Category: Hem/Onc Updates

Neoadjuvant Chemoimmunotherapy Improves Pathologic Complete Response Rates in Early Stage ER-Positive, HER2-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 in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years (Lancet Oncol. 2018;19:27-39).

The promising efficacy observed with single-agent checkpoint blockade for advanced HER2-negative breast cancer, and the significant benefit observed with PD-1 inhibitors combined with chemotherapy for lung cancer and other cancer types, led the researchers to evaluate the efficacy of adding Pembrolizumab to standard neoadjuvant chemotherapy. In the Phase 2 I-SPY2 trial, Pembrolizumab plus neoadjuvant chemotherapy improved estimated pathological Complete Response rates versus neoadjuvant chemotherapy alone, at 30% versus 13%, in patients with HR-positive, HER2-negative breast cancer.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, 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. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity.

Pembrolizumab is approved for the treatment of patients with high-risk early-stage Triple Negative Breast Cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, as well as in combination with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10 or more).

KEYNOTE-756 is a global, randomized, double-blind, Phase III trial, conducted to assess the efficacy and safety of Pembrolizumab versus placebo, in combination with neoadjuvant chemotherapy followed by adjuvant treatment with Pembrolizumab plus endocrine therapy, in adults with high-risk, early stage ER-positive HER2- negative breast cancer. In this study 1,278 enrolled patients (N=1278) were randomized 1:1 to receive Pembrolizumab 200 mg IV ever 3 weeks or placebo, both given with Paclitaxel weekly for 12 weeks, followed by 4 additional cycles of Doxorubicin or Epirubicin plus Cyclophosphamide (neoadjuvant treatment) prior to surgery. Following definitive surgery with or without radiation treatment, patients received Pembrolizumab or placebo every 3 weeks for 9 cycles plus endocrine therapy for up to 10 years, as adjuvant therapy post-surgery. Eligible patients had centrally confirmed T1c-2 (≥2 cm) cN1-2 or T3-4 cN0-2, Grade 3, ER-positive, HER2-negative, invasive ductal carcinoma, and were treatment-naive. Both treatment groups were well balanced. The median age was 49 years, about 76% of patients in each treatment group had a PD-L1 CPS of 1 or higher, about 40% had a CPS of 10 or higher, and about 90% had nodal involvement. About 62% of patients had Stage II disease, and 38% had Stage III disease. The dual Primary endpoints were pathological Complete Response (pCR) rate (ypT0/Tis ypN0), defined as absence of invasive cancer in the breast and axillary lymph nodes at the time of surgery, and Event Free Survival (EFS). Secondary endpoints included Overall Survival and Safety.

With a median follow-up of 33.2 months, the study demonstrated a statistically significant improvement in pCR rates with Pembrolizumab compared to placebo. The pCR rate in the intention-to-treat (ITT) population was 24.3% with Pembrolizumab versus 15.6% with placebo (absolute difference 8.5%; P = 0.00005). Similar improvements were observed across various subgroups, including patients with Stage II or III disease, positive lymph nodes at baseline, and higher PD-L1 expression levels. Pembrolizumab demonstrated superior efficacy across geographic regions and exhibited a linear improvement in pCR rates with increasing PD-L1 expression.

Further analyses showed a greater pCR benefit with Pembrolizumab in patients with low estrogen receptor (ER) positivity (defined as less than 10% of ER-positive cells), node positive disease and those with higher PD-L1 expression. Pembrolizumab recipients who received full-dose chemotherapy had a greater pCR benefit compared to those who received reduced chemotherapy doses. Additionally, Pembrolizumab recipients were more likely to shift to lower Residual Cancer Burden (RCB) groups post-surgery. The trial also observed higher rates of immune-mediated adverse events with Pembrolizumab compared to placebo, with common events including hypothyroidism, hyperthyroidism, and pneumonitis.

