Category: Hem/Onc Updates

TAILORx Long Term Update for Patients with Early Stage Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. 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.

Approximately 50% of all breast cancers are Estrogen Receptor (ER) positive, HER2-negative, axillary node-negative tumors. Patients with early-stage breast cancer often receive adjuvant chemotherapy. The Oncotype DX breast cancer assay, is a multigene genomic test that analyzes the activity of a group of 21 genes and is able to predict the risk of breast cancer recurrence and likelihood of benefit from systemic chemotherapy, following surgery, in women with early-stage breast cancer. Chemotherapy recommendations for Hormone Receptor positive, HER negative, early-stage breast cancer patients, are often made based on tumor size, grade, ImmunoHistoChemical (IHC) markers such as Ki-67, nodal status and Oncotype DX Recurrence Score (RS) assay. Oncotype Dx assay categorizes patients based on Recurrence Scores into Low risk (0-10), Intermediate risk (11-25), and High risk (26-100). It has been unclear whether patients in the Intermediate risk group benefited from the addition of chemotherapy to endocrine therapy. TAILORx was specifically designed to address this question and provide a very definitive answer.

TAILORx ((Trial Assigning Individualized Options for Treatment) is a phase III, randomized, prospective, non-inferiority trial, and is the largest breast cancer treatment trial ever conducted, and the first precision medicine trial ever done, according to the authors. In this study, 10,273 women, 18-75 years of age, with hormone receptor-positive, HER2-negative, T1b-T2N0 early-stage axillary node-negative breast cancer were enrolled. Patients had tumors 1.1-5.0 cm in size (or 0.6-1.0 cm and intermediate/high grade). Patients were divided into three groups based on their Recurrence Score. Women with a Low Recurrence Score of 0-10 received endocrine therapy alone and those with a High Recurrence Score of 26-100 received endocrine therapy in combination with standard adjuvant chemotherapy. Patient with Intermediate Recurrence Score of 11-25 (N=6711) were randomly assigned to receive endocrine therapy alone (N=3399) or endocrine therapy and adjuvant chemotherapy (N=3312). The Primary endpoint was invasive Disease-Free Survival, defined as recurrence of cancer in the breast, regional lymph nodes, and/or distant organs, a second primary cancer in the opposite breast or another organ, or death from any cause. The researchers conducted an updated analysis, in which patients were followed for an additional 3.5 years, for an average of 11 years. The Primary endpoint in the updated analysis was invasive Disease-Free Survival (DFS) at a median follow-up of 11.0 years in the randomized population and 10.4 years in the overall population.

The previous TAILORx study conclusions remain unchanged. Among patients with a Recurrence Score of 11-25, endocrine therapy alone was non-inferior to chemotherapy plus endocrine therapy. The 5-year invasive DFS with endocrine therapy alone was 92.8% versus 93.1% with chemotherapy plus endocrine (HR=1.08; P=0.26). The 12-year invasive DFS with endocrine therapy alone was 76.8% versus 77.4% with chemotherapy plus endocrine therapy (HR =1.08). Although among those patients with a Recurrence Score of 0-25, less than 10% of patients had disease recurrence by 12 years, late recurrence events beyond 5 years exceeded earlier recurrence, regardless of treatment. There was also a higher risk of early recurrence in Black women.

It was concluded that with longer follow-up, the main TAILORx study findings remain unchanged, and clinicians should continue to use the 21-gene recurrence score results to guide decisions about the use of chemotherapy.

Trial Assigning Individualized Options for Treatment (TAILORx): An update including 12-year event rates. Sparano J, Gray RJ, Makower D, et al. Presented at SABCS 2022. December 6-10, 2022. Abstract GS1-05.

Sequential Conditioning and Allogeneic Hematopoietic Cell Transplantation WITHOUT Prior Remission-Induction Chemotherapy in AML

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SUMMARY: The American Cancer Society estimates that for 2023, about 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 can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. 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.

Cytotoxic chemotherapy for AML often consists of induction therapy to achieve remission, followed by consolidation therapy. However, standard induction chemotherapy achieves Complete Remission in only 40-60% of AML patients older than 60 years of age, and majority of these patients will eventually relapse. This had been attributed to clonal evolution and epigenetic reprogramming, leading to aberrant DNA methylation, and persistence of leukemia-initiating cells. Patients with AML who are under age 55 with high-risk cytogenetics in first clinical remission, are considered for allogeneic Hematopoietic Cell Transplantation, as this has shown to offer survival advantage over conventional chemotherapy. Patients receive salvage chemotherapy, targeted therapy for FLT3-mutant and susceptible IDH mutant AML, or treatment with a BCL2 inhibitor and hypomethylating agent, if a donor is not readily available and a prolonged donor search is needed.

ASAP is a randomized Phase III trial, conducted in patients with an unfavorable risk AML who either had a poor response to first induction therapy or had a relapse after first induction therapy. This study enrolled AML patients with poor response after first induction therapy or relapsed AML, who were eligible for intensive chemotherapy and allogeneic Hematopoietic Cell Transplantation with either a matched sibling donor, an HLA-compatible (9 or more/10) unrelated donor, or ongoing donor search with two potential unrelated donors with 90% or more HLA-matching probability. This analysis included 276 patients, of whom 272 patients were treated per protocol. Patients were randomized 1:1 to a Remission Induction arm in which patients received Cytarabine 3 g/m2 IV (1 g/m2 for patients more than 60 years) twice daily on days 1-3 plus Mitoxantrone 10 mg/m2 IV on days 3-5 and subsequent allogeneic Hematopoietic Cell Transplantation (Remission Induction Strategy arm-N=134) or to Disease Control arm (DISC arm-N=138) prior to sequential conditioning and allogeneic Hematopoietic Cell Transplantation. Disease Control Strategy consisted primarily of watchful waiting, but low-dose Cytarabine and single doses of mitoxantrone were permitted for disease-control. The median age was 61 years and at randomization, 39 patients had matched sibling donor, 133 patients had an HLA-compatible unrelated donor with confirmed HLA-typing, and 104 patients had ongoing unrelated donor searches. The Primary endpoint was Disease Free Survival (DFS), defined as Complete Remission at day 56 after allogeneic Hematopoietic Cell Transplantation, although the statistical goal of the study was to show non-inferiority of the Disease Control arm. Major secondary endpoints included Overall Survival (OS) from randomization and Leukemia-Free Survival from Complete Remission at day 56. The median time to allogeneic Hematopoietic Cell Transplantation was 8 weeks in the Remission Induction Strategy arm and 4 weeks in the Disease Control arm. At 24 weeks from randomization 96% and 94% of patients had been transplanted in the Remission Induction Strategy arm and Disease Control arm, respectively.

