Category: Meeting Updates

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)

Late Breaking Abstract – ASCO 2023: Chemotherapy De-escalation using PET Response-Adapted Strategy in Patients with HER2-positive 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. 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.

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. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.

Trastuzumab is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. Pertuzumab is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways. Dual HER2 blockade with Trastuzumab and Pertuzumab, 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.

Pathological Complete Response (pCR) after neoadjuvant therapy has strong prognostic significance in HER2+ breast cancer, and pCR rates in HER2+/HR- negative tumors exceed those in HER2+/HR+ tumors, and this in turn correlates with superior Event Free Survival. The FDA approved anti-HER2 dual blockade with Pertuzumab and Trastuzumab, given along with chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer, based on the NeoSphere trial, and for metastatic disease based on positive survival results in the CLEOPATRA trial. The role of chemotherapy free anti-HER2 dual blockade however has remained unclear.

PHERGain is a multinational, multicenter, randomized, open-label, non-comparative, Phase II trial, designed to explore the feasibility of dual HER2 blockade with a chemotherapy de-escalation strategy, using a response-adapted design. This study design allowed the identification of treatment responders earlier in the study, and non-responders were switched to Standard-of-Care treatment. In this study, 356 patients with Stage I-IIIA, invasive, HER2-positive operable breast cancer, with tumor size 1.5 cm or more, and with at least one breast lesion evaluable by FDG-PET, were included. Patients were randomized 1:4 to receive either Docetaxel 75 mg/m2 IV, Carboplatin AUC 6 mg/mL IV, Trastuzumab 600 mg SC given as a fixed dose, and Pertuzumab 840 mg IV given as a loading dose, followed by 420 mg IV maintenance doses (TCHP) – Group A (N=71) or Trastuzumab and Pertuzumab alone (HP) – Group B (N=285). Patients were stratified by Hormone Receptor status and Hormone Receptor-positive patients allocated to Group B were additionally given Letrozole if postmenopausal (2.5 mg/day orally) or Tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed FDG-PET scans were done before randomization and after two treatment cycles. Patients assigned to Group A completed six cycles of treatment (given every 3 weeks) regardless of FDG-PET results. Patients assigned to Group B initially received two cycles of Trastuzumab and Pertuzumab. FDG-PET responders (reduction in breast lesions of at least 40% from baseline) in Group B continued this treatment for six additional cycles. FDG-PET non-responders in this group were switched to six cycles of Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP). Surgery was performed 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The co-Primary endpoints were the proportion of FDG-PET responders in Group B with a pathological Complete Response in the breast and axilla (ypT0/is ypN0), as determined by a local pathologist after surgery, following eight cycles of treatment, as well as 3-year invasive Disease-Free Survival (DFS) of patients in Group B. In an earlier analysis of this study, at a median follow-up was 5.7 months, 80% of the patients in Group B were FDG-PET responders, of whom 38% had a pathological Complete Response, achieving the first Primary endpoint (Perez-Garcia JM, Lancet Oncol 2021).

The researchers herein presented the results of the second Primary endpoint, 3-year invasive DFS, among patients included in Group B who underwent surgery based on an Intent-to-Treat (ITT) analysis. In Group A, 89% proceeded to surgery and 93.7% proceeded to have surgery in Group B. The 3-year invasive DFS among the 80% of patients in Group B who were FDG-PET responders was 95.4%, meeting the second Primary endpoint (P<0.001). Further, a subgroup analysis showed that of the patients in Group B who were FDG-PET responders and who also achieved a pathological Complete Response (38%), none received chemotherapy at any point in the 3 years they were in the study. These patients had a 3-year invasive DFS of 98.8%, and only one patient experienced invasive event (locoregional ipsilateral recurrence).
As expected, treatment-related Adverse Events and serious Adverse Events were significantly higher in patients assigned to Group A than to Group B, and Group B patients with pathological Complete Response had the lowest incidence of Grade 3 or more Adverse Events.

The authors concluded that among patients with HER2-positive early operable breast cancer, a PET-based, pathological Complete Response-adapted strategy was associated with a substantial 3-year invasive Disease Free Survival. The authors added that this treatment approach identifies about a third of HER2-positive early breast cancer patients who may safely omit chemotherapy and avoid the risk of treatment-related toxicities.

