Author: RR

Bispecific Immune Checkpoint Inhibitor Improves Survival in Gastric and GEJ Cancer Regardless of PD-L1 Status

RR

SUMMARY: The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factor for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 15%. These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

Cadonilimab (AK104) is a human, bispecific IgG1 antibody with high binding avidity especially to high density of PD-1 and CTLA-4 due to its tetravalent design, and could simultaneously bind different cells expressing PD-1 and CTLA-4, respectively. By effective blocking both PD-1 and CTLA-4 pathways, Cadonilimab activates T cells by increasing interleukin-2 (IL-2) and interferon-gamma secretion to similar extent, as compared with anti-PD-1 and anti-CTLA-4 combination.

COMPASSION-15 is a double-blind, randomized, multicenter, Phase III trial that enrolled 610 patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. They were randomly assigned 1:1 to receive either Cadonilimab in combination with Oxaliplatin and Capecitabine chemotherapy, or placebo plus the same chemotherapy. Chemotherapy with Oxaliplatin and Capecitabine was given every 3 weeks for up to six cycles. Capecitabine was administered at 1000 mg/m2 orally twice daily on days 1 through 14 every 3 weeks and Oxaliplatin IV at 130 mg/m2 every 3 weeks. Cadonilimab 10 mg/kg IV or placebo was given on day 1 of each cycle every 3 weeks. Following the 6 cycles, patients then received Cadonilimab 10 mg/kg IV monotherapy or placebo every 3 weeks. Stratification factors included ECOG performance status (0 versus 1), PD-L1 expression (CPS 5% or more, or less than 5%), and the presence or absence of liver metastasis. The Primary endpoint was Overall Survival (OS) in the Intent to Treat (ITT) population.

The researchers herein presented the interim analysis data of COMPASSION-15 trial. The results revealed a significant improvement in Overall Survival with Cadonilimab combination therapy compared to placebo. The median OS was 15.0 months with Cadonilimab combination, compared with 10.8 months for those in the placebo arm (HR=0.60; P<0.001). The 18-month Overall Survival rate was 45.8% in the Cadonilimab group versus 25.5% in the placebo group.

Subgroup analysis based on PD-L1 expression levels (CPS 5% or more, or less than 5%) also demonstrated favorable outcomes with Cadonilimab across all strata. Among patients with a PD-L1 CPS of less than 5%, Cadonilimab combination achieved a median OS of 14.8 months, compared with 11.1 months in the placebo group. The 18-month OS rates were 44.1% compared with 27.5%, respectively.

Progression-Free Survival (PFS), another critical measure of treatment efficacy, showed consistent benefits with Cadonilimab combination compared to placebo plus chemotherapy, irrespective of PD-L1 expression. Median PFS was 7 months versus 5.3 months in the ITT population, with similar trends observed in CPS 5% or more, and less than 5% subgroups.

The safety analysis revealed no new safety signals. However, Grade 3 or higher treatment-related adverse events were more commonly reported in the combination therapy group compared to the placebo group. Treatment-related adverse events leading to therapy discontinuation were also more frequent in the Cadonilimab group.

It was concluded from this study that Cadonilimab is the first PD-1/CTLA-4 bispecific antibody to demonstrate substantial improvements in Overall Survival and Progression-Free Survival benefit in combination with chemotherapy, offering a potential new standard of care for patients diagnosed with locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer. This study represents a significant milestone in the quest for improved first-line treatments for gastric and GEJ cancers, even for patients with low PD-L1 expression tumors.

Cadonilimab plus chemotherapy versus chemotherapy as first-line treatment for unresectable locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (COMPASSION-15): A randomized, double-blind, phase 3 trial. Ji J, Shen L, Li Z, et al. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA.

De-escalation of Treatment for HPV-Associated Oropharyngeal Cancer

RR

SUMMARY: The American Cancer Society estimates that about 58,450 new cases of oral cavity and pharynx cancer will be diagnosed in the US in 2024 and about 12,230 patients will die of the disease. According to the CDC, about 46,711 Human PapillomaVirus (HPV)-associated cancers occur in the United States each year (25,689 among women, and 21,022 among men). Cervical cancer is the most common HPV-associated cancer among women, and Oropharyngeal cancers are the most common among men. There has been a significant increase in the incidence during the past several decades, due to changes in sexual practices.

HPV-positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) is an entirely distinct disease entity from HPV-negative OPSCC. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV. The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC) when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in Head and Neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with Head and Neck cancer, and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.

HPV-positive OPSCC is more sensitive to chemotherapy and radiotherapy than is HPV-negative OPSCC, which translates to a much better prognosis and survival, when treated with a combination of platinum based chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. These tumors, typically being more responsive to therapy than their non-HPV counterparts, appear to benefit from reduced radiation doses, potentially minimizing the severe toxicities linked with conventional radiotherapy, without compromising oncologic outcomes.

