Author: RR

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer

RR

SUMMARY: The American Cancer Society estimates that 45,230 new cases of rectal cancer will be diagnosed in the US in 2021. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined, is 67%. The current standard of care for patients with locally advanced rectal cancer (Stages T3, T4, or N+) consists of Chemoradiation followed by Total Mesorectal Excision (TME), which provides good local disease control, although distant metastases can still occur. Adjuvant chemotherapy after preoperative Chemoradiation remains controversial, as it has not shown an improvement in Overall Survival (OS). This has been attributed in part to poor treatment compliance. Phase II trials of total neoadjuvant therapy have yielded promising results but there is presently no data from Phase III trials.

The Phase III PRODIGE 23 trial sponsored by the French UNICANCER GI group, investigated the role of neoadjuvant modified FOLFIRINOX before standard preoperative chemoradiotherapy, in patients with locally advanced rectal cancer. The aim of the study was to assess whether administering neoadjuvant chemotherapy before preoperative Chemoradiation could reduce the risk of distant recurrences. In this study, 461 patients were randomly assigned 1:1 to either the neoadjuvant chemotherapy group (N=231) or the standard-of-care Chemoradiation group (N=230). Eligible patients had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a Performance Status of 0-1. The neoadjuvant chemotherapy group received preoperative chemotherapy with FOLFIRINOX (Oxaliplatin 85 mg/m2 IV, Irinotecan 180 mg/m2 IV, Leucovorin 400 mg/m2 IV, and Fluorouracil 2400 mg/m2 IV as a continuous infusion over 46 hours every 14 days for 6 cycles), followed by Chemoradiation (50 Gy over 5 weeks along with concurrent Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed by Total Mesorectal Excision, and adjuvant chemotherapy which consisted of modified FOLFOX6 (Oxaliplatin 85 mg/m2 IV and Leucovorin 400 mg/m2 IV, followed by Fluorouracil 400 mg/m2 IV bolus and then Fluorouracil 2400 mg/m2 continuous infusion over 46 hours) every 14 days for six cycles or Capecitabine 1250 mg/m2 orally twice daily on days 1-14 every 21 days.

The Chemoradiotherapy group received preoperative Chemoradiation (50.4 Gy over 5 weeks along with Capecitabine 800 mg/m2 orally twice daily for 5 days per week), followed 7 weeks later by Total Mesorectal Excision and adjuvant chemotherapy, which consisted of 6 months (12 cycles) of modified FOLFOX or 6-8 cycles of Capecitabine. It should be noted that patients received the same schedule of Chemoradiation, the same surgery, and the same total duration of chemotherapy (6 months) in both groups.

The Primary endpoint was Disease Free Survival (DFS) at 3 years. Secondary endpoints included Overall Survival (OS), Metastasis-Free Survival (MFS), and Cancer-Specific Survival (CSS). Safety analyses were performed on treated patients. More than 90% of patients received all planned cycles of FOLFIRINOX.

At a median follow-up of 46.5 months, the 3-year DFS rates were 76% in the neoadjuvant chemotherapy group and 69% in the standard-of-care group (HR=0.69; P=0.034). This represented a 31% reduction in the DFS hazard in the neoadjuvant group. Metastasis-Free-Survival at 3 years was significantly improved in the neoadjuvant group (79% vs 72%, P=0.017) and the pathologic Complete Responses were also significantly higher in the neoadjuvant group (28% versus 12%; P<0.001).
FOLFIRINOX was reported to be well tolerated with 92% compliance rate with this regimen. There were significantly more grade 3 or 4 adverse events in the Chemoradiation group, especially neutropenia and neuropathy. There were significantly more Grade 3 or 4 adverse events associated with adjuvant chemotherapy in the Chemoradiation control group (79% versus 45%, P<0.0001). Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia and neuropathy, all occurred significantly more often in the patients who received 6 months of adjuvant therapy (Chemoradiation group), suggesting that for the same duration of chemotherapy, the perioperative approach was better tolerated than adjuvant chemotherapy.

The authors concluded that chemotherapy intensification using FOLFIRINOX before preoperative Chemoradiation significantly improved outcomes, with better tolerance and decreased neurotoxicity, compared with standard-of-care preoperative Chemoradiation, among patients with cT3 or cT4 M0 rectal cancer.

Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Conroy T, Bosset J-F, Etienne P-L, et al. Lancet Oncol. 2021;22:702-715.

Somatic Tumor Mutations and Risk for Thrombosis

RR

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke. Ambulatory cancer patients initiating chemotherapy are at varying risk for Venous Thromboembolism (VTE), which in turn can have a substantial effect on health care costs, with negative impact on quality of life.

Approximately 20% of cancer patients develop VTE and about 20% of all VTE cases occur in patients with cancer. Cancer patients have a 4-7 fold increased risk of thrombosis, compared with those without cancer, and patients with cancer and VTE are at a markedly increased risk for morbidity and mortality. The high risk of recurrent VTE, as well as bleeding in this patient group, makes anticoagulant treatment challenging.

