Category: Hem/Onc Updates

100 Percent Biochemical Recurrence Free Survival with Apalutamide plus ADT in High-Risk Prostate Cancer Following Radical Prostatectomy

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy is considered PSA failure or biochemical recurrence. The American Urological Association suggested that a PSA of 0.2 ng/mL or higher after Radical Prostatectomy, defines PSA failure or relapse. A PSA rise 2 ng/ml or more above post Radiation Therapy nadir is considered PSA failure or relapse. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patients with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

It is estimated that approximately 15-20% of prostate cancer patients are classified as high-risk (PSA 20 ng/mL or more; or Gleason score 8-10; or clinical stage T3 or more). Approximately, 45-65% of patients with high-risk disease have recurrent disease within five years of undergoing Radical Prostatectomy.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. Apalutamide is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer and non-metastatic Castration Resistant Prostate Cancer

Apa-RP is a multicenter, open-label, single-arm, Phase II study, which included 108 patients across 32 U.S. community urologic practices, and investigated the benefit of Apalutamide plus ADT adjuvant to Radical Prostatectomy, in patients with high-risk localized prostate cancer. Key inclusion criteria were high risk localized prostate cancer with a post-radical prostatectomy PSA of 0.2 ng/mL or less. Patients were treatment-naïve, had undergone Radical Prostatectomy, and were treated with Apalutamide 240 mg, orally once daily, every 28 days for 12 cycles along with ADT for 12 months. The median age was 66 years, 14% were African American and about 60% of patients had prostate cancer with a Gleason Score 9-10. The median preoperative PSA was 7.6 ng/mL and median testosterone level was 340 ng/dL. The Primary endpoint evaluated Biochemical Recurrence (BCR)-free rate, defined as two sequential PSA levels of 0.2 ng/mL or less, at 24 months. The Secondary endpoints included testosterone recovery rate to 150 ng/dL or more at 18 and 24 months, as well as Safety.

The study met its Primary endpoint, showing that patients who received 12 months of Apalutamide plus ADT adjuvant to Radical Prostatectomy experienced 100% biochemical recurrence-free survival (RFS) rate at 24 months, with no confirmed biochemical recurrence at 2 plus years following Radical Prostatectomy. The treatment regimen demonstrated a serum testosterone recovery (150 ng/dL or more) rate of 76.4% at 12 months following treatment completion. The safety profile of Apalutamide with ADT was consistent with previous reports and Adverse Events were reported by 99.1% of patients. Adverse Events led to treatment discontinuation in 10.2% of patients and dose reduction or interruption in 13%.

Based on the results of this study, it was concluded that treatment intensification with 12 cycles of Apalutamide and Androgen Deprivation Therapy following Radical Prostatectomy could become an option for patients with high-risk localized prostate cancer.

Apalutamide for high-risk localized prostate cancer following radical prostatectomy (Apa-RP): a multicenter, open-label, single-arm phase 2 study. Shore N, Hafron J, Saltzstein D, et al. Presented at: 2024 American Urological Association Meeting; May 3-May 6, 2022; San Antonio, TX. Abstract P2-07.

Cardiovascular Adverse Events Associated with Bispecific T-cell Engager Therapy

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SUMMARY: Bispecific T-cell engager (BTE) therapies are a novel class of targeted immunotherapies with activity against hematologic malignancies. These bispecific antibodies have 2 binding domains, one targeting and binding to CD3 on the T-cell receptor, whereas the other is a modifiable domain designed to bind to specific tumor-associated antigens, which can be CD19, CD20, B-Cell Maturation Antigen (BCMA) or GPRC5D. Blinatumomab (BLINCYTO®) targets the CD19 on B-cells and is approved for the treatment of advanced Acute Lymphoblastic Leukemia (ALL); Mosunetuzumab (LUNSUMIO®), Glofitamab (COLUMVI®), and Epcoritamab (EPKINLY®), target CD20 on B cells and have also been approved for the treatment of Non-Hodgkin lymphoma; Teclistamab (TECVAYLI®), targets BCMA expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma; Talquetamab (TALVEY®) targets GPRC5D expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma.