3-year invasive disease-free survival (iDFS) of the strategy-based, randomized phase II PHERGain trial evaluating chemotherapy (CT) de-escalation in human epidermal growth factor receptor 2-positive (HER2[+]) early breast cancer (EBC). Cortes J, Pérez-García JM, Ruiz-Borrego M, J Clin Oncol 41, 2023 (suppl 17; abstr LBA506)

Late Breaking Abstract – ASCO 2023: Tumor Treating Fields Plus Standard of Care Improves Overall Survival in Patients with Metastatic 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.

Tumor Treating Fields (TTFields) delivery system is a non-invasive novel external therapeutic device that slows and reverses tumor growth by disrupting mitosis. The battery operated portable at-home TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields delivered locoregionally to the tumors through 2 pairs of arrays applied to the chest. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Patients wear the device for at least 18 hours a day and for at least four weeks. Currently, TTF therapy is approved for Glioblastoma and Malignant Pleural Mesothelioma. Preclinical NSCLC studies have shown that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. Further, TTFields synergize with taxanes and Immune Checkpoint Inhibitors (ICIs). This was the rationale for the development and design of the LUNAR Phase III trial.

The LUNAR study is a global, randomized, Phase III trial in which the safety and efficacy of Tumor Treating Fields therapy with Standard of Care, was compared to Standard of Care alone, in patients with metastatic Non Small Cell Lung Cancer (NSCLC), who had progression on or after Platinum-based chemotherapy. In this study, 276 eligible patients (N=276) were randomized 1:1 to receive either Tumor Treating Fields therapy (150 kHz) plus Standard of Care, which included investigator’s choice of an Immune Checkpoint Inhibitor (ICI) or Docetaxel, or Standard of Care alone. To be eligible for this study, patients had to be 22 years or older, have metastatic NSCLC, should have progressed on or after a platinum-based therapy, and have an ECOG performance status of 0-2. Both treatment groups were well balanced. The median age was 64 years, 65% were male, 96% of patients had an ECOG PS of 0-1, 56% had non-squamous histology, 89% had one prior line of systemic therapy and 31% received prior therapy with ICI. Patients were followed every 6 weeks and continued on therapy until disease progression or intolerable toxicities. The Primary endpoint was Overall Survival (OS). Secondary endpoints included were OS in ICI and Docetaxel subgroups, Progression Free Survival (PFS) and toxicities.

This study met its Primary end point of Overall Survival and OS was significantly extended with Tumor Treating Fields therapy plus Standard of Care versus Standard of Care. After a minimum follow up of 12 months, the median Overall Survival with Tumor Treating Fields therapy plus Standard of Care was 13.2 months versus 10.0 months with Standard of Care alone (HR=0.74; P=0.037) and 1-year survival rates were 53% and 42% respectively (P=0.040). In patients receiving an Immune Checkpoint Inhibitor (N=134), the addition of Tumor Treating Fields therapy significantly improved median OS versus ICI alone (18.5 months versus 10.6 months; HR=0.63; P=0.032). In those patients treated with Docetaxel, the median OS was numerically higher at 11.1 months with Tumor Treating Fields therapy plus Docetaxel versus 8.9 months with Docetaxel alone (HR=0.87). There was no significant difference in the median PFS between the two treatment groups and were 4.8 months and 4.1 months respectively. The rate of Adverse Events was similar between the treatment groups and majority of the Tumor Treating Fields associated toxicities were Grade 1 and 2 local skin irritations.

The authors concluded that in this Phase III study, the addition of Tumor Treating Fields therapy to Standard of Care therapy significantly extended Overall Survival in patients with metastatic NSCLC following platinum failure, without increasing systemic toxicities, and Tumor Treating Fields therapy may be a potentially paradigm-shifting new treatment modality.

Tumor treating fields (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized phase 3 LUNAR study. Leal T, Kotecha R, Ramlau R, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA9005)

Late Breaking Abstract – ASCO 2023: Biomarker-Driven ELAHERE® Improves Survival in Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. About 85% of all ovarian cancers are epithelial in origin, and 70% of all epithelial ovarian cancers are High-Grade serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival (OS) rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate (ORR) of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha (FR alpha), and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (Mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (P=0.0046). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Moore KN, Angelergues A, Konecny GE, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA5507)

Fixed Dose versus Standard Dose Capecitabine in Metastatic 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. Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients.

Capecitabine (XELODA®) is one of the most frequently prescribed chemotherapeutic agents, for the treatment of breast cancer, and patients with metastatic breast cancer often receive Capecitabine following progression on anthracycline and taxane-based therapy. Capecitabine is preferred as it is not associated with alopecia or neuropathy, and can be administered orally. The FDA approved dosing schedule for Capecitabine is 1250 mg/m2 orally twice daily 14 days on, 7 days off. This dosing and schedule however is associated with poor tolerance and high discontinuation rates. Mathematical models suggest that a fixed, dose-dense schedule may be optimal for Capecitabine efficacy.