The Primary endpoint was met with the Disease Control arm, which is the less intensive treatment strategy, meeting the Primary endpoint of DFS/Complete Remission at day 56 after allogeneic Hematopoietic Cell Transplantation. The Disease-Free Survival at day 56 was 81.3% in the Remission Induction Strategy arm and 84.1% in the Disease Control arm (P for noninferiority=0.047). Among patients who met the Primary endpoint, after a median follow-up from randomization of 37 months, there was no significant difference in the Leukemia-Free Survival or Overall Survival from day 56, in the Remission Induction Strategy arm and Disease Control arm. The Disease Control Strategy was also associated with significantly fewer Grade 3 or more adverse events, compared to the Remission Induction Strategy (23% versus 64%, P<0.001), and fewer mean number of days in hospital prior to transplant (19 versus 42 days, P<0.001).

The researchers concluded from this first randomized controlled trial that intensive remission induction chemotherapy prior to allogeneic Hematopoietic Cell Transplantation for patients with Relapsed/Refractory AML DID NOT result in a higher overall success rate and did not confer a survival advantage. It was noted that watchful waiting followed by sequential conditioning and allogeneic Hematopoietic Cell Transplantation resulted in comparable overall Complete Remission rates and survival. The researchers added that the data from this study support sequential conditioning and Hematopoietic Cell Transplantation, without prior remission-induction chemotherapy, whenever a donor is readily available. Further, the results of this study emphasize the importance of allogeneic Hematopoietic Cell Transplantation in patients with Relapsed/Refractory AML and stress the need for starting donor search at diagnosis.

In Patients with Relapsed/Refractory AML Sequential Conditioning and Immediate Allogeneic Stem Cell Transplantation (allo-HCT) Results in Similar Overall and Leukemia-Free Survival Compared to Intensive Remission Induction Chemotherapy Followed By Allo-HCT: Results from the Randomized Phase III ASAP Trial. Stelljes M, Middeke JM, Bug G, et al. 64th ASH Annual Meeting and Exposition December 10th-13,2022. Abstract#4.

FDA Approves First Gene Therapy for Bladder Cancer

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SUMMARY: The FDA on December 16, 2022, approved ADSTILADRIN® (Nadofaragene firadenovec-vncg) for adult patients with high-risk Bacillus Calmette-Guérin (BCG) unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS) with or without papillary tumors. According to the American Cancer Society, 81,180 new cases of bladder cancer were diagnosed in 2022 and 17,100 died of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. The current standard intervention for superficial bladder cancers-Non-Muscle Invasive Bladder Cancer (NMIBC) involves removing the bladder tumor and intravesical treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, for patients with high-risk Non-Muscle Invasive Bladder Cancer, including those with Carcinoma in Situ, High Grade T1, or large-volume or recurrent Ta tumors, to reduce the risk of recurrence. Although 80% of patients have an initial complete response to BCG, more than half of patients have recurrence and progression within the first year, and develop resistance to BCG. These patients are often given the treatment option of radical cystectomy, which includes removing the entire urinary bladder and a prostatectomy for men or total hysterectomy in women. While highly curative, this surgical procedure carries substantial risk for morbidity and mortality, and can negatively impact patient’s quality of life. Further, a significant proportion of patients are medically ineligible for a radical cystectomy, and even if eligible, refuse surgery and opt for other less effective treatments, which could compromise outcomes. The development of a safe, effective and durable intravesical treatment remains a critical unmet need for patients who want to avoid radical cystectomy or systemic immunotherapy.

ADSTILADRIN® (Nadofaragene firadenovec-vncg) is a nonreplicating recombinant adenovirus vector-based gene therapy, that delivers a copy of the human Interferon alfa-2b gene to the patient’s bladder urothelial cells. This novel gene therapy approach provides a longer duration of exposure of the urothelium to Interferon alfa-2b, by allowing the urothelial cells to produce Interferon on an ongoing basis. The safety and efficacy of intravesical ADSTILADRIN® for patients with BCG-refractory and relapsing non-muscle-invasive bladder cancer, was demonstrated in Phase I and Phase II clinical trials. The present study was conducted to evaluate the efficacy and safety of intravesical ADSTILADRIN® in a larger population of patients with BCG-unresponsive Non-Muscle Invasive Bladder Cancer.

This Phase III multicenter, open-label, single-arm trial enrolled 157 patients with high-risk Non-Muscle Invasive Bladder Cancer, 98 of whom had BCG-unresponsive Carcinoma in Situ, evaluable for response. A single-arm design was adopted as there is no standard treatment for this patient population. BCG-unresponsive high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) was defined as persistent disease despite adequate BCG therapy, disease recurrence after an initial tumor-free state following adequate BCG therapy, or T1 disease following BCG. Patients received ADSTILADRIN® 75 mL intravesical instillation (3 x 1011 viral particles/mL) once every three months up to 12 months, unacceptable toxicity, or recurrent high-grade NMIBC. Patients without high-grade recurrence were allowed to continue ADSTILADRIN® every three months. The major efficacy outcome measures were Complete Response (CR) at any time and Duration of Response (DoR). CR was defined as negative cystoscopy with applicable TransUrethral Resection of Bladder Tumor (TURBT) and biopsies, and urine cytology. Random bladder biopsies of five sites were conducted in patients remaining in CR at 12 months.

The Complete Response Rate was 51%, the median Duration of Response was 9.7 months and 46% of responding patients remained in Complete Response for at least one year. The most common grade 3 adverse reaction was micturition urgency (1%). Most of patients experienced Grade 1 Adverse Events which included mild fatigue and bladder spasms. The most common Grade 3 toxicity was urinary urgency noted in 1% of patients.

