Category: Meeting Updates

Chronic Lymphocytic Leukemia Therapy Guided by Minimal Residual Disease

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SUMMARY: The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

Brutons Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promote programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including CLL, Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). Four BTK inhibitors are presently approved by the FDA. They include first generation Ibrutinib (IMBRUVICA®) and second generation agents such as Acalabrutinib (CALQUENCE®), Zanubrutinib (BRUKINSA®) and Pirtobrutinib (JAYPIRCA®).

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by CLL cells and regulates clonal selection and cell survival. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. The combination of Ibrutinib plus Venetoclax was noted to be synergistic.

The FLAIR trial initially compared Ibrutinib plus Rituximab with Fludarabine, Cyclophosphamide, and Rituximab (FCR) in previously untreated patients with CLL who were candidates for chemoimmunotherapy. This study in 2017 was adapted to include both Ibrutinib monotherapy, and Ibrutinib-Venetoclax, with therapy duration defined according to MRD (Minimal Residual Disease). An interim analysis of Ibrutinib monotherapy as compared with Ibrutinib-Venetoclax showed superiority of Ibrutinib-Venetoclax in achieving undetectable MRD. The researchers herein presented the results of a planned interim analysis, comparing MRD-guided Ibrutinib-Venetoclax with FCR.

The FLAIR study is a Phase III, multicenter, randomized, controlled, open-label platform trial, designed to evaluate the efficacy of the combination of Ibrutinib and Venetoclax compared to the standard of care regimen Fludarabine, Cyclophosphamide, and Rituximab (FCR), in previously untreated CLL patients. The study focused on individualizing the duration of treatment using high-sensitivity testing for Minimal Residual Disease (MRD) in the blood (less than 1 CLL cell in 10,000 by Flow cytometry). A total of 523 eligible patients were randomly assigned to receive either FCR (N=263) or Ibrutinib-Venetoclax (N=260). Patients in the FCR group received Rituximab 375 mg/m2 IV on day 1 of cycle 1, and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle, Fludarabine 24 mg/m2 per day orally on day 1-5 and Cyclophosphamide 150 mg/m2 per day orally on days 1-5, for up to 6 cycles. Ibrutinib-Venetoclax group received 2 months of Ibrutinib lead-in at 420 mg orally daily followed by the addition of Venetoclax 400 mg orally daily, which could last from 2 to 6 years based on MRD. Venetoclax was escalated weekly starting from 20 mg. MRD assessment was conducted at 12 months and then every 6 months in the Ibrutinib-Venetoclax group. If MRD was negative, it was repeated at 3 months and 6 months in both peripheral blood and bone marrow. If all MRD tests were negative, the patient was treated for twice the duration from the start of Ibrutinib-Venetoclax treatment to the first MRD-negative test. Patients with more than 20% 17p deleted cells were excluded from the study. The median age was 62 years, and 41% had Binet Stage C disease. The Primary end point was Progression Free Survival (PFS) in the Ibrutinib-Venetoclax group, as compared with the FCR group. Key Secondary end points included Overall Survival, Response Rates, MRD, and Safety.

The median follow-up was 43.7 months. At 3 years, 97.2% of patients treated with Ibrutinib-Venetoclax remained progression-free compared to 76.8% with FCR (HR=0.13; P<0.0001). The 3 year Overall Survival was 98% in the Ibrutinib-Venetoclax group compared to 93% in the FCR group (HR=0.31; P<0.005). Patients with poor prognostic features, such as unmutated immunoglobulin genes (IGHV) or the 11q chromosome deletion, showed particularly favorable outcomes with Ibrutinib-Venetoclax. For example, patients with unmutated IGHV were about 14 times less likely to have disease progression with Ibrutinib-Venetoclax, than with FCR. At the latest follow-up, none of the patients with 11q chromosome deletion who were treated with Ibrutinib-Venetoclax had disease progression or had died, compared with 31.2% of patients with this deletion who were treated with FCR. At 3 years, 58% of the patients in the Ibrutinib-Venetoclax group had stopped therapy owing to undetectable MRD and after 5 years of Ibrutinib-Venetoclax therapy, 66% of the patients had undetectable MRD in the bone marrow and 93% had undetectable MRD in the peripheral blood.

The risk of infection was similar in the Ibrutinib-Venetoclax group and the FCR group. The incidence of serious cardiac adverse events was higher in the Ibrutinib-Venetoclax group, than in the FCR group (10.7% versus 0.4%).