It was concluded from this study that, the addition of Pembrolizumab to neoadjuvant chemotherapy followed by adjuvant Pembrolizumab plus endocrine therapy, significantly improves pCR rates in patients with early stage, high risk ER-positive, HER2-negative breast cancer. Further assessment of long term outcomes, including Event-Free Survival and Overall Survival is ongoing to fully evaluate the clinical benefit of this treatment approach. The study sponsors added that this is the first positive Phase III study, evaluating an immunotherapy-based regimen for patients with high risk, early stage ER-positive, HER2-negative breast cancer, and an important milestone in advancing research, in early stage breast cancer.

Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2- breast cancer: KEYNOTE-756. Cardoso F, O’Shaughnessy J, McArthur H, et al. Presented at SABCS 2023. December 5-9, 2023. San Antonio, TX. Abstract GS01-02.

Late Breaking Abstract: ASH – 2023: Pomalidomide Reduces Epistaxis and Improves Quality of Life in Hereditary Hemorrhagic Telangiectasia

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SUMMARY: Hereditary Hemorrhagic Telangiectasia (HHT) is an Autosomal Dominant inherited disorder caused by mutations in regulators of angiogenesis. Also known as Osler-Weber-Rendu syndrome, HHT is the second most common inherited bleeding disorder after Von Willebrand Disease, with an estimated prevalence of 1 in 5000. HHT presents with a triad of recurrent epistaxis with iron deficiency anemia, mucocutaneous telangiectasias, and visceral arteriovenous malformations (AVMs) and in more severe cases, patients may experience life-threatening hemorrhage, stroke, or high-output heart failure, requiring hospitalizations, with a negative impact on Quality of Life (QOL). HHT is caused by disruptions in angiogenesis signaling, resulting in impaired vascular development. Three genes in the Transforming Growth Factor-beta (TGF-β) signaling pathway have been implicated and they include Endoglin (ENG), activin A receptor ligand type I (ACVRL1 or ALK-1), and SMAD family member 4 (MADH4 or SMAD4).

Small non-randomized studies suggested that systemic antiangiogenic agent Bevacizumab or immunomodulatory drugs with antiangiogenic properties such as Thalidomide, Lenalidomide, and Pomalidomide may be effective in treating HHT. There are presently no FDA approved therapies for HHT.

PATH-HHT is a randomized, placebo-controlled, multicenter clinical trial, conducted in the US to determine the safety and efficacy of Pomalidomide, for bleeding in HHT. In this study, 144 patients (N=144) diagnosed with HHT were randomly assigned in a 2:1 ratio to receive either Pomalidomide 4 mg orally daily or a matching placebo, for a duration of six months. Pomalidomide, instead of another immunomodulatory drug, was chosen due to its favorable safety profile. Eligibility criteria included a confirmed HHT diagnosis per Curaçao Diagnostic Criteria, documented anemia, and an Epistaxis Severity Score (ESS) of 3 or more over the prior 3 months. Epistaxis Severity Score (ESS) was developed to self- describe epistaxis severity from 0-10, with 10 representing the most severe epistaxis. Mild is ESS of 1-4, moderate is ESS of 4-7 and Severe is ESS of 7-10. The mean age was 59 years and 48% were female. Among the 134 patients who agreed to genetic testing, ENG mutations were detected in 37%, ACVRL1 in 51%, and SMAD4 in 1%. Patients had a mean ESS of 5 at baseline, and mean daily epistaxis duration of 16 minutes. In the preceding 6 months, 84% of patients had required iron infusions and 19% required blood transfusions. More than a third of the patients also had GI bleeding, and 40% had pulmonary AVMs. The Primary endpoint of the study was the change in Epistaxis Severity Score (ESS), from baseline to the end of the six-month treatment period. Secondary endpoints included changes in the average daily self-reported duration of epistaxis from the 4 weeks preceding the baseline visit to weeks 20-24 of treatment, the amount of parenteral iron infused or blood transfused, and change in Quality-of-Life (QOL) measurements, including an HHT-specific QOL score.

The results of this study showed that treatment with Pomalidomide led to a significant reduction in epistaxis severity compared to placebo. The mean ESS decreased by -1.84 in the Pomalidomide group versus -0.89 in the placebo group at 24 weeks (P=0.003). This benefit was seen as early as week 12. Additionally, patients treated with Pomalidomide reported greater improvements in Quality of Life (QOL) related to HHT. The HHT-specific QOL score (ranges from 0-16 with higher scores indicating more limitations) also decreased more in the Pomalidomide group versus the placebo group at 24 weeks (P=0.015). Adverse events were more common in the Pomalidomide group and included mild to moderate neutropenia (45% versus 10%), constipation/diarrhea (60% versus 37%), and rash (36% versus 10%).