The X-7/7 is a randomized Phase II study in which the efficacy and tolerability of fixed-dose Capecitabine was compared with standard-dose Capecitabine, in patients with metastatic breast cancer. This study included 153 patients who were randomly assigned in a 1:1 ratio to receive either fixed-dose Capecitabine at 1500 mg orally twice daily, 7 days on followed by 7 days off (N=80) or the FDA approved standard-dose Capecitabine at 1250 mg/m2 twice daily, 14 days on followed by 7 days off (N=73). Female patients with metastatic breast cancer, regardless of the number of prior lines of endocrine therapy or chemotherapy they had received, were included. HER-2 positive patients were allowed with concurrent Trastuzumab. Majority of patients included in this study had Hormonal Receptor (HR)-positive, HER2-negative disease, 11% were HER-2 positive, 11% were triple negative, and 65% of patients were chemotherapy-naïve. Patients were stratified by line of chemotherapy (first line or subsequent), measurable disease, and ER status. The Primary endpoint was 3-month Progression Free Survival (PFS). Additional endpoints included PFS and Overall Survival (OS).

It was noted that the fixed dosing schedule of Capecitabine was associated with less toxicity and similar survival when compared with the standard dosing schedule. The 3-month PFS was similar at 76% in both the fixed-dose group and standard-dose group (HR=1.01; P=0.99). Landmark analysis of PFS at 12, 24 and 36 months for fixed-dose versus standard-dose Capecitabine was 39% versus 50% at 12 months (P=0.23), 25% versus 23% at 24 months (P=0.77), and 11% versus 0% at 36 months (P=0.24), respectively. The restricted mean PFS at 36 months was 13.9 months in the fixed-dose group versus 14.6 months in the standard-dose group (HR=1.31; P=0.24). The restricted mean OS at 36 months was 21.2 months versus 19.6 months, respectively (HR=0.80; P=0.27)

Patients receiving fixed-dose Capecitabine were less likely to experience Grade 2-4 toxicities than those receiving standard-dose Capecitabine (25% versus 49.3%, P=0.0018). Treatment discontinuation due to toxicities was significantly lower with fixed-dose Capecitabine compared with standard-dose Capecitabine (7.5% versus 28.8%, respectively, P<0.0006).

It was concluded that fixed dose Capecitabine 1500 mg orally twice daily 7 days on followed by 7 days off, has less toxicity and may improve tolerability without compromising efficacy, compared to the standard BSA-based dosing 14 days on followed by 7 days off. For patients receiving Capecitabine in an adjuvant setting with a curative intent (e.g. CREATE-X trial), standard BSA-based dosing and schedule is appropriate.

Randomized trial of fixed dose capecitabine compared to standard dose capecitabine in metastatic breast cancer: the X-7/7 tria. Khan QJ, Bohnenkamp C, Monson T, et al. DOI:10.1200/JCO.2023.41.16_suppl.1007 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 1007-1007.

Late Breaking Abstract – ASCO 2023: First Line versus Second Line Use of CDK4/6 Inhibitors in Advanced HR-Positive/HER-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.

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. 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. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).

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. CDK 4 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.

It has been shown that CDK4/6 inhibitors in combination with endocrine therapy improves Progression Free Survival (PFS) as well as Overall Survival (OS) when given as initial treatment (first-line) and after prior endocrine monotherapy (second-line), in patients with HR-positive, HER2-negative advanced breast cancer. Treatment guidelines recommend first-line use of CDK4/6 inhibitors along with endocrine therapy, but evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking.

SONIA is a real-world, randomized, investigator-initiated, nationwide, Phase III trial, conducted to evaluate the efficacy, safety and cost-effectiveness of CDK4/6 inhibitors added to either first or second-line endocrine therapy, in patients with HR-positive, HER2-negative advanced breast cancer, who have received no prior therapy for their advanced disease. In this study, 1050 pre and postmenopausal women (N=1050) with measurable or evaluable disease, who received no prior therapy for advanced breast cancer, were randomized 1:1 to receive first-line treatment with a non-steroidal Aromatase Inhibitor and a CDK4/6 inhibitor, followed upon progression by Fulvestrant (strategy A) or first-line treatment with a non-steroidal Aromatase Inhibitor, followed upon progression by Fulvestrant and CDK4/6 inhibitor (strategy B). Both treatment groups were well balanced. Neoadjuvant/adjuvant therapy was allowed if the disease-free interval after non-steroidal Aromatase Inhibitor therapy was more than 12 months. The choice of CDK4/6 inhibitor was a stratification factor and was left to the discretion of the treating physician. The Primary endpoint was time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include Overall Survival (OS), Safety, Quality of Life, and cost-effectiveness.