This study concluded that MRD-directed treatment with Ibrutinib-Venetoclax improved Progression Free Survival and Overall Survival, as compared with FCR, among newly diagnosed CLL patients, establishing a new standard for CLL treatment.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. Munir T, Cairns DA, Bloor A, et al. for the National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. December 10, 2023. DOI: 10.1056/NEJMoa2310063.

TUKYSA® Plus KADCYLA® in Advanced HER2-Positive 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 USA, 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 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. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab), KADCYLA® (ado-Trastuzumab emtansine, T-DM1), ENHERTU® (Trastuzumab deruxtecan) and MARGENZA® (Margetuximab). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2-positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Patients progressing on Dual HER2 blockade often receive KADCYLA® which results in an Objective Response Rate (ORR) of 44% and a median PFS of 9.6 months, when administered after HERCEPTIN® and a Taxane.

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. However, systemic HER2-targeted agents, including Tyrosine Kinase Inhibitors, as well as chemotherapy have limited antitumor activity in the brain. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. There is a high unmet need for systemic treatment options to treat established brain metastases and reduce the risk for progression in the Central Nervous System (CNS).

TUKYSA® (Tucatinib) is an oral Tyrosine Kinase Inhibitor that is highly selective for the kinase domain of HER2 with minimal inhibition of Epidermal Growth Factor Receptor. In the HER2CLIMB international, randomized, double-blind, placebo-controlled trial, a combination of TUKYSA® plus HERCEPTIN® and XELODA® (Capecitabine) was compared with placebo plus HERCEPTIN® and XELODA®. TUKYSA® combination significantly improved Progression Free and Overall Survival in heavily pretreated patients, including those with brain metastases.

The HER2CLIMB-02 trial is a randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of the combination of TUKYSA® and KADCYLA® in patients with metastatic HER2-positive breast cancer, particularly those with brain metastases. This study focused on patients with brain metastases, given the limited options for managing breast cancer brain metastases. In this study, 463 patients (N=463) with unresectable locally advanced or metastatic HER2-positive breast cancer were randomly assigned in a 1:1 ratio to receive either 21-day cycles of either TUKYSA® at 300 mg orally twice a day and KADCYLA® 3.6 mg/kg IV every 3 weeks (N=228) or KADCYLA® and placebo (N=235). Both treatment groups were well balanced. The median age was 55 years, eligible patients had been previously treated with HERCEPTIN® and a Taxane in any setting, and trial entry criteria included enrollment of previously treated, stable, progressing, or untreated brain metastases not requiring immediate local therapy. Approximately 40% of all patients had baseline active or stable brain metastasis, and the researchers noted that this was the second large trial, prospectively designed to evaluate systemic therapy in patients with brain metastases. The Primary endpoint was Progression Free Survival (PFS).

At a median follow up was 24.4 months, the combination of TUKYSA® plus KADCYLA® showed a significant improvement in median PFS compared to KADCYLA® alone. The median time to disease progression or death was 9.5 months with TUKYSA® plus KADCYLA® versus 7.4 months with KADCYLA® alone, suggesting a 24% reduction in the risk of disease progression or death with the combination treatment. Among patients with brain metastasis at baseline, the median time to disease progression or death was 7.8 months with the TUKYSA® plus KADCYLA® combination versus 5.7 months with KADCYLA® alone, suggesting a 36% reduction in the risk of disease progression or death with the combination. Further, patients in the TUKYSA® plus KADCYLA® group had a higher Objective Response Rate compared to the control arm (42% versus 36.1%). Overall survival data were immature at the time of this analysis. The combination treatment group reported more treatment related adverse events which included nausea, diarrhea, fatigue and liver function abnormalities.

It was concluded that the combination of TUKYSA® and KADCYLA® demonstrated a statistically significant improvement in Progression Free Survival, compared to KADCYLA® alone, supporting its efficacy in patients with HER2-positive metastatic breast cancer. This study was prospectively designed to evaluate novel systemic therapies in patients with brain metastases, and findings from this study suggested that the combination of TUKYSA® and KADCYLA® could be a favorable treatment option, especially for patients with active or progressing brain metastases. It should be noted that this study did not directly compare the experimental regimen of TUKYSA® and KADCYLA® with other established regimens like TUKYSA® plus HERCEPTIN® and XELODA® or regimens containing ENHERTU®.

HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Hurvitz SA, Loi S, O’Shaughnessy J, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Session GS01-10.

Late Breaking Abstract- ASH 2023: ERG is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy

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SUMMARY: ERG (ETS-Related Gene) is a known oncogene located on chromosome 21, and is a member of the ETS (erythroblast transformation-specific) family of transcription factors. The ERG gene encodes for a protein also called ERG that functions as a transcriptional regulator, and regulates differentiation of early hematopoietic cells.

ERG has been linked to Down syndrome- associated Acute Megakaryocytic Leukemia. ERG typically via gene-fusions can lead to dysregulated ERG overexpression in hematologic malignancies and solid tumors. ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in Hormone-Refractory Prostate Cancer, suggesting that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. EWS1-ERG fusion has been noted in 10% of Ewing’s Sarcoma cases. ERG is also involved in oncogenesis by generating fusion genes with FUS/TLS in Acute Myeloid Leukemia.

The researchers in this study identified a germline ERG variant associated with bone marrow failure and hematological malignancies. The study originated from a family case involving thrombocytopenia and neutropenia, where the mother developed Acute Myeloid Leukemia (AML) and MyeloDysplastic Syndrome (MDS). ERG, a known oncogene, was discovered as a predisposition gene for bone marrow failure and hematological malignancy. A germline ERG ETS domain variant (p.Y373C) was identified, segregating with thrombocytopenia in a family, leading to AML and therapy-related MDS. Copy neutral Loss of Heterozygosity of chromosome 21q, including the ERG locus, was observed in affected individuals. Validation of their findings involved functional assays, demonstrating Loss of Function variants in ERG, affecting DNA binding and nuclear localization. Experiments using a fetal liver assay confirmed the role of ERG in cytokine-independent growth and leukemia development.

Through global collaborations, 15 heterozygous variants in the ERG gene were identified, including 13 missense and 2 truncating variants in 17 individuals with cytopenia, hematological malignancy or lymphedema. Of these 15 variants, 12 have been confirmed germline. Onset of hematological symptoms ranged from birth to 38 years for truncating and constrained ETS domain variants. Functional studies revealed that most ETS domain missense variants displayed Loss-of-Function (LOF) characteristics affecting transcriptional transactivation, DNA binding, and/or nuclear localization.

This ERG syndrome parallels GATA2 deficiency syndrome (hematological malignancy with lymphedema) and RUNX1 Familial Platelet disorder-myeloid malignancy (thrombocytopenia and hematological malignancy). ERG, like the well-known disease genes GATA2, and RUNX1 is a member of the transcription factor heptad involved in hematopoietic stem cell maintenance and differentiation.

The researchers concluded that germline ERG variants predispose to diverse cytopenia, bone marrow failure and hematological malignancies in both children and adults and ERG adds to a growing list of genes whose unregulated expression contributes to hematological malignancy and other cancers. Identification of germline ERG variants has direct clinical implications for patient and family management including diagnosis, counseling, surveillance, and treatment strategies, such as bone marrow transplant and targeted therapies. Potential clinical implications include ERG screening in germline panels for bone marrow failures and hematological malignancies. Additionally there is a need for further longitudinal studies to understand the natural history of ERG-related syndromes.

ERG is a New Predisposition Gene for Bone Marrow Failure and Hematological Malignancy. Scott HS, Zerella J, Homan C, et al. ASH Annual Meeting & Exposition 2023. LBA-6.

Late Breaking Abstract – ASH 2023: Daratumumab Combination Superior to VRd in Newly Diagnosed 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, 35,730new cases will be diagnosed in 2023 and 12,590 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 2023 remains an incurable disease.

Transplantation-eligible patients with newly diagnosed multiple myeloma are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd) induction therapy followed by Autologous Stem-Cell Transplantation, consolidation therapy with VRd, and maintenance therapy with Lenalidomide. 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.

Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. Daratumumab exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, Daratumumab may have a role in immunomodulation by depleting CD38-positive regulator immune suppressor cells, and thereby expanding T cells, in patients responding to therapy.

PERSEUS trial is an open-label, multicenter, randomized Phase III study, conducted to evaluate the efficacy and safety of subcutaneous Daratumumab combined with VRd induction and consolidation therapy and with Lenalidomide maintenance therapy (D-VRd group), as compared with VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group), for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma. The subcutaneous formulation of Daratumumab was chosen as it has been found to be noninferior to intravenous Daratumumab, as it is associated with a lower incidence of infusion-related reactions, can be administered in a single dose for all patients, and has a shorter duration of administration of 3-5 minutes.