It was concluded from this largest HHT study that treatment with Pomalidomide demonstrated a significant and highly clinically relevant reduction in epistaxis, as well as an improvement in the HHT-specific QOL score. Pomalidomide holds promise as a therapeutic option for patients with HHT, addressing an unmet medical need, in managing this challenging genetic disorder. Additional studies may identify biomarkers predicting responses to Pomalidomide.

PATH-HHT, a Double-Blind, Randomized, Placebo-Controlled Trial in Hereditary Hemorrhagic Telangiectasia Demonstrates That Pomalidomide Reduces Epistaxis and Improves Quality of Life. Al-Samkari H, Kasthuri RS, Iyer V, et al. Blood (2023) 142 (Supplement 2): LBA-3. https://doi.org/10.1182/blood-2023-191983.

Dato-DXd for Patients with HR-Positive HER2-Negative Advanced Breast Cancer

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

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 chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

Datopotamab-deruxtecan (Dato-DXd) is an ADC composed of a TROP2-directed monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a stable tetrapeptide-based cleavable linker. Trop-2 is a transmembrane calcium signal transducer that stimulates cancer cell growth. Trop-2 is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. It has been associated with poor Overall and Disease-Free Survival in several types of solid tumors. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers the payload directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables the payload to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Dato-DXd showed encouraging antitumor activity in the TROPION-PanTumor01 trial, an ongoing multicenter, open-label study, evaluating Dato-DXd in different dose levels in solid tumors.

TROPION-Breast01 is an open-label, global, Phase III study in which 732 patients (N=732) with HR-positive HER2-negative previously treated metastatic breast cancer were randomly assigned in a 1:1 manner to receive either Dato-DXd (N=365) or investigators choice of chemotherapy (N=367). Dato-DXd was given at a dose of 6 mg/kg IV on day 1 every 3 weeks. Investigators choice of chemotherapy consisted of Eribulin mesylate, Vinorelbine, or Gemcitabine, all given IV on days 1 and 8 every 3 weeks, as well as Capecitabine given orally on days 1-14 every 3 weeks. Treatment was continued until disease progression or unacceptable toxicities. The median age was 55 years and enrolled patients had received 1 or 2 prior lines of chemotherapy in the inoperable or metastatic setting. Eligible patients had progressed on, or were deemed unsuitable for endocrine therapy. Patients were stratified by number of lines of chemotherapy received in the unresectable/metastatic setting, and treatment with a previous CDK4/6 inhibitor. The Co-Primary end points were Progression Free Survival (PFS) by Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary end points included Overall Response Rate (ORR), Safety, Patient Reported Outcomes, and Time to First Subsequent Therapy (TFST).

The Median PFS by BICR in the Dato-DXd arm was 6.9 months versus 4.9 months in the chemotherapy arm (HR=0.63; P < 0.0001). The PFS rates at 6, 9, and 12-months in Dato-DXd arm were 55.2%, 34.7%, and 21.7%, respectively. In the chemotherapy arm, these rates were 36.9%, 20.9%, and 9.9%, respectively. The PFS benefit with Dato-DXd over chemotherapy was noted irrespective of brain metastases and prior duration of treatment with CDK4/6 inhibitors. The median Time to First Subsequent Therapy was 8.2 months with Dato-DXd and 5.0 months with chemotherapy. Dato-DXd also demonstrated a delay in time to deterioration in global health status/quality of life, compared to chemotherapy.

Treatment-related adverse effects occurred in 94% of patients in the Dato-DXd arm versus 86% in the chemotherapy group, with grade 3 or higher severity in 21% versus 45%, respectively. Neutropenia was more common in the chemotherapy arm.