This study has demonstrated that Intravesical delivery of the adenoviral vector containing the human recombinant Interferon alfa-2b gene was associated with promising efficacy outcomes, with an acceptable safety profile. ADSTILADRIN® is a novel treatment option and alternative to chemotherapy and systemic therapies and is the first FDA-approved gene therapy for bladder cancer.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-first-adenoviral-vector-based-gene-therapy-high-risk-bacillus-calmette-guerin

FDA Approves Bispecific Antibody LUNSUMIO® for Follicular Lymphoma

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SUMMARY: The FDA on December 22, 2022, granted accelerated approval to LUNSUMIO® (Mosunetuzumab-axgb), a bispecific CD20-directed CD3 T-cell engager for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after two or more lines of systemic therapy.

The American Cancer Society estimates that in 2022, about 80,470 people were diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals died of this disease. Indolent Non Hodgkin Lymphomas are mature B cell lymphoproliferative disorders and include Follicular Lymphoma, Nodal Marginal Zone Lymphoma (NMZL), Extranodal Marginal Zone Lymphoma (ENMZL) of Mucosa-Associated Lymphoid Tissue (MALT), Splenic Marginal Zone Lymphoma (SMZL), LymphoPlasmacytic Lymphoma (LPL) and Small Lymphocytic Lymphoma (SLL). Follicular Lymphoma is the most indolent form and second most common form of all NHLs and they are a heterogeneous group of lymphoproliferative malignancies. Approximately 22% of all NHLs are Follicular Lymphomas (FL).

Advanced stage indolent NHL is not curable and as such, prolonging Progression Free Survival (PFS) and Overall Survival (OS), while maintaining Quality of Life, have been the goals of treatment intervention. Asymptomatic patients with indolent NHL are generally considered candidates for “watch and wait” approach. Patients with advanced stage symptomatic Follicular Lymphoma are often treated with induction chemoimmunotherapy followed by maintenance RITUXAN® (Rituximab). This can result in a median Progression Free Survival of 6-8 years. However, approximately 30% of the patients will relapse in 3 years, and treatment options are limited for patients with relapses after multiple treatments. Patients with Follicular Lymphomas often experience a relapsing and remitting pattern of disease and may be exposed to multiple lines of therapy over the course of their disease. In spite of the availability of multiple systemic therapies for Follicular Lymphoma, the efficacy of these regimens drops off rapidly with later lines of therapy. Novel therapies are therefore being investigated to improve outcomes.

LUNSUMIO® is a first-in-class CD20 x CD3 T-cell engaging bispecific antibody designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells.

This FDA approval was based on the positive results from the Phase II GO29781 study, which is a multicenter, open-label, dose-escalation and dose-expansion trial evaluating the safety, efficacy, and pharmacokinetics of LUNSUMIO® in patients with heavily pretreated Follicular Lymphoma, including those who were at high risk of disease progression or whose disease was refractory to prior therapies. The efficacy population consisted of 90 enrolled patients with Relapsed or Refractory FL (Grade 1-3a) who had received at least two prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

LUNSUMIO® was administered IV in 21-day cycles with Cycle 1 step-up dosing of 1 mg on Cycle 1, Day 1, 2 mg on Cycle 1 Day 8, 60 mg on Cycle 1 Day 15, 60 mg on Cycle 2 Day 1, and 30 mg on Day 1 in subsequent cycles. Patients with a Complete Response discontinued therapy after 8 cycles. Patients with a Partial Response or Stable disease continued treatment for up to 17 cycles unless they experienced progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (ORR) assessed by an Independent Review Committee according to standard criteria for Non-Hodgkins Lymphoma.

The ORR was seen in 80% of patients treated with LUNSUMIO® with 60% achieving Complete Responses. A majority of patients (57%) maintained responses for at least 18 months. With a median follow up of 14.9 months among responders, the estimated median Duration of Response was 22.8 months and the estimated Duration of Response at 12 months and 18 months was 62% and 57%, respectively. Among 218 patients with hematologic malignancies who received LUNSUMIO® at the recommended dose, the most common Adverse Event was Cytokine Release Syndrome (CRS) seen in 39% of patients, which can be severe and life-threatening. The median duration of CRS events was 3 days. Other common Adverse Events included fatigue, rash, fever and headache.

It was concluded from this study that in patients with heavily pretreated Follicular Lymphoma, chemotherapy-free, fixed-duration treatment with LUNSUMIO® induced high rates of Complete Remissions with favorable safety profile, allowing potential administration as an outpatient regimen.

Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Budde LE, Sehn LH, Matasar M, et al. The Lancet Oncology 2022; 23:1055-1065.

Neoadjuvant Chemotherapy, Endocrine Therapy and Targeted Therapy for Breast Cancer: ASCO Updated Guideline

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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 290,560 new cases of breast cancer were diagnosed in 2022 and about 43,780 individuals died of the disease, largely due to metastatic recurrence.

Adjuvant or postoperative systemic therapy is the mainstay of treatment for early-stage breast cancer, to eradicate micrometastatic disease and reduce the likelihood of metastatic disease. Neoadjuvant refers to the use of systemic therapy prior to surgery. Neoadjuvant therapy was initially used in breast cancer for the treatment of inoperable, locally advanced disease. Subsequently, multiple studies of both chemotherapy and endocrine therapy have shown that neoadjuvant treatment can increase the likelihood of breast-conserving surgery, reduce the extent and morbidity of curative surgery, establishing neoadjuvant treatment as a viable option in patients with operable disease. Further, interest in neoadjuvant therapy has focused on examining the role of response to neoadjuvant treatment as a predictive marker for benefit in long term outcomes.

ASCO convened an Expert Panel to conduct a systematic review of the literature on neoadjuvant therapy for breast cancer and the purpose of this guideline is to develop recommendations concerning the optimal use of systemic neoadjuvant therapy, including chemotherapy, endocrine therapy, and targeted therapy for patients with invasive breast cancer.

Guideline Question
What is the optimal use of neoadjuvant therapy for women with invasive, nonmetastatic breast cancer?

CLINICAL QUESTION 1
Which patients with breast cancer are appropriate candidates for neoadjuvant systemic therapy?