At a median follow-up was 37.7 months, the median duration of CDK4/6 inhibitor treatment/usage was 24.6 months in the first-line group and 8.1 months in the second-line group. The median PFS with strategy A as expected was significantly longer in the CDK4/6 inhibitor group than in the non-steroidal Aromatase Inhibitor group (24.7 months and 16.1 months respectively, HR=0.59; P<0.0001).  However, with regards to PFS2, there was no significant difference between the two treatment groups. The median PFS2 was 31.0 months with strategy A versus 27.8 months with strategy B (HR=0.89; P=0.14) and this similar PFS2 treatment effect was consistent across pre-defined subgroups. There was no significant difference in Overall Survival between the two treatment groups (HR=0.98; P=0.83).

There were more grade 3 or 4 adverse events when CDK4/6 inhibitors were used in the first-line setting and the use of strategy A increased the cost of treatment by an average of $200,000 per patient. Quality of life, as measured by Functional Assessment of Cancer Therapy – Breast (FACT-B) total score, was not different between the 2 arms.

It was concluded that first-line use of CDK4/6 inhibitor along with endocrine therapy does not provide statistically significant and clinically meaningful Progression Free Survival benefit compared to second-line use in women with HR-positive and HER2-negative advanced breast cancer. The authors added that second-line use may thus be a preferred option for the majority of these patients, as the use in first-line prolongs the time on CDK4/6 inhibitors by over 16 months and increases toxicity and cost of treatment. It should however be noted that in this study, patients received single-agent Fulvestrant as second-line treatment which may not be the standard treatment intervention, given the approval of Alpelisib for patients with PIK3CA mutations. Treatment selection based on biomarkers testing therefore is important. Based on the SONIA trial data, offering endocrine therapy alone in the first line setting may not be inappropriate for favorable risk patients without high visceral tumor burden.

Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Sonke GS, Van Ommen-Nijhof A, Wortelboer N, et al. DOI: 10.1200/JCO.2023.41.17_suppl. LBA1000 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA1000

Late Breaking Abstract – ASCO 2023: Superior Outcomes with First Line Nivolumab versus Brentuximab Vedotin in Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2023, about 8830 new cases of Hodgkin Lymphoma will be diagnosed and about 900 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD to Brentuximab Vedotin plus AVD, in patients with advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD IV (Doxorubicin, Vinblastine, Dacarbazine ) on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.

At the planned 2nd interim analysis, upon recommendation from the SWOG Data and Safety Monitoring Committee, the primary results were reported. With a median follow up of 12.1 months, PFS was superior in the N-AVD group compared to the BV-AVD group. The estimated 1 year PFS was 94% in the N-AVD group compared with 86% among patients treated with BV-AVD (HR=0.48; P=0.0005). The PFS benefit was consistent across treatment subgroups. This benefit was most pronounced among patients over 60 years of age, those with an IPS of 4-7 and those with Stage IV disease. The estimated 1 year EFS was 91% with N-AVD versus 84% with BV-AVD (HR=0.56; P=0.0019). The 1 year OS data were not mature and the OS rates were 99% versus 98% respectively. The rate of Grade 3 or more hematologic AEs were 48.4% after N-AVD, compared to 30.5% after BV-AVD. There was however no increase in infectious complications even though there was a higher rate of neutropenia in the N-AVD group. Hypo/Hyperthyroidism was more frequent after N-AVD whereas peripheral neuropathy was more common after BV-AVD.

The researchers concluded that in this largest Hodgkin Lymphoma study in National Clinical Trials Network (NCTN) history, Nivolumab in combination with AVD significantly improved Progression Free Survival, compared to Brentuximab Vedotin in combination with AVD, in patients with advanced stage Hodgkin Lymphoma, and may be the new standard therapy for this group of patients. Follow-up is ongoing to confirm the durability of PFS benefit, assess Overall Survival and Patient Reported Outcomes.

SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). Herrer AF, LeBlanc ML, Castellino SM, et al. J Clin Oncol. 2023;41(suppl 17): DOI: 10.1200/JCO.2023.41.17_suppl.LBA4