Two pivotal studies presented at the 2024 Multidisciplinary Head and Neck Cancers Symposium have provided compelling evidence supporting the deintensification of radiotherapy in early-stage Oropharyngeal Squamous Cell Carcinomas associated with HPV. The approach for the first study was de-escalated postoperative adjuvant therapy, whereas the second study utilized mid-treatment FDG-PET response criteria to select patients eligible for de-escalated radiotherapy

Study by Washington University School of Medicine: De-escalation of Postoperative Adjuvant Therapy
The MINT trial (The Minimalist Trial) is a nonrandomized Phase II study which enrolled 58 patients with clinical Stage I–III HPV-positive Oropharyngeal Squamous Cell Carcinoma, or with a positive neck node with an unknown primary, who underwent surgery and selective neck dissection. Out of these, 54 patients were stratified post-surgery into three treatment groups based on pathologic risk:
Group 1: High-risk pathology patients (extracapsular extension or positive margin but not clinical or pathologic T4 or clinical N3 disease) received de-escalated postoperative adjuvant chemoradiotherapy with Cisplatin at 100 mg/m2 for one dose plus 42 Gy of radiotherapy in 21 daily fractions (N=20)
Group 2: Intermediate-risk pathology patients (lymphovascular invasion, perineural invasion, at least two positive nodes, at least one positive node 3 mm, T3 or N2 disease, but no extracapsular extension or positive margins, and not clinical or pathologic T4 or clinical N3 disease) received de-escalated postoperative adjuvant radiotherapy with 42 Gy in 21 daily fractions (N=30)
Group 3: Highest-risk pathology (Patients with clinical or pathologic T4 or clinical N3 disease) received standard-of-care treatment with higher doses of Cisplatin at 100 mg/m2 for three doses plus 60 Gy of radiotherapy delivered concurrently (N=4).

So, the experimental arms involved de-escalating postoperative chemoradiotherapy in Group 1 and de-escalating postoperative radiotherapy in Group 2. The Primary outcome measure was mean percent weight change starting at Day 1 and ending on the last day of radiation therapy (approximately 4 weeks). The hypothesis was that de-escalated treatment would result in less weight loss, which served as a quantitative surrogate for the severity of mucositis. Secondary outcome measures included disease Recurrence Rate, Progression Free Survival (PFS) and Overall Survival (OS).

It was noted that the de-escalated treatment resulted in significantly less weight loss. Specifically, the mean percent weight loss during de-escalated postoperative adjuvant chemoradiotherapy (Group 1) was 4.9%, compared to 7.4% in a historical cohort treated with conventional therapy (P=0.0003). For de-escalated radiotherapy alone (Group 2), the mean percent weight loss was 3.18%. The follow-up data of this study at a median of 50 months indicated low recurrence rates: 10% in Group 1 and 3.3% in Group 2. The 4-year PFS rates were 90.0% for Group 1 and 90.1% for Group 2, with OS rates of 100% and 94%, respectively. These results suggest that reduced radiation doses do not compromise the efficacy of treatment for patients with HPV-positive Oropharyngeal Squamous Cell Carcinoma.

Study by University of Michigan: FDG-PET-Guided Deintensification
The second study is a Phase II trial which enrolled 89 patients with Stage I–II HPV-positive Oropharyngeal Squamous Cell Carcinoma confirmed to have FDG-PET avidity. The treatment plan included an initial course of 70 Gy to gross disease and 56 Gy to elective nodal regions, administered concurrently with Carboplatin and Paclitaxel. Mid-treatment FDG-PET assessments were performed to evaluate metabolic tumor volume reduction. Patients with at least a 50% reduction in tumor volume had their radiotherapy de-escalated to 54 Gy, whereas the others completed the entire course of 70 Gy. The Primary endpoint was noninferiority of 2-year locoregional recurrence in the entire cohort, compared with an institutional historical control.

At a median follow-up of 32 months, the 2-year locoregional recurrence rate for the entire cohort was 6.8%. Patients continuing with the standard 70 Gy therapy had a 2-year locoregional recurrence rate of 4.6%, while those de-escalated to 54 Gy had a rate of 9.4%. These figures translate to two and three locoregional recurrences, respectively, which suggests overlapping confidence intervals and precludes definitive comparisons between the cohorts. The study also assessed other endpoints such as weight loss, swallowing function, and quality of life. Patients in the de-escalated group experienced significantly less weight loss (11 lbs versus 23 lbs in the standard-treatment group, P=0.001), and showed better maintenance of swallowing function and quality of life. The authors concluded that FDG-PET may be a reliable predictive biomarker to selectively de-escalate the radiation dose in early-stage HPV-positive disease.

The findings from these two studies underscore the feasibility and potential benefits of de-escalating radiotherapy in HPV-positive Oropharyngeal Squamous Cell Carcinoma. By tailoring treatment intensity, based on individual patient risk profiles and early responses to therapy, clinicians can achieve effective disease control while minimizing the severe side effects traditionally associated with high-dose radiation. This shift towards personalized, less intensive treatment protocols promises to enhance the quality of life and long-term outcomes for patients with this particular subset of Head and Neck cancers.