It was concluded that Dato-DXd showed statistically significant and clinically meaningful improvement in Progression Free Survival compared to chemotherapy. The improved outcomes were observed across subgroups, including patients with and without brain metastases, and those with varying durations of prior CDK4/6 inhibitor treatment. Dato-DXd was associated with a favorable safety profile and impact on quality of life.

Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01. Bardia A, Jhaveri K, Im S-A, et al. Presented at San Antonio Breast Cancer Symposium 2023. December 5-9, 2023. San Antonio, TX. Abstract GS02-01.

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.

Benign Breast Disease and Increased Breast Cancer Risk

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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 were diagnosed in 2023 and about 43,700 individuals died of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

Benign breast disease comprises approximately 75% of breast biopsy diagnoses, performed following abnormal mammographic findings. Benign breast disease can be, based on Dupont and Page, classified into nonproliferative diseases such as fibroadenomas, cysts, microcalcifications, fibrosis, apocrine, metaplasia, atrophy, fatty tissue necrosis, inflammatory tissue and ectasia, or proliferative disease which includes scar, hyperplasia, sclerosing adenosis, papilloma, adenosis, intraductal hyperplasia, lobular hyperplasia, benign Phylloides tumor, benign mesenchymal tumors, epithelial benign tumors, atypia, atypical ductal hyperplasia, and lobular intraepithelial neoplasia. Surgical biopsy specimens diagnosed as nonproliferative disease, proliferative disease without atypia, or atypical ductal hyperplasia are associated with long term risk of breast cancer. However, there is limited knowledge on breast cancer risk associated with percutaneously diagnosed benign breast diseases.

The researchers conducted this retrospective cohort study to estimate breast cancer risk among women diagnosed with benign breast disease (BBD) through percutaneous biopsies from 2002 to 2013. The study included 4,819 women with a median age of 51 years. The participants were followed from 6 months after biopsy until breast cancer diagnosis, or December 2021. Researchers compared breast cancer risk for women with benign breast disease with the female breast cancer incidence rates obtained from the Iowa Surveillance, Epidemiology, and End Results (SEER) program. The Primary outcome was overall breast cancer diagnoses, as well as diagnoses stratified as Ductal Carcinoma In Situ (DCIS) or invasive breast cancer. About 79% of women underwent core biopsy only, 10% underwent core biopsy and surgical excision and 11% underwent excisional biopsy only. Based on the most severe lesion identified, 50.8% of biopsy specimens were nonproliferative, 42% were proliferative disease without atypia, and 7.2% were atypical hyperplasia.

It was noted that women with benign breast disease diagnosed by percutaneous biopsies had a significantly higher overall breast cancer risk compared to the general population (Standard Incidence Ratio [SIR] = 1.95).

Breast cancer risk increased with the severity of benign breast disease, with SIR = 1.42 for nonproliferative lesions, SIR = 2.19 for proliferative disease without atypia and SIR = 3.91 for atypical hyperplasia. This pattern was comparable to surgical cohorts with benign breast disease.

The risk of breast cancer also increased with the multiplicity of lesions. Women with three or more foci of nonproliferative lesions had an SIR of 2.40, proliferative disease without atypia had an SIR of 3.72, and atypical hyperplasia had an SIR of 5.29, all compared with the general population.

Women with benign breast disease had an increased risk for both invasive breast cancer (SIR = 1.56) and Ductal Carcinoma In Situ (DCIS) (SIR = 3.10), compared to the general population.

The 10-year cumulative breast cancer incidence was 4.3% for nonproliferative lesions, 6.6% for proliferative disease without atypia and 14.6% for atypical hyperplasia, compared with the expected population cumulative incidence of 2.9%.

It was concluded from this study that there is an increased breast cancer risk among women with benign breast diseases diagnosed through percutaneous biopsies. The findings from this study emphasize the importance of considering both the severity and multiplicity of benign breast disease lesions for improved breast cancer risk stratification. The authors also suggest that advancements in digital imaging and computational pathology approaches may enhance future analysis of benign breast disease biopsy specimens, for better risk prediction.

