 approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for adult patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.

Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

The efficacy of Amivantamab was assessed in the Phase 3 MARIPOSA-2 trial, a multicenter, open-label study involving 657 patients. These participants, all with EGFR-mutant NSCLC, who had progressed on Osimertinib treatment, were randomly assigned in a 1:2:2 ratio to receive either Amivantamab with Carboplatin and Pemetrexed (referred to as Amivantamab plus chemotherapy-N=131), Carboplatin and Pemetrexed alone (chemotherapy alone-N=263), or Amivantamab combined with other regimens (N=263). Eligible patients had documented presence of EGFR exon 19 deletion or exon 21 L858R mutation and experienced disease progression after receiving Osimertinib as their most recent line of therapy. Patients received Amivantamab 1400 mg IV (1750 mg for body weight 80 kg or greater) weekly for the first 4 weeks, then 1750 mg (2100 mg for body weight 80 kg or greater) every 3 weeks starting at cycle 3 (week 7). The first Amivantamab infusion was split over 2 days, with 350 mg IV on cycle 1, day 1 and the remainder on cycle 1, day 2. Chemotherapy consisted of Carboplatin AUC 5 IV, starting on day 1 every 3 weeks for the first 4 cycles along with Pemetrexed 500 mg/m2 IV every 3 weeks until disease progression. The median age was 62 years, 48% of patients were Asian and approximately 70% of patients had Osimertinib as first line treatment and 30% had Osimertinib as second line treatment. Randomization was stratified by Osimertinib line of therapy (first or second), and race (Asian or non-Asian). All three treatment groups were well balanced. The Primary endpoint of the study was Progression-Free Survival (PFS), assessed by Blinded Independent Central Review (BICR). Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Time to Treatment Discontinuation (TTD), Time to Subsequent Therapy (TTST), Progression-Free Survival after first subsequent therapy (PFS2) and Time to Symptomatic Progression (TTSP).

At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy versus chemotherapy alone. The median PFS was 6.3 months in the Amivantamab plus chemotherapy group and 4.2 months in the chemotherapy alone group (HR for disease progression or death=0.48; P<0.0001), indicating a a 52% reduction in the risk of progression or death. The ORR was significantly higher in the Amivantamab plus chemotherapy group at 53%, compared to 29% in the chemotherapy alone group (P<0.0001).

In the prespecified second interim analysis, a numerical improvement in OS was noted for the Amivantamab plus chemotherapy group with a median OS of 17.7 months compared to 15.3 months for the chemotherapy alone group (HR=0.73; P=0.039). However, this did not meet the prespecified significance level.

With regards to Post-Progression Endpoints, the median TTD was significantly longer in the Amivantamab plus chemotherapy group versus chemotherapy alone group (10.4 months versus 4.5 months; HR=0.42; P<0.0001). The Median TTST was also prolonged in the Amivantamab plus chemotherapy group versus chemotherapy alone group (12.2 months compared to 6.6 months HR=0.51; P< 0.0001). The median PFS2 was significantly longer in the Amivantamab plus chemotherapy group compared to the chemotherapy alone group (16.0 months versus 11.6 months (HR= 0.64; P=0.002). Common adverse reactions observed in patients receiving Amivantamab plus chemotherapy included rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.

In conclusion, the results from the MARIPOSA-2 trial provide compelling evidence for the use of Amivantamab in combination with Carboplatin and Pemetrexed in the treatment of advanced EGFR-mutant NSCLC post-Osimertinib progression. While the PFS outcomes were significantly improved, the OS benefits, promising as they may be, require further follow-up for conclusive results. The final Overall Survival analysis will be eagerly awaited, as it will further illuminate the long-term efficacy of this treatment approach.

Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Popat S, Reckamp KL, Califano R, et al. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA54.