The etiology of thrombosis in cancer is multifactorial, and the vascular system is an important interface between the malignant cells and their systemic and external environments. Genetic alterations in malignant cells, as they respond to their microenvironment, can result in inflammation, angiogenesis, and tissue repair. This in turn leads to the local and systemic activation of the coagulation system. It has been postulated that the procoagulant effect of malignant cells may be related to the release of soluble mediators such as G-CSF into the circulation or by the shedding of procoagulant Extracellular Vesicles (EVs) harboring Tissue Factor. Previously published studies had entertained the notion that certain oncogenic mutations may deregulate hemostatic genes (coagulome) in cancer cells.

The researchers conducted this study to assess potential associations between tumor molecular signatures and Cancer Associated Thrombosis, including tumor-specific mutations, and the presence of Clonal Hematopoiesis. The authors analyzed deep-coverage targeted DNA-sequencing data of more than 14,000 solid tumor samples from 11,695 patients, using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform, to identify somatic alterations associated with Venous ThromboEmbolism (VTE). Among the patients included, more than 15 different solid tumor types were represented and 72% had metastatic disease at time of analysis.
Among these patients, there were 693 episodes of Cancer Associated Thrombosis, and the authors in addition to looking for associations with standard clinical variables such as diagnosis, stage and therapy, also assessed potential linkage of Cancer Associated Thrombosis with oncogenic mutations. The Primary endpoint was defined as the first instance of cancer-associated Pulmonary Embolism and/or proximal/distal lower extremity Deep Vein Thrombosis.

It was noted that several genes were found to be significantly associated with the VTE risk, regardless of tumor type. Independent of tumor type, the following mutations were associated with increased risk of Cancer Associated Thrombosis: KRAS (HR=1.34 suggesting 1.34 times higher risk), STK11 (HR=2.12), KEAP1 (HR=1.84), CTNNB1 (HR=1.73), CDKN2B (HR=1.45) and MET (HR=1.83). Mutations in SETD2 were associated with a decreased risk of Cancer Associated Thrombosis (HR=0.35). Clonal Hematopoiesis (CH) is an aging associated biologic state, with genetic mutations occurring in the background of active malignancies. The presence of Clonal Hematopoiesis was not associated with an increased risk of Cancer Associated Thrombosis.

The authors from this study concluded that this is the first large-scale study to explore the link between cancer genomics and thrombosis. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B, and MET were associated with an increased risk of VTE in patients with solid tumors. It remains unclear whether drugs targeting these genetic alterations would alter the course of Cancer Associated Thrombosis.

Genomic profiling identifies somatic mutations predicting thromboembolic risk in patients with solid tumors. Dunbar A, Bolton KL, Devlin SM, et al. Blood 2021;137:2103-2113.

ABECMA® (Idecabtagene vicleucel)

RR

The FDA on March 26, 2021 approved ABECMA® for the treatment of adult patients with Relapsed or Refractory Multiple Myeloma after four or more prior lines of therapy, including an Immunomodulatory agent, a Proteasome Inhibitor, and an anti-CD38 monoclonal antibody. This is the first FDA-approved cell-based gene therapy for Multiple Myeloma. ABECMA® is a product of Bristol-Myers Squibb Company.

Five-Year Efficacy Outcomes with KEYTRUDA® versus Chemotherapy in Metastatic NSCLC

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

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. Immune Checkpoint Inhibitors (ICIs) target Programmed cell Death protein-1 (PD-1) receptors on T cells, as well as Programmed cell Death Ligand-1 (PD-L1), PD-L2 and Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system, which are upregulated in some tumor types. T-cell proliferation and cytokine production is inhibited upon binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response. Unleashing the T cells results in T cell proliferation, activation and a therapeutic response. High level of PD-L1 expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced NSCLC have a high level of PD-L1 expression, and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, Phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of Platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety. In an updated analysis of the KEYNOTE-024 study, after a median follow up of 25.2 months, the median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). This OS benefit was maintained even after adjusting for crossover.

The authors in this publication reported the 5-year efficacy and safety outcomes from this pivotal Phase III KEYNOTE-024 trial. The median time from randomization to data cutoff was 59.9 months. Among patients initially assigned to chemotherapy, 66% received subsequent anti PD-1 or PD-L1 therapy (66% cross over rate). In the KEYTRUDA® group, 52.9% received additional anticancer therapy.

The median OS was 26.3 months for KEYTRUDA® and 13.4 months for chemotherapy (HR=0.62). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the KEYTRUDA group and 16.3% for the chemotherapy group. The ORR was 46.1% among patients in the KEYTRUDA® group versus 31.1% in the chemotherapy group and the median Duration of Response was 29.1 months in the KEYTRUDA® group and 6.3 months in the chemotherapy group.

The authors concluded that first line KEYTRUDA® provides a durable and clinically meaningful long-term Overall Survival benefit, when compared to chemotherapy, in patients with metastatic NSCLC, with PD-L1 Tumor Proportion Score of at least 50%.They added that this is first 5-year follow up of any first line Phase III immunotherapy trial for Non Small Cell Lung Cancer.

Five-Year Efficacy Outcomes With Pembrolizumab vs Chemotherapy in Metastatic NSCLC With PD-L1 Tumor Proportion Score of at Least 50%: KEYNOTE-024 Trial. Reck M , Rodríguez–Abreu D, Robinson AG, et al. DOI: 10.1200/JCO.21.00174 Journal of Clinical Oncology. Published online April 19, 2021.