Benign Breast Disease and Breast Cancer Risk in the Percutaneous Biopsy Era. Sherman ME, Vierkant RA, Winham SJ, et al. JAMA Surg. Published online December 13, 2023. doi:10.1001/jamasurg.2023.6382

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

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SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

Sotorasib (LUMAKRAS&reg;) is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

CodeBreaK 300 trial is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively. Overall survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960-mg dose appeared to yield more clinically significant benefits than the 240-mg dose, across all efficacy endpoints, without additional toxic effects. Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

FDA Approves Two Gene Therapies to Treat Patients with Sickle Cell Disease

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SUMMARY: The FDA on December 8, 2023, approved CASGEVY® and LYFGENIA®, representing the first cell-based gene therapies for the treatment of Sickle Cell Disease in patients 12 years and older. Both products are made from the patients’ own hematopoietic stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a Hematopoietic Stem Cell Transplant. Prior to treatment, a patients’ own stem cells are collected, and then the patient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells.

Sickle Cell Disease or Sickle Cell anemia is an Autosomal Recessive disorder caused by mutations in the hemoglobin beta-globin gene, and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell Disease in the US is approximately 40-60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell Disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (Vaso-Occlusive Crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 Thalassemia (double heterozygote for HbS and b-0 Thalassemia) is clinically indistinguishable from HbSS disease. Management of Sickle Cell Disease includes pain control, transfusion support and Hydroxyurea. None of the presently available therapies addresses the underlying cause of this disease nor do they fully ameliorate disease manifestations. Allogeneic bone marrow transplantation can cure this genetic disorder, but less than 20% of eligible patients have a related HLA-matched donor. There is therefore a great unmet need to find new therapies for Sickle Cell Disease.

CASGEVY&reg: (Exagamglogene Autotemcel)
Fetal hemoglobin which consists of two alpha and two gamma chains is produced in utero, but the level of gamma-globulin decreases postnatally as the production of beta-globin and adult hemoglobin, which consists of two alpha and two beta chains, increases. It has been noted that elevated levels of fetal hemoglobin facilitates oxygen delivery, prevents the sickling of red blood cells, and is associated with decreased morbidity and mortality in patients with Sickle Cell Disease. BCL11A gene is a repressor of gamma-globin expression and fetal hemoglobin production in adult red blood cells. Downregulating BCL11A can therefore reactivate gamma-globin expression and increase fetal hemoglobin in RBC.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 nuclease gene editing technique can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. The modified hematopoietic stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin. The researchers in this study used this gene-editing technique in Hematopoietic Stem and Progenitor Cells at the erythroid-specific enhancer region of BCL11A to down-regulate BCL11A expression in erythroid-lineage cells, restore gamma-globin synthesis, and reactivate production of fetal hemoglobin. CASGEVY® is the first FDA-approved treatment to utilize CRISPR/Cas9, a type of genome editing technology, to modify patients hematopoietic stem cells.

The FDA approval of CASGEVY® is based on the ongoing single-arm, multi-center trial, involving adult and adolescent patients with Sickle Cell Disease. The trial focused on individuals with a history of at least two protocol-defined severe Vaso-Occlusive Crises (VOCs) during each of the two years prior to screening. The Primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. Out of the 44 patients treated with CASGEVY®, 31 had sufficient follow-up time to be evaluable. Remarkably, 29 of these patients, representing 93.5%, achieved the Primary efficacy outcome, which is freedom from severe VOC episodes for at least 12 consecutive months. Notably, all treated patients achieved successful engraftment, a crucial aspect confirming the efficacy of the CRISPR/Cas9 genome editing technology in modifying hematopoietic stem cells. Importantly, no instances of graft failure or rejection were reported, affirming the safety and viability of CASGEVY® as a therapeutic option. This high success rate underscores the therapeutic potential of CASGEVY® in mitigating the recurrent and debilitating crises associated with Sickle Cell Disease. The most common side effects were stomatitis, cytopenias, febrile neutropenia, nausea, vomiting, headache and itching.