In this study, 709 eligible patients were randomly assigned in a 1:1 ratio to receive either subcutaneous Daratumumab combined with VRd induction therapy before transplantation, with VRd consolidation therapy after transplantation, and with Lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and Lenalidomide maintenance therapy alone (VRd group). All patients received VRd in six 28-day cycles (four induction cycles and two consolidation cycles) and VRd consisted of Bortezomib 1.3 mg/m2 subcutaneous on days 1, 4, 8, and 11 of each cycle, Lenalidomide 25 mg orally on days 1 through 21 of each cycle, and Dexamethasone 40 mg oral or IV given on days 1-4 and days 9-12 of each cycle. Patients in the D-VRd group also received Daratumumab 1800 mg given subcutaneous weekly during cycles 1 and 2, 1800 mg subcutaneous every 2 weeks cycles 3-6. Patients underwent Autologous Stem-Cell Transplantation after the completion of induction therapy (cycle 4) and consolidation therapy began 30-60 days after transplantation. After completion of consolidation therapy (cycle 6), all the patients received Lenalidomide 10 mg orally in 28-day maintenance cycles until disease progression or unacceptable toxicities. Patients in the D-VRd group also received maintenance therapy with subcutaneous Daratumumab 1800 mg subcutaneous every 4 weeks for at least 24 months and Daratumumab therapy was discontinued in patients who had a Complete Response or better and had sustained Minimal Residual Disease (MRD)–negative status (defined as absence of malignant cells at a sensitivity threshold of 10−5 or lower) for at least 12 months. The median age was 60 years and randomization was stratified according to the Stage (I, II, or III) and cytogenetic risk (standard risk or high risk, defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16] cytogenetic abnormality). The Primary end point was Progression Free Survival. Secondary end points included a Complete Response or better and Minimal Residual Disease negative status.

At a median follow-up of 47.5 months, at the first interim analysis, the risk of disease progression or death in the D-VRd group was significantly lower than the risk in the VRd group. The 4-year PFS was 84.3% in the D-VRd group and 67.7% in the VRd group (HR for disease progression or death=0.42; P<0.001). The percentage of patients with a Complete Response or better was higher in the D-VRd group than in the VRd group (87.9% versus 70.1%; P<0.001). The same was true with MRD-negative status (75.2% versus 47.5% respectively, P<0.001). Serious adverse events occurred in 57% of the patients in the D-VRd group and 49.3% of those in the VRd group. Treatment discontinuation due to adverse events however occurred less often in the quadruplet group.

The researchers concluded that the addition of subcutaneous Daratumumab to VRd induction and consolidation therapy and to Lenalidomide maintenance therapy conferred a significant and clinically meaningful benefit with respect to Progression Free Survival, Complete Response rate and MRD-negative status, with a favorable benefit–risk profile, among transplantation-eligible patients with newly diagnosed multiple myeloma.

Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. for the PERSEUS Trial Investigators. Published on December 12, 2023, at NEJM.org. DOI: 10.1056/NEJMoa2312054.

Late Breaking Abstract – ESMO 2023: WELIREG® Significantly Improves Outcomes in Advanced Pretreated Clear Cell Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 81,800 new cases of kidney and renal pelvis cancers will be diagnosed in the United States in 2023 and about 14,890 people will die from this disease. Clear cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant need for improved therapies for this disease.

Patients with advanced RCC are often treated with immune checkpoint inhibitors and Vascular Endothelial Growth Factor Receptor (VEGFR) targeted Tyrosine Kinase Inhibitors, either in combination or sequentially. However upon progression on these therapies, there are limited treatment options and there is an unmet medical need.

The VHL (Von Hippel-Lindau) protein is a tumor suppressor gene located on the short arm of chromosome 3p. It is frequently mutated and inactivated in approximately 90% of clear cell Renal Cell Carcinomas (ccRCC). The VHL gene under normal conditions binds to Hypoxia-Inducible Factors (HIFs) and facilitates degradation of this factor. Under hypoxic conditions and in patients having biallelic loss of function and mutation of VHL genes, HIFs are not degraded. High HIF levels and subsequent overproduction of VEGF, PDGF and TGF-alpha, resulting in increased angiogenesis, increased tumor cell proliferation and survival, as well as metastasis.