FDA Approves SARCLISA® with VRd Regimen for Newly Diagnosed Multiple Myeloma

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SUMMARY: The FDA on September 20, 2024, approved Isatuximab-irfc (SARCLISA®) with Bortezomib, Lenalidomide, and Dexamethasone for adults with newly diagnosed multiple myeloma who are not eligible for Autologous Stem Cell Transplant (ASCT). Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2024 remains an incurable disease.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails. Additionally, Isatuximab infusions are less cumbersome. The FDA in 2021, approved Isatuximab in combination with Carfilzomib (KYPROLIS®) and Dexamethasone, for the treatment of adult patients with Relapsed or Refractory multiple myeloma who have received one to three prior lines of therapy.

The IMROZ trial (NCT03319667) was an international, multicenter, open-label, Phase 3 randomized controlled trial, designed to evaluate the efficacy and safety of Isatuximab in combination with the established regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRd) compared to VRd alone. This study aimed to address a critical gap in treatment options for patients with newly diagnosed multiple myeloma who are ineligible for ASCT, a situation often faced by older patients or those with significant comorbidities. A total of 446 patients, aged 18 to 80 years, with symptomatic, previously untreated multiple myeloma were randomly assigned in a 3:2 ratio to receive either the Isatuximab-VRd regimen (N=263) or the standard VRd regimen alone (N=181). The Induction phase of the treatment consisted of 4 cycles, with each cycle lasting 6 weeks. Patients in the Isatuximab-VRd Group received Isatuximab 10 mg/kg IV weekly during Cycle 1, then every 2 weeks for subsequent cycles. Patients received subcutaneous Bortezomib (1.3 mg/m²) on specified days, along with oral Lenalidomide (25 mg daily for 14 days) and Dexamethasone (20 mg on specified days). The VRd group received the same VRd regimen without Isatuximab. Following the induction phase, both groups continued treatment with a regimen consisting of Lenalidomide and Dexamethasone. For the Isatuximab-VRd group, Isatuximab was given every 2 weeks, transitioning to monthly administration starting at Cycle 18. The median patient age was 72 years and treatment groups were well balanced. The Primary endpoint of the trial was Progression-Free Survival (PFS), assessed by an Independent Review Committee in accordance with International Myeloma Working Group criteria. Secondary endpoints included Complete Response (CR) or better, Minimal Residual Disease (MRD) negativity in patients achieving a Complete Response, assessed at a sensitivity level of 10⁻⁵ using Next-Generation Sequencing, Overall Survival (OS) and Quality of Life measures.

The results from the interim analysis at a median follow-up of 59.7 months demonstrated a significant improvement in PFS for the Isatuximab-VRd group compared to the VRd group. The 60-month PFS was estimated at 63.2% in the Isatuximab-VRd group versus 45.2% in the VRd group (HR=0.60; P<0.001), indicating a 40% reduction in the risk of disease progression or death for the Isatuximab group. Approximately 75% of patients in the Isatuximab-VRd group achieved a Complete Response or better compared to 64.1% in the VRd group (P=0.01). Higher rates of MRD negativity (55.5% vs. 40.9%; P=0.003) were also observed in the Isatuximab group. The safety profile of the Isatuximab-VRd combination mirrored that of established regimens, with no new safety signals identified. Incidences of serious adverse events were comparable between the two groups, though a slight increase in infections and neutropenia was noted with the addition of Isatuximab.

In conclusion, the results from the IMROZ trial clearly indicate that the addition of Isatuximab to the VRd regimen provides significant benefits in terms of Progression-Free Survival and Response Rates in patients with newly diagnosed multiple myeloma who are ineligible for transplantation, addressing an important unmet need. Further follow-up and analyses will continue to elucidate the long-term benefits and safety of this promising therapeutic strategy.

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Thierry Facon, M.D., Meletios-Athanasios Dimopoulos, M.D., Xavier P. Leleu, et al. for the IMROZ Study Group. Published June 3, 2024. DOI: 10.1056/NEJMoa2400712.