Author: RR

TRUQAP® (Capivasertib)

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The FDA on November 16, 2023, approved TRUQAP® with Fulvestrant for adult patients with hormone receptor (HR)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations, as detected by an FDA-approved test, following progression on at least one endocrine-based regimen in the metastatic setting, or recurrence on or within 12 months of completing adjuvant therapy. TRUQAP® is a product of AstraZeneca Pharmaceuticals.

New ASCO Guideline Recommends Germline Testing in ALL Newly Diagnosed Breast Cancer Patients 65 Years or Younger

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

The availability of multigene panel testing and next-generation sequencing can change the landscape of cancer prevention and treatment. However, there is lack of guidance for clinicians on whom to test and/or which genes to include in germline genetic testing panels for Pathogenic Variants.

The American Society of Clinical Oncology along with the Society of Surgical Oncology on January 4, 2024 provided new clinical practice guideline for clinicians and other Health Care Providers, regarding the role of germline mutation testing in patients with breast cancer, based on the best available evidence. These recommendations were developed based on a systematic review of 47 articles that met eligibility criteria for the germline mutation testing recommendations, and 18 articles that met eligibility criteria for the genetic counseling recommendations.

The guideline addressed the following question: Which patients with breast cancer should have germline genetic testing for Pathogenic Variants (PVs) in cancer susceptibility genes?

Question 1. Should clinicians offer BRCA1/2 testing to all patients with newly diagnosed breast cancer?
Recommendation 1.1
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are 65 years or younger at diagnosis should be offered BRCA1/2 testing.
Recommendation 1.2
All patients newly diagnosed with breast cancer with Stage I-III or de novo Stage IV/metastatic disease who are older than age 65 should be offered BRCA1/2 testing if:
a) They are candidates for poly(ADP–ribose) polymerase (PARP) inhibitor therapy for early-stage or metastatic disease.
b) They have triple-negative breast cancer.
c) Their personal or family history suggests the possibility of a pathogenic variant.
d) They were assigned male sex at birth.
e) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.
Recommendation 1.3
Patients undergoing BRCA1/2 testing should also be offered testing for other cancer predisposition genes as suggested by their personal or family history. Consultation with a provider experienced in clinical cancer genetics can help guide this decision-making and should be made available to patients when possible.

Question 2. Should all people with recurrent disease, local or metastatic, or with second breast primary, be offered BRCA1/2 testing?
Recommendation 2.1
All patients with recurrent breast cancer (local or metastatic) who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing regardless of family history.
Qualifying statement.
Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in women with metastatic breast cancer and germline pathogenic variants in PALB2.
Recommendation 2.2
BRCA1/2 testing should be offered to patients with a second primary cancer either in the contralateral or ipsilateral breast.

Question 3. Should people with a personal history of breast cancer (and no active disease) be offered BRCA1/2 testing?
Recommendation 3.1
All patients with a personal history of breast cancer diagnosed 65 years or less who are without active disease should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment.
Recommendation 3.2
All patients with a personal history of breast cancer diagnosed over age 65 with no active disease, who meet one of the following criteria, should be offered BRCA1/2 testing if the result will inform personal risk management or family risk assessment:
a) Their personal or family history suggests the possibility of a pathogenic variant.
b) They were assigned male sex at birth.
c) They had triple-negative breast cancer.
d) They are of Ashkenazi Jewish ancestry or are members of a population with an increased prevalence of founder mutations.

Question 4. What is the value of testing patients with a diagnosis of breast cancer for breast cancer predisposition genes other than BRCA1/2?
Recommendation 4.1
Testing for high penetrance genes beyond BRCA1/2, including PALB2, TP53, PTEN, STK11, and CDH1, could inform medical therapy, influence surgical decision making, refine estimates of risks of second primary cancer, and inform family risk assessment, and thus should be offered to appropriate patients.
Recommendation 4.2
Testing for moderate penetrance breast cancer genes currently offers no benefits for treatment of the index breast cancer but may inform risks of second primary cancer or family risk assessment, and thus may be offered to appropriate patients who are undergoing BRCA1/2 testing.
Recommendation 4.3
If a multi-gene panel is ordered, the specific panel chosen should take into account the patients personal and family history. Consultation with a provider experienced in clinical cancer genetics can be helpful in selecting a specific multi-gene panel or interpreting its results and should be made available to patients when possible.