1. Long-term efficacy of risk-directed, de-escalated post-operative adjuvant therapy for surgically resected locally advanced, human papillomavirus-positive oropharynx squamous-cell carcinoma: A non-randomized, multi-arm phase 2 trial. Thorstad WL, Jackson RS, Oppelt P, et al.: 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 14. Presented March 1, 2024.

2. FDG-PET-based selective de-escalation of radiotherapy for HPV-related oropharynx cancer: Results from a phase II trial. Regan SN, Rosen BS, Suresh K, et al.: 2024 Multidisciplinary Head and Neck Cancers Symposium. Abstract 16. Presented March 1, 2024.

Benefits of Neoadjuvant Chemoimmunotherapy in Early Stage Non Small Cell Lung Cancer

RR

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Approximately 50% of NSCLC patients are diagnosed at an early stage, when surgical resection is a viable treatment option. Among patients with early stage disease, 20% present with Stage I or II disease, while 30% present with Stage IIIA or IIIB disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

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 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. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Combining cytotoxic chemotherapy with a PD-1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

Neoadjuvant Immune Checkpoint Inhibitors (ICIs) have emerged as a promising approach to enhance the surgical resectability of tumors and reduce the risk of distant relapse. Clinical trials investigating the combination of neoadjuvant ICIs with platinum-based chemotherapy (ICI-chemotherapy) in resectable NSCLC have demonstrated improvements in Event-Free Survival (EFS) and a notable increase in pathologic Complete Response (pCR), which is considered a potential surrogate for Overall Survival. Consequently, regulatory agencies such as the US FDA and the European Medicines Agency have approved neoadjuvant ICI regimens for resectable NSCLC.

Several studies have suggested greater benefits in EFS and/or pCR in patients with higher PD-L1 expression in tumor cells. As a result, the European Medicines Agency has limited the use of neoadjuvant ICI therapy in combination with platinum-based chemotherapy to NSCLC patients with tumor cell PD-L1 expression of at least 1%. Other factors potentially influencing treatment outcomes include histologic features, disease stage, and smoking history. However, uncertainties remain regarding the necessity of adjuvant postoperative ICI treatment for all patients receiving neoadjuvant ICIs with chemotherapy, and the optimal duration of preoperative treatment.

The researchers therefore conducted a systematic review and meta-analysis of Randomized Clinical Trials with neoadjuvant Immune Checkpoint Inhibitors (ICIs) plus chemotherapy (ICI-chemotherapy) with or without adjuvant ICIs, to evaluate the collective benefits of neoadjuvant ICI-chemotherapy in Event-Free Survival (EFS) and pathologic Complete Response (pCR) among early-stage NSCLC patients, and additionally investigate the impact of various clinical, pathologic, and treatment-related factors. The analysis included 8 Phase II and III Randomized Clinical Trials involving 3387 previously untreated Stage IB-IIIB NSCLC patients. It compared 2-year EFS and pCR rates between patients receiving neoadjuvant chemoimmunotherapy and those patients receiving neoadjuvant chemotherapy alone. The current analysis unlike other meta-analyses that aimed to compare different perioperative ICI-based therapies, focused on limiting heterogeneity and providing consistent and clinically helpful evidence from the subgroup analysis.

The results indicated that neoadjuvant chemoimmunotherapy significantly improved both 2-year EFS and pCR rates, compared to chemotherapy alone. Neoadjuvant chemoimmunotherapy was associated with improved 2-year EFS (HR=0.57; P<0.001) and increased pCR rate (RR=5.58; P<0.001), compared to neoadjuvant chemotherapy alone. This benefit was noted regardless of age, sex, ECOG performance status, smoking history, histologic features including tumor PD=L1 status, tumor stage, type of platinum-compound chemotherapy, number of cycles of neoadjuvant chemoimmunotherapy, or addition of adjuvant Immune Checkpoint Inhibitors. Patients with tumor cells negative for PD-L1 were at higher risk of relapse (HR=0.75), than were those with low PD-L1 (HR=0.61) or high PD-L1 (HR=0.40) and this was statistically significant (P=0.005).

In conclusion, this systemic review and meta-analysis suggests that 3 cycles of neoadjuvant platinum-based Immune Checkpoint Inhibitors plus chemotherapy for early-stage NSCLC patients leads to meaningful improvements in 2-year Event Free Survival and pathologic Complete Response. It underscores the potential of this treatment approach in enhancing outcomes for NSCLC patients and provides valuable insights into optimizing treatment strategies.

Neoadjuvant Chemo-Immunotherapy for Early-Stage Non–Small Cell Lung Cancer; A Systematic Review and Meta-Analysis. Banna GL, Hassan MA, Signori A, et al. JAMA Netw Open. 2024;7(4):e246837. doi:10.1001/jamanetworkopen.2024.6837.

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

RR

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

RR

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

RR

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

RR

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

RR

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

RR

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

RR

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.