Recommendation 1.1.
Neoadjuvant chemotherapy is the treatment of choice for patients with inflammatory breast cancer or those with unresectable or locally advanced disease at presentation whose disease may be rendered resectable with neoadjuvant treatment
Recommendation 1.2.
Tumor histology, grade, stage and estrogen, progesterone, and HER2 expression should routinely be used to guide clinical decisions as to whether or not to pursue neoadjuvant chemotherapy. There is insufficient evidence to support the use of other immunochemical markers, morphological markers (eg, tumor-infiltrating lymphocytes) or genomic profiles to guide a clinical decision as to whether or not to pursue neoadjuvant chemotherapy
Recommendation 1.3.
Neoadjuvant systemic therapy should be offered to patients with high-risk HER2-positive or triple-negative breast cancer (TNBC) in whom the finding of residual disease would guide recommendations related to adjuvant therapy
Recommendation 1.4.
Neoadjuvant systemic therapy may be offered to reduce the extent of surgery (breast-conserving surgery and axillary lymph node dissection). Chemotherapy with or without targeted therapy, or endocrine therapy (if hormone receptor–positive [HR-positive]) may be offered
Recommendation 1.5.
In patients for whom a delay in surgery is preferable (eg, for genetic testing required for surgical treatment decision making, to allow time to consider reconstructive options) or unavoidable, neoadjuvant systemic therapy may be offered

CLINICAL QUESTION 2
How should response be measured in patients receiving neoadjuvant chemotherapy?

Recommendation 2.1.
Patients receiving neoadjuvant therapy should be monitored for response with clinical examination at regular intervals. Breast imaging may be used to confirm clinical suspicion of progression and for surgical planning. When imaging is used, the modality that was most informative at baseline-mammography, ultrasound, or magnetic resonance imaging—should be used at follow-up
Recommendation 2.2.
Blood- and tissue-based biomarkers should not be used for monitoring patients receiving neoadjuvant therapy
Recommendation 2.3.
Pathologic complete response (pCR), defined as absence of invasive disease in breast and lymph nodes, should be used to measure response to guide clinical decision making

CLINICAL QUESTION 3
What neoadjuvant treatment is recommended for patients with HR-positive/HER2-negative breast cancer?

Recommendation 3.1.
Neoadjuvant chemotherapy can be used instead of adjuvant chemotherapy in any patient with HR-positive, HER2-negative breast cancer in whom the chemotherapy decision can be made without surgical pathology data and/or tumor-specific genomic testing
Recommendation 3.2.
For postmenopausal patients with HR-positive/HER2-negative disease, neoadjuvant endocrine therapy with an aromatase inhibitor may be offered to increase locoregional treatment options. If there is no intent for surgery, endocrine therapy may be used for disease control
Recommendation 3.3.
For premenopausal patients with HR-positive/HER2-negative early-stage disease, neoadjuvant endocrine therapy should not be routinely offered outside of a clinical trial (Type: evidence-based; benefits outweigh harms; Evidence quality: intermediate; Strength of recommendation: moderate).

CLINICAL QUESTION 4
What neoadjuvant treatment is recommended for patients with HER2-positive disease?

Recommendation 4.1.
Patients with node-positive or high-risk node-negative, HER2-positive disease should be offered neoadjuvant therapy with an anthracycline and taxane or non–anthracycline-based regimen in combination with trastuzumab. Pertuzumab may be used with trastuzumab in the neoadjuvant setting
Recommendation 4.2.
Patients with T1a N0 and T1b N0, HER2-positive disease should not be routinely offered neoadjuvant chemotherapy or anti-HER2 agents outside of a clinical trial

CLINICAL QUESTION 5
What neoadjuvant systemic therapy regimens are recommended for patients with TNBC?

Recommendation 5.1.
Patients with TNBC who have clinically node-positive and/or at least T1c disease should be offered an anthracycline and taxane-containing regimen in the neoadjuvant setting
Recommendation 5.2.
Patients with cT1a or cT1bN0 TNBC should not routinely be offered neoadjuvant therapy outside of a clinical trial
Recommendation 5.3.
Carboplatin may be offered as part of a neoadjuvant regimen in patients with TNBC to increase likelihood of pCR. The decision to offer carboplatin should take into account the balance of potential benefits and harms
Recommendation 5.4. (UPDATED ASCO RECOMMENDATION FROM 2022: GUIDELINE RAPID RECOMMENDATION UPDATE)
For patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage TNBC, the Panel recommends use of pembrolizumab (200 mg once every 3 weeks or 400 mg once every 6 weeks) in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery. Adjuvant pembrolizumab may be given either concurrent with or after completion of radiation therapy. Given that irAEs associated with pembrolizumab therapy can be severe and permanent, careful screening for and management of common toxicities are required.

The guideline panel addressed some of the questions that clinicians may encounter as they incorporate these recommendations into clinical practice.

QUESTION: SHOULD PEMBROLIZUMAB BE CONTINUED IN PATIENTS WHO ACHIEVE pCR AFTER NEOADJUVANT CHEMOTHERAPY PLUS PEMBROLIZUMAB?
The panel supports continuation of pembrolizumab in the adjuvant setting in all patients while awaiting data from other trials addressing this question.

QUESTION: CAN A CHEMOTHERAPY REGIMEN DIFFERENT FROM THE ONE USED IN KEYNOTE-522 BE USED WITH PEMBROLIZUMAB?
The panel supports the use of the full KEYNOTE-522 regimen. However, if a patient experiences toxicity, it is not unreasonable to dose reduce or discontinue the drug. In patients with TNBC who have contraindications to anthracycline therapy and are being considered for regimens such as docetaxel and cyclophosphamide, it would be reasonable to add pembrolizumab to their regimen.

QUESTION: SHOULD ADJUVANT CAPECITABINE BE ADMINISTERED WITH PEMBROLIZUMAB IN PATIENTS WHO FAIL TO ACHIEVE pCR WITH PEMBROLIZUMAB-BASED NEOADJUVANT THERAPY?
Patients with TNBC who have residual disease after neoadjuvant chemotherapy are currently offered adjuvant capecitabine chemotherapy on the basis of improved survival shown in CREATE-X trial. It is reasonable to administer capecitabine concurrently or sequentially in patients at high risk of recurrence although the long-term safety of this combination is not known.