LYFGENIA® (Lovotibeglogene Autotemcel)
LYFGENIA® is a cell-based gene therapy that uses a lentiviral vector as the gene delivery vehicle to add a functional gene to the hematopoietic stem cells, thereby enabling production of HbAT87Q, which is a gene therapy-derived hemoglobin, that functions similarly to hemoglobin A (normal adult hemoglobin produced in persons not affected by Sickle Cell Disease). Red blood cells containing HbAT87Q have a lower risk of sickling , resulting in VOCs. These modified stem cells are then delivered to the patient.

The safety and effectiveness of LYFGENIA® was based on the analysis of data from a single-arm, 24-month, multicenter study in patients with Sickle Cell Disease and history of Vaso Occlusive Events (VOEs). The assessment of efficacy was based on the complete resolution of VOEs between 6 and 18 months after LYFGENIA® infusion. Of the 32 patients included in the study, 88% (28 patients) achieved complete resolution of VOEs within the stipulated timeframe. The most common side effects included stomatitis, cytopenias and febrile neutropenia. Hematologic malignancy has occurred in patients treated with LYFGENIA®, and patients receiving this product should have lifelong monitoring for these malignancies.

In conclusion, the two revolutionary cell-based gene therapies with CASGEVY® and LYFGENIA® heralds a transformative era in the management of Sickle Cell Disease (SCD), for individuals aged 12 and above.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease

FDA Approves AUGTYRO® for ROS1-positive Non-Small Cell Lung Cancer

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SUMMARY: The FDA on November 15, 2023, approved AUGTYRO® (Repotrectinib) for locally advanced or metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This is the first FDA approval that includes patients with ROS1-positive NSCLC who have previously received a ROS1 Tyrosine Kinase Inhibitor (TKI), in addition to patients who are TKI naïve.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years), and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. There are currently two FDA-approved treatment options for ROS1-positive metastatic NSCLC- Crizotinib and Entrectinib.

Repotrectinib is a next-generation TKI targeting ROS1 or NTRK-positive locally advanced or metastatic solid tumors, including NSCLC. Repotrectinib was designed to improve durability of response and with favorable properties to enhance intracranial activity.

The FDA approval was based on the results of the TRIDENT-1 global, multicenter, single-arm, Phase I/II, open-label, multi-cohort clinical trial, designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib, in patients with advanced solid tumors, including locally advanced or metastatic NSCLC. Phase I component of the trial evaluated the safety and pharmacokinetics, whereas in the Phase II component of the study included six distinct expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Eligibility requirements included locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Patients with asymptomatic CNS metastases were allowed. Patients received Repotrectinib 160 mg once daily, orally for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicities. The Primary endpoint was Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR), and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and Clinical Benefit Rate (CBR). The efficacy was evaluated in ROS1 TKI-naïve patients (N=71) who received up to one prior line of platinum-based chemotherapy and/or immunotherapy, and in patients who received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (N=56).

In TKI-naïve patients with median follow-up of 24.0 months, the confirmed Objective Response Rate by BICR was 79%, median Duration of Response was 34.1 months and PFS was 35.7 months. In patients with measurable brain metastases at baseline (N=9), intracranial ORR per BICR was 89% and these responses were prolonged.

In patients who received one prior ROS1 TKI with no prior chemotherapy or immunotherapy, at a median follow-up of 21.5 months, the confirmed Objective Response Rate by BICR was 38%, median Duration of Response was 14.8 months and PFS was 9.0 months. In this subset of patients with measurable brain metastases at baseline (N=13), intracranial ORR per BICR was 38%.

The most common adverse reactions were fatigue, dizziness, dyspnea, dysgeusia, peripheral neuropathy, constipation, ataxia, cognitive disorders, and muscular weakness.

It was concluded that the TRIDENT-1 trial demonstrated the efficacy of Repotrectinib in both, TKI-naïve and previously treated patients, showcasing high response rates and durable outcomes. These data will provide physicians with valuable insights into the clinical benefits with Repotrectinib , paving the way for its potential adoption as a new standard of care, in the treatment of ROS1-positive NSCLC. TRIDENT-1 trial is ongoing to assess long term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC, and NTRK-positive advanced solid tumors.

Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: Update from the pivotal phase 1/2 TRIDENT-1 trial. Cho BC, Camidge DR, Lin JJ, et al. Presented at the IASLC 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA03.06.