Adverse events of BTEs include Cytokine Release Syndrome (CRS), hematological toxicities, and neurotoxicity. Serious CardioVascular Adverse Events (CVAEs) have been reported with certain BTEs. However, this has not been clearly defined. Given that CVAEs have not been observed in a previous pharmacovigilance analysis focused on CAR-T therapy, it appears that the pathophysiology of CVAEs associated with novel T-cell modulatory therapies (BTEs) may be different.

The present study was conducted to examine the CardioVascular Adverse Events (CVAEs) associated with Bispecific T-cell Engager therapies (BTEs). The five BTE products considered for analysis were Blinatumomab, Teclistamab, Mosunetuzumab, Glofitamab, and Epcoritamab. Leveraging the vast repository of the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), researchers embarked on a meticulous analysis, investigating the frequency and association of CVAE reporting with BTE, the prognostic implications of CVAEs in patients receiving BTEs, as well as the extent these adverse events overlap with CRS, spanning from October 2014 to March 2023. The primary objective was to delineate the frequency and fatality rates of CVAEs associated with BTEs, encompassing a spectrum of conditions including bleeding, hypotension or shock, thromboembolic disease, heart failure, and conduction abnormalities, myocarditis, pericarditis, sudden death, and vasculitis.

Utilizing multivariable logistic regression models, adjusted for age, sex, and disease status, the researchers calculated adjusted Reporting Odds Ratios (RORs). These RORs served as a metric to gauge the likelihood of reporting a given adverse event with BTEs compared to reporting the same event with all other drugs in the FAERS database.

Their study examined 3,668 cases of reported adverse events, 73.9% of which involved Blinatumomab and 11.2% involved Teclistamab as the primary suspected drug. Mosunetuzumab, Glofitamab and Epcoritamab accounted for a smaller proportion of events. (7.4%, 5.2% and 2.3%, respectively). The median age of patients was 52.0 years, with individuals from 52 countries represented in this analysis, with 43.2% of cases coming from the U.S. The indication for BTE therapy was leukemia/lymphoma in 88.7% of cases, multiple myeloma in 11.2% of cases, and both in 0.1% of cases.

The results of the study unveiled several significant findings:
1) Of the 3668 BTE-related cases reported to FAERS, 20.4% involved CVAEs.
2) BTEs were associated with disproportionately higher rates of fatal CVAEs, an association mainly driven by Teclistamab. Teclistamab was also associated with a disproportionate risk of myocarditis and shock, whereas Blinatumomab was associated with a disproportionate risk of Disseminated Intravascular Coagulation and hypotension.
3) Majority of these fatal CVAEs (96.7%) occurred in individuals without previously documented cardiovascular comorbidities.
4) CVAEs were more likely to be fatal compared with non-CVAEs (31.1% versus 17.4%).
5) CVAEs were not necessarily a consequence of Cytokine Release Syndrome (CRS), as approximately 85% of CVAE reports did not involve concurrent CRS.
6) In general, CVAEs tended to occur sooner following BTE therapy compared with non-CVAEs (median time to onset 6 days versus17 days; p<0.001).
7) No significant associations with CVAEs were observed with the other three BTE products (Glofitamab, Mosunetuzumab, and Epcoritamab).
8) Compared with CVAEs, neurotoxicity and CRS commonly associated with BTEs were associated with lower mortality. The elevated risk of death following CVAEs was especially noted for myocarditis, heart failure, bleeding, and DIC, with which mortality rates were 2-3 times higher than other AEs.

The researchers concluded that in this first postmarketing pharmacovigilance analysis of BTEs, CVAEs were involved in approximately 1 in 5 Adverse Event reports, and carried a significantly high mortality rate. The researchers cautioned that clinicians must be cognizant of the potential of CVAEs when treating patients with BTEs, and consider either stopping or switching therapies when CVAEs are suspected.

Cardiovascular toxicities associated with bispecific T-cell engager therapy. Sayed A, Munir M, Ghazi SM, et al. J Immunother Cancer. 2024 Feb 21;12(2):e008518. doi: 10.1136/jitc-2023-008518.

Minimal Residual Disease Status Predicts Outcome in Patients with Previously Untreated Follicular Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2024, about 80,620 people will be diagnosed with Non-Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die 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 20% of all NHLs are Follicular Lymphomas. 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 (PFS) of 6-8 yrs and a median Overall Survival of 12-15 yrs. However, approximately 30% of the patients will relapse in 3 years.