QUESTION: SHOULD OLAPARIB BE ADDED TO PEMBROLIZUMAB FOR gBRCA1m AND/OR gBRCA2m CARRIERS WITH TNBC WHO HAVE RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY?
Patients with TNBC are more likely to harbor a gBRCA1m and/or gBRCA2m, and such mutations have been reported in about 15% of patients with TNBC. The use of adjuvant pembrolizumab and olaparib concurrently or sequentially can be considered for eligible patients. The relative risks and benefits of a concurrent approach should be weighed, as the long-term safety of these combinations is not known.

QUESTION: SHOULD OTHER CHECKPOINT INHIBITORS BE USED IN THE NEOADJUVANT SETTING INSTEAD OF PEMBROLIZUMAB?
As only pembrolizumab has received regulatory approval, the panel does not recommend use of alternate immunotherapeutic agents.

QUESTION: SHOULD ADJUVANT PEMBROLIZUMAB BE USED IN PATIENTS WITH RESIDUAL DISEASE AFTER NEOADJUVANT CHEMOTHERAPY WITHOUT PEMBROLIZUMAB?
There are currently no data to support adjuvant pembrolizumab use in patients who did not receive neoadjuvant pembrolizumab.

In summary, addition of pembrolizumab to chemotherapy in the neoadjuvant setting followed by continuation in the adjuvant setting is the new standard of care for patients with high-risk TNBC as defined in KEYNOTE-522.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer Guideline Expert Panel. Use of Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of High-risk, Early-stage Triple Negative Breast Cancer: ASCO Guideline Rapid Recommendation Update. Korde LA, Somerfield MR, Hershman DL, et al. J Clin Oncol. 2022;40:1696-1698.

Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. Korde LA, Somerfield MR, Carey LA, et al. DOI: 10.1200/JCO.20.03399 Journal of Clinical Oncology 39, no. 13 (May 01, 2021) 1485-1505.

Tumor-Infiltrating Lymphocyte Therapy in Advanced Refractory Melanoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 99,780 new cases of melanoma of the skin were diagnosed in the United States and 7,650 people died of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. They are therefore frequently used first-line treatment in patients with metastatic melanoma.

Over 50% of untreated patients receiving a combination of PD-1 and CTLA-4 inhibitors are alive after five years. However, combination immunotherapy with YERVOY® and OPDIVO® is associated with a high incidence of severe adverse events and is currently recommended primarily for a subgroup of patients with poor prognostic factors such as a high serum LDH levels or liver or brain metastases. Approximately 50% of melanomas harbor BRAF V600E mutation and are often treated with a combination of BRAF and MEK inhibitors. This combination is associated with a high response, but resistance develops in most patients over time. YERVOY® is presently often used as second line therapy, but only 15-30% of patients benefit from this intervention. There is an unmet need for this group of patients.

Adoptive immunotherapy, also known as cellular immunotherapy, is a form of treatment in which naturally occurring or gene-engineered T cells with antitumor activity are transferred to a tumor-bearing host to eliminate cancer. These killer T cells bind to antigens on the surface of cancer cells and destroy them. Cellular immunotherapies include Tumor-Infiltrating Lymphocyte (TIL) Therapy, Engineered T Cell Receptor (TCR) Therapy, Chimeric Antigen Receptor (CAR) T Cell Therapy and Natural Killer (NK) Cell Therapy.

Adoptive immunotherapy with Tumor-Infiltrating Lymphocytes (TILs) is a personalized autologous therapy in which lymphocytes which have infiltrated the tumor are expanded in vitro and administered intravenously following nonmyeloablative, lymphodepleting chemotherapy, and supported by the IV administration of Interleukin-2 (IL-2) to enhance the in vivo expansion of the cells and augment antitumor responses. In contrast to Lymphokine-Activated Killer cells (LAK), human TILs demonstrate cytolytic specificity against only the tumor from which they were derived or against closely related tumors, and in preclinical models have proved to be 50 to 100 times more potent than LAK cells. Evidence of clinical activity of TIL therapy in patients with advanced melanoma was initially reported by Rosenberg and colleagues in the 1990s and subsequent Phase 1-2 trials showed responses in 30-70% of patients, with responses noted even among those who had disease progression while receiving anti-PD1 treatment. Nonetheless, there has been no direct comparison of TILs with standard treatment.

This multicenter, open-label, Phase III, randomized trial was conducted to compared TILs with Yervoy® as first or second-line treatment in patients with advanced melanoma. In this study, a total of 168 patients with unresectable Stage IIIC or IV melanoma were randomly assigned in a 1:1 ratio to receive either TILs (N=84) or YERVOY® (N=84). Patients assigned to receive TILs underwent metastasectomy for the retrieval and expansion of TILs, followed by inpatient administration of nonmyeloablative, lymphodepleting chemotherapy, which consisted of Cyclophosphamide 60 mg/kg IV QD for 2 days and Fludarabine 25 mg/m2 IV QD for 5 days, single adoptive transfer of 5×109 to 2×1011 TILs intravenously, and subsequent high-dose IL-2, 600,000 IU/kg IV every 8 hours, for a maximum of 15 doses. Patients in the YERVOY® group received 3 mg/kg IV every 3 weeks, for a maximum of 4 doses. Administration of YERVOY® could be delayed or discontinued if adverse events occurred, and no dose reductions were allowed. Both treatment groups were well balanced and 86% of patients were refractory to PD-1 inhibitor therapy, mostly adjuvant or first line therapy. The median patient age was 59 years and patients were stratified according to BRAF V600-mutation status, line of treatment, and treatment center. The Primary end point was Progression Free Survival (PFS). Secondary end points included Objective Response Rate (ORR), Complete Response (CR), Overall Survival (OS), Health-Related Quality of Life and Safety.The median follow-up was 33.0 months.