Question 5. How should patients with breast cancer considering genetic testing be counseled?
Recommendation 5.1
Patients undergoing genetic testing should be given sufficient information before testing to provide informed consent.
Recommendation 5.2
Patients with pathogenic variants should be provided with individualized post-test genetic counseling and offered referral to a provider experienced in clinical cancer genetics.
Recommendation 5.3
Variants of uncertain significance should not alter management. Patients should be made aware that variants of uncertain significance may be reclassified as being pathogenic, and they should understand that periodic follow up is necessary. Consultation with a provider experienced in clinical cancer genetics can be helpful and should be made available to patients when possible.
Recommendation 5.4
Patients without a pathogenic variant on genetic testing may still benefit from counseling, if there is a significant family history of cancer, and referral to a provider experienced in clinical cancer genetics is recommended.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline. Bedrosian I, MD , Somerfield MR, PhD, Achatz MI, et al. Journal of Clinical Oncology January 04, 2024. https://doi.org/10.1200/JCO.23.02225.

Late Breaking Abstract – ASH 2023: Oral Ibrutinib-Venetoclax Combination Improved Outcomes in Mantle Cell Lymphoma

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SUMMARY: It is estimated that approximately 3,300 new cases of Mantle Cell Lymphoma (MCL) are diagnosed in the US each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. The four BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, BRUKINSA® (Zanubrutinib) approved in 2019 and JAYPIRCA® (Pirtobrutinib) approved in 2023.

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. Single agent Ibrutinib is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. Venetoclax (VENCLEXTA®) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. By virtue of their unique and complementary mechanism of action, Ibrutinib in combination with Venetoclax demonstrated promising clinical activity in early phase MCL studies (N Engl J Med 2018; 378:1211-1223).

The Sympatico trial, is a multinational, randomized, double-blind, phase III study conducted to compare the combination of Ibrutinib and Venetoclax with Ibrutinib plus placebo, in patients with relapsed or refractory Mantle Cell Lymphoma (MCL). In this study, a total of 267 adult patients (N=267) with relapsed or refractory MCL who had previously received at least one prior line of therapy were randomly assigned in a 1:1 ratio to receive Ibrutinib 560 mg orally once daily concurrently with, either oral Venetoclax given at a standard 5-week ramp-up dose to a target dose of 400 mg once daily (N=134), or Placebo (N=133) for 2 years, followed by single-agent Ibrutinib until progressive disease (PD) or unacceptable toxicity. The median age was 68 years, 96% of patients had an ECOG PS of 0-1, 17% had 3 or more prior lines of therapy, and 22% were at increased risk for Tumor Lysis Syndrome (TLS). Both treatment groups were well balanced, and randomization was stratified based on ECOG PS, prior lines of therapy, and TLS risk based on tumor burden and Creatinine Clearance. The study evaluated the efficacy of the combination therapy across various subgroups, including those with high-risk features such as blastoid variant or TP53-mutated MCL. The Primary endpoint was investigator assessed Progression Free Survival (PFS) using Lugano criteria, and key Secondary endpoints included Complete Response (CR) rate, Time To Next Treatment (TTNT), Overall Survival (OS), and Overall Response Rate (ORR) by investigator assessment.

With a median follow up of 51.2 months, the median PFS was significantly longer with the Ibrutinib-Venetoclax combination, compared with the Placebo group (31.9 months versus 22.1 months; HR=0.65; P=0.0052). These PFS benefits were consistent across patient subgroups, including those with blastoid-variant or TP53-mutated MCL. In the combination group, 54% of patients achieved a Complete Remission, compared to 32% in the Placebo group (P=0.0004). The Time to Next Treatment in the combination group was median Not Reached (NR) versus 35.4 months in the Placebo group. At the time of this primary analysis, the median OS was 44.9 months with the Ibrutinib-Venetoclax combination versus 38.6 months with Ibrutinib plus Placebo, but the difference was not statistically significant. Adverse events were more common among patients who received the combination therapy, and included cytopenias and pneumonia.

It was concluded that a combination of Ibrutinib and Venetoclax was synergistic and demonstrated efficacy and safety, for the treatment of relapsed or refractory Mantle Cell Lymphoma, providing a potential new standard of care for this patient population. This chemo-free treatment option represents a milestone achievement in Mantle Cell Lymphoma treatment.

Ibrutinib Combined with Venetoclax in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis Results from the Randomized Phase 3 Sympatico Study. Wang M, Jurczak W, Trněný M, et al. Presented at the 2023 ASH Annual Meeting & Exposition December 9-12, 2023. LBA-2.

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.