GAZYVA® (Obinutuzumab) is glycoengineered, fully humanized, third generation, type II anti-CD20 antibody (IgG1 monoclonal antibody) that selectivity binds to the extracellular domain of the CD20 antigen on malignant human B cells. By virtue of binding affinity of the glycoengineered Fc portion of GAZYVA® to Fcγ receptor III on innate immune effector cells (natural killer cells, macrophages and neutrophils), Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) and Antibody-Dependent Cellular phagocytosis are significantly enhanced but induces very little Complement-Dependent Cytotoxicity. This is in contrast to RITUXAN® which is a first-generation type I, chimeric, anti-CD20 targeted monoclonal antibody that kills lymphoma cells primarily by Complement-Dependent Cytotoxicity and also ADCC.

GALLIUM is a randomized, Phase III trial, which included 1,202 patients with newly diagnosed Follicular Lymphoma, who had Grade I-IIIa tumors and had an ECOG PS of 2 or less. Patients were randomly assigned to receive either GAZYVA® plus chemotherapy, followed by GAZYVA® maintenance (N=601), or RITUXAN® plus chemotherapy, followed by RITUXAN® maintenance (N=601). The chemotherapy regimens used were CHOP, CVP or Bendamustine, based on the discretion of the treating physician. Patients received either RITUXAN® 375mg/m2 IV on day 1 of each cycle or GAZYVA® 1000 mg IV on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (Bendamustine). Patients who achieved a Complete Response (CR) or Partial Response (PR) at the end of induction therapy, received maintenance therapy with RITUXAN® or GAZYVA® every 2 months for 2 years or until disease progression. The median age was 59 years and 57.1% of patients received Bendamustine, 33.1% received CHOP, and 9.8% received CVP. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Response Rate, Overall Survival (OS), Disease Free Survival and safety. After a median follow up of 34.5 months, upon recommendations from the Independent Monitoring Committee, the study was unblinded after a preplanned interim efficacy analysis. The estimated 3-year rate of Progression Free Survival in the GAZYVA® group was 80% compared with 73.3% in the RITUXAN® group, with a 34% reduction in the risk of progression or death noted in the GAZYVA® group (HR=0.66; P=0.001).

The researchers conducted a preplanned analysis of the Phase III Gallium study and explored the role of Minimal Residual Disease (MRD) as a predictor of outcome after GAZYVA® or RITUXAN® based treatment, in these previously untreated patients with Follicular Lymphoma. MRD status was assessed at predefined time points (Mid-Induction-Day 85 for all treatment groups, End of Induction, and at 4-6 monthly intervals during maintenance and follow-up) and the study objectives were to evaluate the depth and kinetics of MRD response to first-line GAZYVA® plus chemotherapy or RITUXAN® plus chemotherapy, and explore the prognostic role of MRD-status prospectively, to evaluate the use of MRD as a dynamic parameter for treatment modification. Patients with evaluable biomarker data at diagnosis were included in the survival analysis.

MRD analysis was performed at the central reference laboratory and was assessed by nested and quantitative PCR for clonal immunoglobulin gene rearrangement and the t(14;18) translocation. MRD status was classified as positive if both quantitative PCR and nested PCR were positive and were detectable at or above 104 sensitivity. Both peripheral blood and bone marrow samples were collected and MRD status was evaluated at Mid-Induction, End of Induction, during maintenance treatment and follow up. MRD status at End of Induction was determined as positive if at least one sample (PB or BM) was positive. Assessments during maintenance were conducted every 4 months during the first year, every 6 months thereafter, and at the final termination/discontinuation visit. Assessments were conducted every 6 months during follow-up. Patients who progressed during induction were excluded from the corresponding MRD analysis. Of the 1064 patients enrolled for MRD evaluation, 249 patients (23%) had no clonal PCR marker detected or had samples that did not meet MRD evaluability criteria.

At a median follow up of 59 months, MRD positivity at the Mid-Induction or End of Induction was significantly associated with inferior Progression Free Survival compared with MRD negativity. (PFS for those with detectable MRD at the Middle of Induction-HR=3.03, P<0.0001) and at the End of Induction- HR= 2.25, P<0.0001).