Belzutifan (WELIREG®) is a a first-in-class, oral, HIF-2alfa inhibitor approved in the US for adult patients with Von Hippel-Lindau (VHL) disease who require therapy for associated Renal Cell Carcinoma (RCC), Central Nervous System (CNS) Hemangioblastomas, or Pancreatic NeuroEndocrine Tumors (pNET), not requiring immediate surgery. This approval was based on the Overall Response Rate (ORR) and Duration of Response (DOR) data from the Phase II LITESPARK-004 trial.

LITESPARK-005 is a randomized, open-label, Phase III trial in which Belzutifan was compared with Everolimus in pretreated advanced ccRCC. In this study, 746 enrolled patients with metastatic clear cell renal cell carcinoma whose disease progressed after treatment with both an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and VEGF-TKI, in sequence or in combination, were randomly assigned 1:1 to receive either Belzutifan 120 mg orally daily (N=374) or Everolimus 10 mg orally daily (N=372), until disease progression or unacceptable toxicity. The dual Primary endpoints were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included Overall Response Rate (ORR) by BICR and Safety.

At the first pre-specified interim analysis at a median follow up of 18.4 months, Belzutifan significantly reduced the risk of disease progression or death by 25% compared to Everolimus (HR=0.75; P<0.001). The results at the second pre-specified interim analysis were consistent with first interim analysis. At a median follow-up of 25.7 months, Belzutifan significantly reduced the risk of disease progression or death by 26% compared to Everolimus (HR=0.74; P<0.001). The estimated 12-month PFS rate was 33.7% for patients who received Belzutifan versus 17.6% for patients who received Everolimus, and the estimated 18-month PFS rate was 22.5% and 9.0%, respectively. The Overall Survival data favored Belzutifan compared to Everolimus at both the first and second interim analysis, but did not reach statistical significance and will be tested at a subsequent analysis.

There was a statistically significant improvement in ORR at both the first and second interim analysis, and the ORR was 22.7% with a Complete Response rate 3.5% for patients who received Belzutifan versus an ORR of 3.5% with no patients achieving a Complete Response for patients who received Everolimus (P<0.00001). The time to response with Belzutifan was about three months. Quality of Life favored Belzutifan.

Treatment-related adverse events and in particular Grade 3 adverse events were similar in both treatment groups. Adverse events leading to treatment discontinuation occurred in 5.9% of patients who received Belzutifan and 14.7% among those who received Everolimus. The most common side effects associated with Belzutifan were anemia, fatigue, nausea, constipation, peripheral edema, dyspnea and arthralgia.

It was concluded that Belzutifan was associated with a statistically significant improvement in Progression Free Survival and Overall Response Rate compared to Everolimus in patients with advanced clear cell Renal Cell Carcinoma, after immune checkpoint and anti-angiogenic therapies. They added that this is the first Phase III trial to show positive results in advanced RCC following standard therapies and the first drug with a new mechanism of action to demonstrate efficacy in this group of patients.

Belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Randomized open-label phase III LITESPARK-005 study. Albiges L, Rini BI, Peltola K, et al. DOI:https://doi.org/10.1016/j.annonc.2023.10.090. LBA88

Late Breaking Abstract – ESMO Congress 2023: Perioperative OPDIVO® Plus Chemotherapy Improves Survival in Resectable Non Small Cell Lung Cancer

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SUMMARY: 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 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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 (OPDIVO®) 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 among those receiving Nivolumab plus chemotherapy group, compared to those receiving chemotherapy alone.

CheckMate 77T, a multicenter, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of perioperative Nivolumab + 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%.

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 3) Now 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.

CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Cascone T, Awad M, Spicer J, et al. ESMO Congress 2023. Abstract LBA1. Presented on October 21, 2023.

Long Term Overall Survival Benefit with VIDAZA® plus VENCLEXTA® in Elderly AML Patients

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SUMMARY: The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The pro-survival (anti-apoptotic) protein BCL2 is over expressed by AML cells and regulates clonal selection and cell survival. A new class of anticancer agents known as BH3-mimetic drugs mimic the activity of the physiologic antagonists of BCL2 and related proteins and promote apoptosis (programmed cell death). VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. VIDAZA® (Azacitidine) is a hypomethylating agent that promotes DNA hypomethylation by inhibiting DNA methyltransferases. VIDAZA® has been shown to significantly improve Overall Survival (OS), when compared to conventional care regimens, in elderly unfit patients with newly diagnosed AML, who are not candidates for intensive chemotherapy. The combination of VIDAZA® and VENCLEXTA® in a previously published Phase Ib study was highly efficacious, with significant responses, duration of response and Overall Survival benefit.