The median PFS was 7.2 months in the TIL group and 3.1 months in the YERVOY® group (HR=0.50;P<0.001).The Objective Response Rate was 49% in the TIL group and 21% in the YERVOY® group, with a Complete Response rate of 20% in the TIL group and 7% in the YERVOY® group, with durable Complete Responses in both treatment groups. The median Overall Survival was 25.8 months in the TIL group and 18.9 months in the YERVOY® group(HR=0.83). The 2-year OS was 54.3% in the TIL group and 44.1% in the YERVOY® group. Treatment-related adverse events of Grade 3 or higher occurred in all patients in the TIL group and in 57% of those in the YERVOY® group, and these events were mainly chemotherapy-related myelosuppression. Treatment-related serious adverse events occurred in 15% of the patients in the TIL group and 27% of those in the YERVOY® group.

It was concluded that in patients with advanced melanoma including those patients refractory to PD-1 inhibitor therapy, treatment with TILs was associated with significantly longer Progression Free Survival than treatment with YERVOY®.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. Rohaan MW, Borch TH, Van den Berg JH, et al. N Engl J Med 2022; 387:2113-2125

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update

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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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.

Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on  a systematic review of evidence published from January 2016 to October 2021, of 24 Phase III randomized clinical trials (RCTs), prospective-retrospective studies, and clinical experience. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Three important questions were addressed by this guideline update

  1. For patients with early-stage ER-positive, HER2-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy for a newly diagnosed cancer or in the extended setting?
  2. For patients with early-stage HER2-positive breast cancer, which biomarkers should be used to guide decisions on adjuvant endocrine and chemotherapy?
  3. For patients with early-stage triple-negative breast cancer, which biomarkers should be used to guide decisions on adjuvant chemotherapy?

 Newly Diagnosed ER-Positive, HER2-Negative Breast Cancer

Oncotype DX (21-gene recurrence score, 21-gene RS).

Recommendation 1.1. If a patient has node-negative breast cancer, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.2. In the group of patients in Recommendation 1.1 with Oncotype DX recurrence score ≥ 26, the clinician should offer chemoendocrine therapy

Recommendation 1.3. In the group of patients in Recommendation 1.1 who are 50 years of age or younger with Oncotype DX recurrence score 16 to 25, the clinician may offer chemoendocrine therapy

Recommendation 1.4. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the clinician may use the Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.5. In the group of patients in Recommendation 1.4, the clinician should offer chemoendocrine therapy for those whose Oncotype DX recurrence score is ≥ 26

Recommendation 1.6. If a patient is premenopausal and has node-positive breast cancer with 1-3 positive nodes, the Oncotype DX test should not be offered to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.7. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine Oncotype DX test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

MammaPrint (70-gene signature).

Recommendation 1.8. If a patient is older than 50 and has high clinical risk breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.9. If a patient is 50 years of age or younger and has high clinical risk, node-negative or node-positive with 1-3 positive nodes breast cancer, the clinician should not use the MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.10. If a patient has low clinical risk, regardless of age, the evidence on clinical utility of routine MammaPrint test is insufficient to recommend its use

Recommendation 1.11. If a patient has node-positive breast cancer with ≥ 4 positive nodes, the evidence on the clinical utility of routine MammaPrint test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Qualifying statement: The genomic assay is prognostic and may be used for shared patient-physician treatment decision making.

EndoPredict (12-gene risk score).

Recommendation 1.12. If a patient is postmenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician may use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.13. If a patient is premenopausal and has breast cancer that is node-negative or node-positive with 1-3 positive nodes, the clinician should not use the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.14. If a patient has breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the EndoPredict test to guide decisions for adjuvant endocrine and chemotherapy is insufficient

Prosigna (PAM50).

Recommendation 1.15. If a patient is postmenopausal and has breast cancer that is node-negative, the clinician may use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.16. If a patient is premenopausal and has node-negative or node-positive breast cancer, the clinician should not use the Prosigna test to guide decisions for adjuvant systemic chemotherapy

Recommendation 1.17. If a patient is postmenopausal and has node-positive breast cancer with 1-3 positive nodes, the evidence is inconclusive to recommend the use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy

Recommendation 1.18. If a patient has node-positive breast cancer with ≥ 4 positive nodes, evidence on the clinical utility of routine use of the Prosigna test to guide decisions for adjuvant endocrine and chemotherapy is insufficient to recommend its use

Ki67.

Recommendation 1.19. If a patient is postmenopausal and has stage I-II breast cancer, the clinician may use Ki67 expression in conjunction with other clinical and pathologic parameters to guide decisions on adjuvant endocrine and chemotherapy when multigene assays are not available. Ki67 expression levels are most informative for prognosis when the level is < 5% (low proliferation) or > 30% (high proliferation) because technical reliability of distinguishing values within this range is limited

Recommendation 1.20. If a patient is postmenopausal and has breast cancer, there is insufficient evidence to use baseline Ki67 expression or Ki67 level after 2 weeks of neoadjuvant aromatase inhibitor (AI) therapy to guide decisions on adjuvant endocrine and chemotherapy

Recommendation 1.21. Despite the limitations associated with Ki67 testing, a patient with node-positive breast cancer with a high risk of recurrence and a Ki67 score of ≥ 20% as determined by a US Food and Drug Administration (FDA)–approved test may be offered 2 years of abemaciclib plus endocrine therapy

Immunohistochemistry 4.

Recommendation 1.22. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes, the clinician may use immunohistochemistry 4 (IHC4) score to guide decisions for adjuvant endocrine and chemotherapy if the score has been validated in the performing laboratory and if multigene assays are not available

Extended Endocrine Therapy for ER-Positive HER2-Negative Breast Cancer

Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4.

Recommendation 1.23. If a patient has node-negative breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, there is insufficient evidence to use Oncotype DX, EndoPredict, Prosigna, Ki67, or IHC4 scores to guide decisions about extended endocrine therapy

Breast Cancer Index.

Recommendation 1.24. If a patient has node-negative or node-positive breast cancer with 1-3 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, the clinician may offer the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Recommendation 1.25. If a patient has node-positive breast cancer with ≥ 4 positive nodes and has been treated with 5 years of primary endocrine therapy without evidence of recurrence, there is insufficient evidence to use the BCI test to guide decisions about extended endocrine therapy with either tamoxifen, an AI, or a sequence of tamoxifen followed by AI

Clinical treatment score post-5 years.