MRD response was higher after GAZYVA® plus chemotherapy versus RITUXAN® plus chemotherapy at the Middle of Induction (94.2% vs 88.9%, P=0.013) and at the End of Induction (93.1% vs 86.7%, P=0.0077), respectively.

Late responders with detectable MRD at the Middle of Induction and undetectable MRD at the End of Induction had significantly poorer PFS versus early responders who had undetectable MRD at both the Middle of induction and the End of Induction (HR=3.11, P=0.00011).

MRD positivity at the Middle of Induction was observed in a smaller proportion of patients receiving Bendamustine than CHOP (4.8% versus 16.0%; P<0.0001).

GAZYVA® appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the GAZYVA® plus chemotherapy groups.

During maintenance, more patients treated with RITUXAN® had detectable MRD compared to GAZYVA®, and throughout maintenance treatment, MRD positivity was associated with clinical relapse.

The researchers concluded that based on this analysis, early and continuous MRD negativity after immunochemotherapy is the most important prognostic factor for long-term disease control and outcomes, following first line treatment in Follicular Lymphoma. Further, this analysis has also suggested that the higher MRD responses after GAZYVA®, compared to RITUXAN® based chemotherapy, confirm more effective tumor cell clearance with GAZYVA® based chemotherapy regimens.

Minimal Residual Disease Status Predicts Outcome in Patients with Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study. Pott C, Jurinovic V, Trotman J, et al. J Clin Oncol. 2024;42:550-561.

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. J Clinical Oncol. 2024;42:584-604.

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 ALECENSA® as Adjuvant Treatment for ALK-Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on April 18, 2024, approved ALECENSA® (Alectinib) for adjuvant treatment following tumor resection in patients with Anaplastic Lymphoma Kinase (ALK)-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 12% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas.

The discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib), ZYKADIA® (Ceritinib), ALECENSA® (Alectinib), ALUNBRIG® (Brigatinib) and LORBRENA® (Lorlatinib), with promising results. It has become clear that appropriate molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 5%, as well as other mutations in BRAF, HER2, AKT1, fusions involving RET and ROS oncogenes and MET gene alterations. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare.

Patients with ALK-positive NSCLC tend be younger nonsmokers and present with more advanced disease. Approximately 50-60% of these patients develop brain metastases. These patients are often treated with ALK TKIs that cross the blood brain barrier. Patients with early stage resected ALK-positive NSCLC receive adjuvant treatment with platinum-based combination chemotherapy, with 5-year survival ranging from 70% for Stage IB disease to about 35% for Stage IIIA disease, with associated chemotherapy related toxicities.

Alectinib is a potent, second-generation ALK Tyrosine Kinase Inhibitor, and is effective against several ALK mutations that confer resistance to Crizotinib. In the Phase III, randomized ALEX trial, treatment naïve patients with advanced ALK-positive NSCLC who received Alectinib had significantly longer Progression Free Survival and 5-year Overall Survival, compared to those who received Crizotinib, with substantial CNS activity.

The ADAURA trial investigated adjuvant TAGRISSO® (Osimertinib), a third-generation EGFR TKI, in patients with resected EGFR-mutated NSCLC of stage IB, II, or IIIA. Results showed benefits in Disease-Free and Overall Survival, along with reduced CNS recurrence. The ALINA trial similarly assessed the efficacy of Alectinib, in resected ALK-rearranged NSCLC.