VIALE-A is a Phase III, multicenter, randomized, double-blind, placebo-controlled confirmatory trial, conducted to evaluate the efficacy and safety of a combination of VIDAZA® and VENCLEXTA®, as compared with VIDAZA® plus placebo (the control regimen), in previously untreated patients with AML, who were ineligible for intensive induction therapy. In this study, 431 patients (N=431) with previously untreated AML were randomly assigned in a 2:1 ratio to receive either VIDAZA® plus VENCLEXTA® (N=286), or VIDAZA® plus placebo (N=145). Enrolled patients were ineligible for standard induction chemotherapy because of coexisting conditions, 75 years of age or older, or both. All patients received VIDAZA® 75 mg/m2 subcutaneously or IV on days 1 through 7 of every 28-day cycle. Patients in the study group also received VENCLEXTA® 100 mg orally on day 1 and 200 mg on day 2 and target dose of 400 mg on day 3, and continued daily until day 28 during cycle 1, to mitigate Tumor Lysis Syndrome. The dose of VENCLEXTA® was initiated at 400 mg daily in all subsequent 28-day cycles. In the control group, a matching placebo was administered orally, once daily, in 28-day cycles. The median age was 76 years in both groups, approximately 60% were male and 76% were Caucasian. Molecular abnormalities of interest included FLT-3, observed in 14% of patients receiving VIDAZA® plus VENCLEXTA®, IDH1/2, observed in 25% of patients, TP53, observed in 23.3% of patients and NPM1, observed in 16.6% of patients. Secondary AML was reported in 25% of the patients in the VIDAZA® plus VENCLEXTA® group and in 24% of the patients in the control group. All the patients were hospitalized on or before day 1 of cycle 1 and for at least 24 hours after receiving the final dose of VENCLEXTA®, in order to receive prophylaxis against the Tumor Lysis Syndrome and for monitoring. The Primary endpoint was Overall Survival (OS). The Secondary end points included Complete Remission (CR) rates, composite Complete Remission (Complete Remission or Complete Remission with incomplete hematologic recovery), RBC and platelet transfusion independence, and Quality of Life according to Patient-Reported Outcomes.

At a median follow up of 20.5 months, the median OS was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.66; P<0.001). VIDAZA® plus VENCLEXTA® combination resulted in a CR rate of 36.7% versus 17.9%; P<0.001 and composite CR of 66.4% versus 28.3%; P<0.001, when compared to the control regimen. Most responses were seen after the first 28-day cycle. The median time to first response was 1.3 versus and 2.8 months respectively, duration of CR was 17.5 months versus 13.3 months and median duration of composite CR was 17.5 months in the VIDAZA® plus VENCLEXTA® group and 13.4 months in the control group. RBC transfusion independence occurred in 59.8% of the patients in the VIDAZA® plus VENCLEXTA® group and in 35.2% of those in the control group (P<0.001), and platelet transfusion independence occurred in 68.5% and 49.7% (P<0.001), respectively. The benefits with VIDAZA® plus VENCLEXTA® were noted in almost all molecular subgroups compared to the control regimen. The response rates were highest among patients with FLT3 mutations (72.4% versus 36.4%, P=0.02) and those with IDH1 or IDH2 mutations (75.4 % versus 10.7%, P<0.001), respectively.

The researchers conducted 2 years of additional follow-up to determine the long-term survival benefit of VIDAZA® plus VENCLEXTA® combination and at this meeting reported the analysis of VIALE-A trial, after the occurrence of 100% of the pre-planned survival events. With a median follow-up of 43.2 months, the median Overall Survival (OS) benefit since the interim analysis in the overall population was maintained and was 14.7 months in the VIDAZA® plus VENCLEXTA® group versus 9.6 months in the VIDAZA® plus placebo group (HR=0.58; P<0.001). Among patients with Measurable Residual Disease (MRD) <10-3 who had achieved either Complete Remission (CR) or CR with incomplete hematologic recovery (CRi), the median OS was reached at 34.2 months in the VIDAZA® plus VENCLEXTA® group and 25.0 months in the control group. For patients in the IDH1/2 mutant subgroup, the median OS at final analysis with VIDAZA® plus VENCLEXTA® was 19.9 months and was 6.2 months in the control group (HR=0.31; P<0.001). Overall safety profiles were comparable between the treatment groups.