Recommendation 1.26. If a patient is postmenopausal and had invasive breast cancer and is recurrence-free after 5 years of adjuvant endocrine therapy, the clinical treatment score post-5 years (CTS5) web tool may be used to calculate the estimated risk of late recurrence (recurrence between years 5-10), which could assist in decisions about extended endocrine therapy

HER2-Positive Breast Cancer or Triple-Negative Breast Cancer

Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4.

Recommendation 1.27. If a patient has HER2-positive breast cancer or TNBC, the clinician should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, MammaPrint, BCI, Prosigna, Ki67, or IHC4) to guide decisions for adjuvant endocrine and chemotherapy

Emerging Biomarkers

Tumor-infiltrating lymphocytes.

Recommendation 1.28. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use TILs to guide decisions for (neo)adjuvant endocrine and chemotherapy

PD-L1 testing.

Recommendation 1.29. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use PD-L1 testing to guide decisions for (neo)adjuvant endocrine and chemotherapy

Circulating tumor cells.

Recommendation 1.30. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use circulating tumor cells (CTC) to guide decisions for adjuvant endocrine and chemotherapy

Circulating tumor DNA.

Recommendation 1.31. If a patient has node-negative or node-positive ER-positive, HER2-positive, or TNBC, the clinician should not use ctDNA to guide decisions for adjuvant endocrine and chemotherapy

ASCO additionally recommended that all patients should be given the opportunity to participate in cancer clinical trials.

Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. Andre F, Ismaila N, Allison KH, et al. DOI: 10.1200/JCO.22.00069 Journal of Clinical Oncology 40, no. 16 (June 01, 2022) 1816-1837.

Landmark Five Year Overall Survival Rates for OPDIVO® and YERVOY® Combination in Advanced NSCLC

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SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) 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. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. This study consisted of Part 1a/Part 1b and Part 2. In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere.

Part 1a: Patients received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks (N=396), OPDIVO® monotherapy 240 mg IV every 2 weeks (N=396) or chemotherapy alone given every 3 weeks for up to four cycles (N=397), in patients whose tumors had PD-L1 expression of 1% or more.
Part 1b: Patients received OPDIVO® plus YERVOY® (N=187), OPDIVO® 360 mg IV every 3 weeks plus chemotherapy IV every 3 weeks for up to four cycles (N=177), or chemotherapy alone IV every 3 weeks for up to four cycles (N=186), in patients whose tumors did not express PD-L1 (less than 1%)

Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

There were two independent Primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Part 1a and Part 1b). Other assessments included Objective Response Rate (ORR), Duration of Response (DOR), and treatment-free interval. Treatment-free interval was measured in patients who discontinued study therapy and was defined as the time from last study dose to start of subsequent systemic therapy.

The Overall Survival (OS) data was previously reported at a minimum follow up of 29 months, and the median OS was of 17.1 months for the OPDIVO® plus YERVOY® group, compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rate of 40.0% and 32.8%, respectively. The researchers here in presented data after a minimum follow up of 61.3 months (5 years).

Patients whose tumors had PD-L1 expression of 1% or more continued to have sustained long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR=0.77), and the 5-year OS rates were 24% with OPDIVO® plus YERVOY® compared to 14% with chemotherapy alone.

Patients with a PD-L1 expression of less than 1% also demonstrated continued long term OS benefit with OPDIVO® plus YERVOY® when compared to chemotherapy (HR = 0.65), and the 5-year OS rates were 19% for OPDIVO® plus YERVOY&reg compared to 7% for chemotherapy alone.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 months for PD-L1–negative patients who received OPDIVO® plus YERVOY®, compared to 9.5 months and 24.9 months respectively, for those who received chemotherapy.

Among those who responded to treatment, more patients who received OPDIVO® plus YERVOY® remained in response at five years, compared to chemotherapy, in both PD-L1 expression of 1% or more group (28% versus 3%) and PD-L1 expression of less than 1% group (21% versus 0%), respectively.

Among patients treated with OPDIVO® plus YERVOY® who were alive at five years, approximately two-thirds of patients did not receive any subsequent therapy for more than three years after stopping treatment, regardless of PD-L1 expression.

It was concluded that in this longest reported follow up of a Phase III trial of first line, chemotherapy free, combination immunotherapy, in metastatic Non Small cell Lung Cancer, a combination of OPDIVO® plus YERVOY® continued to provide long term durable clinical benefit and increased 5-year survivorship, when compared to chemotherapy, in previously untreated patients with metastatic NSCLC, regardless of PD-L1 expression.

Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. Brahmer JR, Lee J-S, Ciuleanu T-E, et al. DOI: 10.1200/JCO.22.01503 Journal of Clinical Oncology. Published online October 12, 2022.

TUKYSA® Combination in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases

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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. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 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), 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. There is however no standard treatment option for this patient population following progression on KADCYLA®.

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 a Phase 1b dose-escalation trial, TUKYSA® in combination with HERCEPTIN® and XELODA® (Capecitabine) showed encouraging antitumor activity in patients with HER2-positive metastatic breast cancer, including those with brain metastases.

HER2CLIMB is an international, randomized, double-blind, placebo-controlled trial in which the combination of TUKYSA® plus HERCEPTIN® and XELODA® was compared with placebo plus HERCEPTIN® and XELODA®. A total of 612 patients with unresectable locally advanced or metastatic HER2-positive breast cancer, who were previously treated with HERCEPTIN®, PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine) were enrolled. Patients were randomly assigned in a 2:1 ratio to receive either TUKYSA® 300 mg orally twice daily throughout the treatment period (N=410) or placebo orally twice daily (N=201), in combination with HERCEPTIN® 6 mg/kg IV once every 21 days, following an initial loading dose of 8 mg/kg, and XELODA® 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle. Stratification factors included presence or absence of brain metastases, ECOG Performance Status and geographic region. The median patient age was 52 years and patient demographics as well as disease characteristics at baseline were well balanced between the two treatment groups. In the total treatment population, 47.5% had brain metastases at baseline, 48.3% in the TUKYSA® combination group and 46% in the placebo combination group. The Primary endpoint was Progression Free Survival (PFS). Secondary end points included Overall Survival (OS), PFS among patients with brain metastases, confirmed Objective Response Rate (ORR), and Safety.