ALINA is a global, open-label, randomized, Phase III trial, conducted to investigate the efficacy and safety of adjuvant Alectinib as compared with standard chemotherapy in patients with resected ALK-positive NSCLC. In this study, 257 eligible enrolled patients (N=257) were randomly assigned 4-12 weeks after patients had undergone complete surgical resection (lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy) in a 1:1 ratio to receive Alectinib 600 mg orally twice daily or platinum-based chemotherapy IV every 21 days for 4 cycles. Alectinib was given for 24 months. Chemotherapy consisted of Cisplatin 75 mg/m2 IV on day 1 of each cycle, plus Vinorelbine 25 mg/m2 IV on days 1 and 8, Gemcitabine 1250 mg/m2 IV on days 1 and 8, or Pemetrexed 500 mg/m2 on day 1. In the event of Cisplatin intolerance, Carboplatin AUC 5 or 6 IV was substituted. Eligible patients had completely resected, histologically confirmed Stage IB (tumors 4 cm or more), II, or IIIA NSCLC, and randomization was stratified according to disease stage and race (Asian versus non-Asian). A total of 231 patients had Stage II or IIIA disease, 116 in the Alectinib group and 115 in the chemotherapy group. The Primary end point was Disease Free Survival (DFS), tested hierarchically among patients with Stage II or IIIA disease and then in the Intention-To-Treat (ITT) population. Secondary end points included CNS Disease Free Survival, Overall Survival, and Safety. The median duration of follow up was 28 months.

The DFS among patients with Stage II or IIIA disease at 2 years was 93.8% in the Alectinib group and 63.0% in the chemotherapy group, and 88.3% and 53.3% respectively at 3 years. The Hazard Ratio for disease recurrence or death was 0.24 (P<0.001), which corresponds to a 76% lower risk with adjuvant Alectinib than with chemotherapy. This DFS benefit was seen consistently across prespecified subgroups, including those defined according to disease stage, race, sex, and smoking status. An exploratory analysis showed a clinically meaningful prolongation of CNS Disease Free Survival with Alectinib. Fewer patients in the Alectinib group had CNS recurrence compared to the chemotherapy group (3.1% versus 11%), consistent with the intracranial efficacy of Alectinib in advanced NSCLC. Overall Survival data were immature at the time of data-cutoff.

The authors concluded that Adjuvant Alectinib significantly improved Disease Free Survival, as compared with platinum-based chemotherapy, among patients with resected ALK-positive NSCLC of Stage IB, II, or IIIA, with few discontinuations due to adverse events. The researchers added that this study reinforces the need for implementation of biomarker testing for ALK alterations, across all stages of NSCLC.

Alectinib in Resected ALK-Positive Non–Small-Cell Lung Cancer. Wu Y-L, Dziadziuszko R, Ahn JS, et al. for the ALINA Investigators. N Engl J Med 2024;390:1265-1276.

Long Term Benefits of RUBRACA® Maintenance in Newly Diagnosed Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,680 women will be diagnosed with ovarian cancer in 2024 and 12,740 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 are tumor suppressor genes, and they recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity.

Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers 15% of ovarian cancers, in addition to other cancers such as colon, pancreas and prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic).

The PARP (Poly ADP Ribose Polymerase) family of enzymes includes PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors traps PARP onto DNA at sites of single-strand breaks, thereby preventing their repair and generate double-strand breaks. These breaks cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

RUBRACA® (Rucaparib) is an oral, small molecule PARP inhibitor, developed for treatment of ovarian cancer associated with Homologous Recombination DNA repair deficiency (HRD). With regards to ovarian cancer, RUBRACA® is presently approved by the FDA for the maintenance treatment of patients with a deleterious BRCA mutation (germline and/or somatic)- associated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.

ATHENA is an international, multicenter, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated first-line maintenance treatment for patients with newly diagnosed advanced ovarian cancer. ATHENA was designed to evaluate RUBRACA® first-line maintenance treatment in a broad group of patients, including those WITHOUT BRCA1 or BRCA2 (BRCA) mutations or other evidence of Homologous Recombination Deficiency (HRD), or high-risk clinical characteristics such as residual disease. ATHENA study has two separate and fully independently powered comparisons evaluating RUBRACA® monotherapy (ATHENA-MONO) and RUBRACA® plus Nivolumab (ATHENA-COMBO), as maintenance treatment in this patient population.