The 2-year follow up analysis of the VIALE-A trial confirmed the sustained Overall Survival benefit of VIDAZA® plus VENCLEXTA® combination in patients with AML, ineligible for intensive chemotherapy, with no new safety findings noted.

Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Pratz KW, Jonas BA, Pullarkat VA, et al. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 219

Late Breaking Abstract – ASCO 2023: Toripalimab Plus Chemotherapy Improves Progression Free Survival in Metastatic Triple Negative 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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC. Toripalimab, a checkpoint inhibitor, is a humanized IgG4K monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. Toripalimab provided significant clinical activity with a favorable safety profile in several solid tumors.

The purpose of this study is to compare the efficacy and safety of Toripalimab versus placebo, in combination with nab-Paclitaxel for metastatic or recurrent TNBC. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Toripalimab when given along with chemotherapy can enhance endogenous anticancer immunity.

TORCHLIGHT is a randomized, double-blind, placebo-controlled, multi-center, Phase III trial, in which the safety and efficacy of Toripalimab plus nab-Paclitaxel was compared with placebo plus nab-Paclitaxel in patients with Stage IV or recurrent/metastatic TNBC. In this study, 531 (N=531) eligible patients were randomly assigned 2:1 to receive Toripalimab 240mg IV on Day 1 every 3 weeks (N=353) or placebo (N=178), along with nab-Paclitaxel given at 125 mg/m2 on days 1 and 8 of each cycle. Treatment was continued until disease progression or intolerable toxicity. Patients could not have received more than one line of chemotherapy in the metastatic setting and had to be eligible for taxane monotherapy. Baseline characteristics were well balanced between the treatment groups and patients were stratified based on PD-L1 expression, Paclitaxel therapy history and line of prior therapy at enrollment. In the Toripalimab group, 200 patients had PD-L1 positive disease, whereas 100 patients in the placebo group had PD-L1-positive disease. The Primary endpoint was Progression Free Survival (PFS) assessed by a Blinded Independent Central Review (BICR), first in the PD-L1-positive population and then in the Intent-To-Treat (ITT) population. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate and Safety.

At interim analysis, with the median follow up of 14 months, a statistically significant improvement in PFS was demonstrated with Toripalimab in the PD-L1 positive subgroup. The median PFS was 8.4 months versus 5.6 months respectively (HR=0.65; P=0.01). The PFS in the overall population showed a similar trend and was 8.4 months in the Toripalimab group and 6.9 months in the placebo group (HR=0.77; P=0.04). A descriptive Overall Survival analysis showed a trend towards improved OS with Toripalimab in the PD-L1 positive group (median OS 32.8 versus 19.5 months; HR=0.61; P=0.01). In the overall population, the median OS was 33.1 versus 23.5 months (HR=0.69, P=0.01). No new safety signals were identified.

The authors concluded that, for PD-L1 positive metastatic or recurrent Triple Negative Breast Cancer patients receiving first-line treatment, the addition of Toripalimab to nab-Paclitaxel resulted in a significant improvement in Progression Free Survival with an acceptable safety profile. Patients are being followed for the final PFS and OS analysis.

TORCHLIGHT: A randomized, double-blind, phase III trial of toripalimab versus placebo, in combination with nab-paclitaxel(nab-P) for patients with metastatic or recurrent triple-negative breast cancer (TNBC). Jiang Z, Ouyang Q, Sun T, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA1013)

Late Breaking Abstract- ASCO 2023: BCMA-directed CAR T-cell therapy Cilta-cel in Lenalidomide Refractory 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, 35,730new cases will be diagnosed in 2023 and 12,590 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 2023 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. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

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 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

Ciltacabtagene autoleucel (Cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with Relapsed or Refractory multiple myeloma and was approved by the FDA in February 2022 for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including a Proteasome Inhibitor (PI), an Immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. The researchers in this study investigated the efficacy of cilta-cel in earlier treatment lines among patients with Lenalidomide-refractory disease.