At median follow-up of 29.6 months, median OS in all patients with brain metastases at baseline was 9.1 months longer in the TUKYSA® combination group compared to the placebo combination group (21.6 versus 12.5 months, HR=0.60; P<0.001), with a 40% reduction in the risk of death with the TUKYSA® combination. The estimated 1-year OS was 70.0% for the TUKYSA® combination group and 50.6% for the placebo combination group and the estimated 2-year OS was 48.5% and 25.1% respectively.

The researchers in this exploratory subgroup analyses reported efficacy outcomes for patients with brain metastases, as well as time to new brain lesion(s) as the site of first progression or death, in all patients enrolled in HER2CLIMB trial, at a median follow up of 29.6 months.

There was greater CNS Progression Free Survival in the TUKYSA® combination group compared with the placebo combination group and was 5.7 months longer (9.9 versus 4.2 months, HR=0.39; P<0.001), with a 61% reduction in the risk of CNS progression with the TUKYSA® combination. The estimated 1 and 2-year CNS Progression Free Survivals were 38.4% versus 7.9% and 19.3% versus 0%, respectively.

Among those with active brain metastases and measurable disease at baseline, the intracranial Objective Response Rates for the TUKYSA® combination group were 47.3% versus 20.0% for the placebo combination group, with a median duration of intra cranial response of 8.6 versus 3.0 months, respectively.

The risk of developing new brain lesions as the site of first progression or death was reduced by 45% in the TUKYSA® combination group versus the placebo-combination group (HR=0.55; P =0.006).

The authors concluded that in this exploratory subgroup analysis, TUKYSA® in combination with HERCEPTIN® and XELODA® provided a clinically meaningful survival benefit, while reducing the risk of developing new brain lesions. The authors added that HER2CLIMB is currently the only double-blind, randomized, controlled clinical trial for patients with HER2-positive metastatic breast cancer, that prospectively included patients with both active and stable brain metastases.

Tucatinib vs Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. Lin NU, Murthy RK, Abramson V, et al. JAMA Oncol. Published online December 1, 2022. doi:10.1001/jamaoncol.2022.5610

FDA Grants Accelerated Approval to KRAZATI® for KRAS G12C-mutated NSCLC

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SUMMARY: The FDA on December 12, 2022, granted accelerated approval to KRAZATI® (Adagrasib), a RAS GTPase family inhibitor, for adult patients with KRAS G12C-mutated locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy. FDA also approved the QIAGEN therascreen KRAS RGQ PCR kit (tissue) and the Agilent Resolution ctDx FIRST Assay (plasma) as companion diagnostics for KRAZATI®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 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. The KRAS protein is a GTPase and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The 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 25% of Non-Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.

KRAZATI® (Adagrasib) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike LUMAKRAS® (Sotorasib), which is also a selective covalent inhibitor of KRAS G12C, KRAZATI® has a longer drug half-life of 23 hours, as compared to 5 hours for LUMAKRAS®, has dose-dependent extended exposure, and can penetrate the CNS. Approximately, 27-42% of patients with NSCLC harboring KRAS G12C mutations have CNS metastases, with poor outcomes. KRYSTAL-1 is a Phase I/II multiple expansion cohort trial involving patients with advanced solid tumors harboring a KRAS G12C mutation. KRAZATI® demonstrated clinical activity in patients with KRAS G12C-mutated solid tumors, including colorectal, pancreatic, and biliary tract cancers. Further, preliminary data from two patients with untreated CNS metastases from a Phase 1b cohort showed antitumor activity against CNS metastases, with satisfactory concentrations of KRAZATI® in the CSF.

The present FDA approval was based on the results from Cohort A, a Phase 2 cohort of the KRYSTAL-1 study in which KRAZATI® at a dose of 600 mg orally twice daily was evaluated in patients with KRAS G12C-mutated NSCLC, previously treated with chemotherapy and anti-Programmed Death 1 (PD-1) or Programmed Death Ligand 1 (PD-L1) therapy. This registration study included a total of 116 unresectable or metastatic NSCLC patients, with histologically confirmed diagnosis, with KRAS G12C mutation (detected in tumor tissue at a local or central laboratory), who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy (in sequence or concurrently), and who had measurable tumor lesions. Enrolled patients received KRAZATI® 600 mg capsule twice daily, and treatment was continued until disease progression or unacceptable toxicities. The median patient age was 64 years, 97% had adenocarcinoma histology, 98% had both platinum-based therapy and checkpoint inhibitor therapy, and 21% of patients had CNS metastases. Key exclusion criteria included active CNS metastases (patients were eligible if CNS metastases were adequately treated and neurologically stable), carcinomatous meningitis, and previous treatment with a KRAS G12C inhibitor. Exploratory Biomarker Analyses included candidate biomarkers (PD-L1 Tumor Proportion Score and mutational status of STK11, KEAP1, TP53, and CDKN2A on tumor-tissue specimens, blood specimens, or both, for their association with tumor response. The Primary end point was Objective Response Rate as assessed by blinded Independent Central Review. Secondary end points included the Duration of Response, Progression Free Survival, Overall Survival, and safety. The median follow up was 12.9 months and the median duration of treatment was 5.7 months.

Of 112 patients with measurable disease at baseline, the confirmed Objective Response Rate was 42.9% and the median Duration of Response was 8.5 months. The median Progression Free Survival was 6.5 months, and the median Overall Survival was 12.6 months, at a median follow up of 15.6 months. Among 33 patients with previously treated, stable CNS metastases, the intracranial confirmed Objective Response Rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients and 53% were Grade 1 or 2 toxicities. KRAZATI® was discontinued in 6.9% of patients due to adverse events.

It was concluded that among patients with previously treated KRAS G12C-mutated NSCLC, KRAZATI® showed significant clinical efficacy without new safety signals and encouraging intracranial activity. The researchers added that these are the first clinical data demonstrating CNS-specific activity of a KRAS G12C inhibitor in this patient population.

Adagrasib in Non–Small-Cell Lung Cancer Harboring a KRASG12C Mutation. Jänne PA, Riely GJ, Gadgeel SM, et al. N Engl J Med 2022; 387:1238-1239