In the ATHENA-MONO trial, patients with Stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to 4-8 cycles of first-line platinum-doublet chemotherapy, were randomly assigned 4:1 to receive RUBRACA® 600 mg orally twice daily (N=427) or placebo (N=111). A total of 234 patients had HRD, of whom 185 received RUBRACA® and 49 received placebo. Treatment was continued for 24 months, or until disease progression or unacceptable toxicity. Patients were stratified by HRD test status, residual disease after chemotherapy, and timing of surgery (primary surgery versus interval debulking). The median age was 61 yrs, majority of the patients (78%) did not have a BRCA mutation. Patients were stratified by HRD classification (BRCA wild-type/LOH (Loss of Heterozygosity) high-16% or more, BRCA wild-type/LOH low-less than 16%, and BRCA wild-type/LOH indeterminate). The Primary end point of investigator-assessed Progression Free Survival (PFS) was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/LOH high tumor), and then in the Intent-To-Treat (ITT) population. Secondary end points included Overall Survival (OS), investigator-assessed Objective Response Rate (ORR) in patients with measurable disease at baseline, and Duration of Response (DOR) for patients with investigator-assessed confirmed radiographic Complete Response (CR) or Partial Response (PR).

At a median follow up of 26 months, RUBRACA® maintenance after chemotherapy and surgery significantly improved PFS, compared to placebo maintenance, among all subgroups in the Intent-to Treat population including BRCA-mutant, BRCA wild-type/LOH high, and BRCA wild-type/LOH low (HRD-negative) groups.

The researchers have now provided long term follow-up analysis (median follow-up of 37.0 months). In the Intent-To-Treat (ITT) population, the median Time to First Subsequent Treatment (TFST) was 23.3 months in the RUBRACA® group and 12.1 months in the placebo group (HR=0.52). In the HRD population, the median TFST was 32.7 months in the RUBRACA® group and 15.1 months in the placebo group (HR=0.50).

In the ITT population, the median PFS2 was 36.0 months and 26.8 months in the RUBRACA® and placebo groups respectively (HR=0.84). In the HRD population, the median PFS2 was Not Reached in the RUBRACA® group and was 39.9 months in the placebo group (HR=0.75).

The researchers noted that the clinical benefit of RUBRACA® extended beyond first progression and beyond the 2-year completion of treatment, suggesting that starting RUBRACA® maintenance in the first-line setting benefitted patients through and following their second-line treatment. Overall Survival (OS) data were not mature at the time of this analysis.

It was concluded that first line maintenance therapy with RUBRACA® in addition to providing Progression Free Survival benefit compared to placebo, was found to prolong both Time to First Subsequent Treatment and second Progression Free Survival, with manageable toxicity, in patients with newly diagnosed ovarian cancer, regardless of Homologous Recombination Deficiency (HRD) or BRCA mutation status.

Interim post-progression data and updated survival in patients with newly diagnosed advanced ovarian cancer in ATHENA-MONO. Kristeleit RS, O’Malley DM, Lim, MC, et al. Presented at the 2024 SGO Annual Meeting on Women’s Cancer; San Diego, CA; March 16-18, 2024.

Omitting Axillary Lymph Node Dissection in Breast Cancer with Sentinel-Node 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. 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.

Axillary lymph node status is a significant prognostic factor in patients with operable primary breast cancer, and is the most important predictor of recurrence and survival. Axillary lymph node dissection is used for staging of breast cancer and treatment of the axilla, if necessary. It is estimated that approximately 20-25% of women will have positive axillary lymph nodes when their breast cancer is detected through screening, whereas those with symptomatic early breast cancer have a 30-40% chance of having positive axillary nodes.

Axillary lymph node dissection is indicated for patients with proven axillary disease preoperatively or with a positive sentinel node biopsy. However, the landscape of breast cancer management has undergone significant evolution in recent years, particularly regarding the role of axillary surgery in node-negative disease. Among patients with clinically node negative breast cancer and 1-2 sentinel node metastases undergoing breast-conserving surgery and whole-breast radiation therapy, studies have shown that omission of axillary lymph node dissection did not have an impact on Overall Survival. However, questions remained about the necessity of completion axillary lymph node dissection in cases of sentinel-node metastases.

The SENOMAC trial was conducted in a large cohort of patients, to validate results from previous trials by comparing sentinel-node biopsy only with completion axillary lymph node dissection, in patients with clinically node-negative breast cancer and sentinel-lymph-node metastases. This study specifically focused only on patients with sentinel node macrometastases and extended eligibility criteria to include underrepresented subgroups such as those patients undergoing mastectomy, those with sentinel-node extracapsular extension or T3 tumors (tumor size more than 5 cm in the largest dimension), and men, thus broadening its applicability and relevance to real-world clinical scenarios.