CARTITUDE-4 is an open-label, multicenter, randomized Phase III trial conducted to compare cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

Treatment with cilta-cel resulted in a significantly lower risk of disease progression or death than standard-of-care (HR=0.26; P<0.001). The median PFS was not reached in the cilta-cel group and was 11.8 months in the standard-of-care group. Progression-free survival at 12 months was 75.9% in the cilta-cel group and 48.6% in the standard-of-care group. The ORR was 84.6% in the cilta-cel group and 67.3% in the standard-of-care group (P<0.001), the CR rate or better was 73.1% versus 21.8% (P<0.001), and MRD negativity was 60.6% versus 15.6% (P<0.001), respectively. Among the patients who had a response, an estimated 84.7% in the cilta-cel group as compared with 63.0% in the standard-of-care group continued to have a response for at least 12 months.

The most common Grade 3 or 4 adverse events in both groups were hematologic and most high-grade cytopenias in patients who received cilta-cel recovered to Grade 2 or less by day 60. Serious adverse events were reported in 44% of patients in the cilta-cel group and in 39% of patients in the standard-of-care group. Lower rates of cytopenias, Cytokine Release Syndrome, and CAR-T–related neurotoxicity were seen in this study compared to previous cilta-cel studies suggesting that cilta-cel may have a better side-effect profile when used earlier in treatment.

It was concluded that a single cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. San-Miguel J, Dhakal B, Yong K, et al. N Engl J Med 2023;389:335-347.

Ovarian Ablation or Suppression May Lower the Risk of Breast Cancer Recurrence

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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 approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 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 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.

It has been hypothesized that estrogen in breast cancer acts as a catalyst/promoter for cancer growth, by stimulating the division and proliferation of breast tissue and increasing the risk for cancer causing mutations. A recently published study (Nature 2023;618:1024–1032) suggests that estrogen might be involved in the genomic reshuffling that gave rise to cancer-gene activation in breast cancer, acting as an initiator as well.

The researchers in this study postulated that suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual/microscopic cancer, particularly among pre-menopausal women with Estrogen Receptor (ER)-positive tumors. To further clarify this benefit, the researchers from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials, that compared ovarian ablation or suppression with no ovarian ablation or suppression. Primary analyses included only premenopausal women age less than 55 years, with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained.

The following observations were noted from this meta-analysis:

–Fewer breast cancer recurrences were seen overall with ovarian ablation/suppression than control (RR=0.82, P< 0.0001).

• Among women receiving no chemotherapy or remaining premenopausal after chemotherapy (N=7,213), similar benefits were seen and the reduction in recurrent breast cancer was significant with ovarian ablation/suppression than control. The breast cancer recurrence rate at 15 years was 39.3% in the control group versus 29.5% in the ovarian ablation or suppression group, with an absolute benefit of 9.8% and a Rate Ratio (RR) of 0.71 (P<0.0001).

• Breast cancer mortality and all-cause mortality in the ovarian ablation or suppression group at 15 years, were improved by 8.0% (20.9% versus 28.9%; RR 0.69, P<0.0001) and 7.2% (26.0% versus 33.1%; RR = 0.73, P< 0.0001), respectively, with no increase in deaths without recurrence (RR = 0•88, P=0.33).

• Among those women who were premenopausal before chemotherapy and whose menopausal status was uncertain after chemotherapy (N=7,786), the rate of recurrence at 15 years was 43.1% in those who received ovarian ablation/suppression and 44.4% in the control group (RR=0.91; P =0.03).

• Recurrence reductions were significantly larger among premenopausal women under 45 years, than among those 45-54 years, and did not differ significantly by tumor characteristics. Among premenopausal women under 45 years (N=4,437), the recurrence rate was 41.3% in the control group and 30.4% with ovarian ablation or suppression, representing a 15-year benefit of 10.9% and a Rate Ratio of 0.66 (P<0.00001). Among those women 45-54 years (N=2,776), the recurrence rate was 36.1% in the control group and 28.6% with ovarian ablation or suppression, suggesting a 15-year benefit of 7.5% and Rate Ratio of 0.82 (P=0.02).

• Among those taking Tamoxifen, the benefit with ovarian ablation or suppression was less, and was only 4.5% (RR = 0.80; P =0.002).

The authors concluded that ovarian ablation or suppression in pre-menopausal women less than 45 years with ER-positive breast cancer, substantially reduces the 15-year risk of recurrence and death from breast cancer, without increasing mortality from other causes.

Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials. Gray RG, Bradley R, Braybrooke J, et al. J Clin Oncol 41, 2023 (suppl 16; abstr 503)