In this ongoing, Phase III, international, randomized, non-inferiority trial which included 2540 patients (N=2540) from 5 European countries, 1335 had been assigned to undergo sentinel-node biopsy only with no further axillary surgery and 1205 to undergo completion axillary lymph node dissection (dissection group). Eligible patients had clinically node-negative breast cancer, with a tumor stage of T1, T2, or T3 (tumor size, T1, 2 cm or less; T2, 2-5 cm; and T3, more than 5 cm in greatest dimension) and one or two sentinel-node macrometastases (metastasis size, more than 2 mm in the greatest dimension). Patients who had suspicious but nonpalpable axillary lymph nodes on ultrasonography were eligible even if metastasis was confirmed by fine-needle aspiration. Adjuvant treatments and radiation therapy were administered in accordance with national guidelines, ensuring consistency in the approach to postoperative care across study participants. Whole-breast radiation therapy after breast-conserving surgery was mandatory, and radiation therapy including nodal target volumes was administered to 89.9% in the sentinel node biopsy-only group and to 88.4% in the dissection group. The median patient age was 61 yrs, approximately 64% had breast conserving surgery, 36% had mastectomy and 6% had T3 tumors. The Primary end point was Overall Survival (OS), and prespecified Secondary end points were Recurrence-Free Survival (RFS), Breast Cancer-Specific Survival, and Patient-Reported Outcomes. The median follow-up was 46.8 months.

Results from the trial demonstrated that the omission of completion axillary lymph node dissection was noninferior to the more extensive surgery in terms of Recurrence-Free Survival (RFS), and the estimated 5-year Recurrence-Free Survival was similar in the two treatment groups. The estimated 5-year RFS was 89.7% in the sentinel-node biopsy-only group and 88.7% in the dissection group, with a country-adjusted HR for recurrence or death of 0.89, which was significantly below the prespecified noninferiority margin (P<0.001).

These findings align with previous trials such as ACOSOG Z0011 and AMAROS, which also questioned the necessity of completion axillary lymph node dissection in certain patient populations. Yet, the SENOMAC trial offers distinct contributions. It included patients with T3 tumors and allowed for mastectomy, thus addressing gaps in previous research. Furthermore, the trial enrolled a substantial number of older patients, enhancing the generalizability of its results. Additionally, the trial adds to the growing body of evidence questioning the necessity of axillary surgery in diverse clinical scenarios, particularly in the era of advanced diagnostic imaging and tailored adjuvant therapies.

While the study has limitations, such as variations in radiation therapy practices and the predominantly luminal subtype of breast cancer among enrolled patients, its robust methodology and outcomes provide valuable insights. The results support the notion that axillary surgery may be unnecessary for certain patients with early-stage breast cancer and sentinel-node metastases, especially when combined with appropriate adjuvant therapies.

The researchers concluded that the omission of complete axillary lymph node dissection was noninferior to the more extensive surgery in patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most of whom received nodal radiation therapy. The SENOMAC trial represents a significant milestone in advancing the evidence base and shaping clinical guidelines for the management of early-stage breast cancer with sentinel-node metastases.

Omitting Axillary Dissection in Breast Cancer with Sentinel-Node Metastases. de Boniface J, Tvedskov TF, Rydén L, et al. For the SENOMAC Trialists Group. N Engl J Med 2024;390:1163-1175.

FDA Approves ENHERTU® for Unresectable or Metastatic HER2-Positive Solid Tumors

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SUMMARY: The FDA on April 5, 2024, granted accelerated approval to ENHERTU® (fam-Trastuzumab Deruxtecan-nxki) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment, and have no satisfactory alternative treatment options. This tumor agnostic indication was approved based on Objective Response Rate and Duration of Response.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor growth-promoting protein and is involved in normal cell growth. It is expressed on the surface of various tissue cells throughout the body. In some cancers, HER2 expression is amplified or the cells have activating mutations. HER2 gene amplification can result in HER2 protein overexpression which is often associated with aggressive disease and poor prognosis. Approximately 15-20% of invasive breast cancers as well as advanced Gastric and GastroEsophageal (GE) junction cancers overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody. Additionally, HER2 directed therapies have been used to treat lung and colorectal cancers. HER2 is an emerging biomarker in other solid tumor types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers with HER2 positive expression rates varying from 1-28%. There are currently no approved HER2 directed therapies for these cancers following progression on standard of care therapies. There is an unmet need for effective therapies for these HER2 expressing tumor types.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), another ADC targeting HER2, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

The FDA approval was based on the efficacy of ENHERTU® in 192 adult patients with previously treated unresectable or metastatic HER2-positive (IHC 3+) solid tumors who were enrolled in one of three multicenter trials: DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831). All three trials excluded patients with a history of Interstitial Lung Disease /pneumonitis requiring treatment with steroids or Interstitial Lung Disease /pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for active brain metastases or ECOG performance status more than 1. Treatment was administered until disease progression or unacceptable toxicity. The major efficacy outcome measure in all three trials was confirmed Objective Response Rate (ORR), and an additional efficacy outcome was Duration of Response (DOR). All outcomes were assessed by Independent Central Review based on RECIST criteria.

DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label, ongoing Phase II trial evaluating the efficacy and safety of ENHERTU® 5.4 mg/kg IV for the treatment of previously treated HER2 expressing tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumors. DESTINY-PanTumor02 enrolled 267 patients (N=267) at multiple sites in Asia, Europe and North America. Patients had received a median of two prior cancer therapies. In this study, the ORR was 51.4% and median DOR was 19.4 months.

DESTINY-Lung01 is a global, open-label, two-cohort, Phase II trial evaluating the efficacy and safety of ENHERTU® 6.4 mg/kg IV and 5.4 mg/kg IV in patients with HER2 mutant (cohort 2, N=91) or HER2 overexpressing (cohort 1 and 1a, N=90) (defined as IHC 3+ or IHC 2+) unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC), who had progressed after one or more systemic therapies. In this study, the ORR was 52.9% and the median DOR was 6.9 months.

DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter Phase II trial evaluating the efficacy and safety of two doses, 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU® in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor types, previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (N=80) were randomized 1:1 to receive either 5.4 mg/kg IV or 6.4 mg/kg IV of ENHERTU®. In the second stage, additional patients (N=42) were enrolled in the 5.4 mg/kg IV arm. In DESTINY-CRC02, ORR was 46.9%, and DOR was 5.5 months.

The most common adverse reactions were cytopenias, nausea, vomiting, fatigue, liver function abnormalities and upper respiratory tract infection. The recommended dose of ENHERTU® for this indication is 5.4 mg/kg IV every 3 weeks until disease progression or unacceptable toxicity.

The forementioned trials validate HER2 as an actionable biomarker across a broad range of tumor types, and ENHERTU® has the potential to benefit patients with HER2 expressing advanced disease, who may face a poor prognosis and currently have limited treatment options.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2.

April 2024: Current Tumor-Agnostic Therapies

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The FDA on April 5, 2024, granted accelerated approval to Fam-trastuzumab deruxtecan-nxki (ENHERTU®) for adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

This is the 6th Tumor-Agnostic therapeutic target for which an agent has received regulatory agency approval.

A current summary of the Tumor-Agnostic therapeutic targets, and agents approved, is provided below. Please review the drug Prescribing Information for the respective therapeutic agents, as NOT all products are approved for First Line therapy.

MMRd/MSI-H: Pembrolizumab (KEYTRUDA®) and Dostarlimab (JEMPERLI®)
TMB-H: Pembrolizumab (KEYTRUDA®)
NTRK fusions: Larotrectinib (VITRAKVI) and Entrectinib (ROZLYTREK®)
BRAF V600E: Dabrafenib (TAFINLAR®) plus Trametinib (MEKINIST®)
RET Fusions: Selpercatinib (RETEVMO®)
HER2 Overexpression: Fam-trastuzumab deruxtecan (ENHERTU®)

The National Cancer Institute describes Tumor-Agnostic therapy as a type of targeted treatment that uses drugs or other substances to treat cancer based on the cancer’s genetic and molecular features, without regard to the cancer type or where the cancer started in the body. Tissue-Agnostic therapy uses the same drug to treat all cancer types that have the genetic mutation or biomarker, that is targeted by the drug.