Category: Hem/Onc Updates

Late Breaking Abstract – ASCO 2022: Circulating Tumor DNA in the Peripheral Blood Can Guide Adjuvant Therapy Decision in Stage II Colon Cancer

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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 151,030 new cases of CRC will be diagnosed in the United States in 2022 and about 52,580 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. Even though 80% of patients with Stage II colon cancer are cured with surgery alone, adjuvant chemotherapy is recommended for patients who have Stage II colon cancer with high-risk clinicopathological features, including tumor penetration of the serosa (T4 disease). However, the benefit of adjuvant chemotherapy for patients with Stage II disease remains unclear, with less than 5% of patients benefitting from adjuvant chemotherapy. There is therefore an unmet need for more precise markers to predict risk of recurrence after surgery for Stage II colon cancer, other than clinicopathological risk factors, and thus avoid exposure to unnecessary chemotherapy.

Circulating Tumor DNA (ctDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis, and can be detected in the cell-free component of peripheral blood samples (Liquid Biopsy) in almost all patients with advanced solid tumors including advanced colorectal cancer. ctDNA is a valuable biomarker and is directly evaluated for evidence of Minimal Residual Disease and allows early detection of relapse. Several studies have shown that detectable ctDNA following curative intent surgery for early stage cancers, including those with Stage II colon cancer, is associated with a very high risk of recurrence (more than 80%) without further adjuvant therapy. It has remained unclear whether adjuvant treatment is beneficial for these ctDNA-positive patients who are at high risk for recurrence.

The Circulating Tumor DNA Analysis Informing Adjuvant Chemotherapy in Stage II Colon Cancer (DYNAMIC) trial is a randomized trial designed to investigate whether a ctDNA-guided treatment approach could reduce the use of adjuvant treatment without compromising the risk of recurrence, as compared with a standard approach in patients with Stage II colon cancer. The researchers also evaluated outcomes among ctDNA-positive patients who received adjuvant chemotherapy, to assess the benefit of treating this high-risk group of patients, as well as outcomes among ctDNA-negative patients whose disease was managed by surveillance alone. In this Phase II, multicenter, randomized, controlled trial of biomarker-driven adjuvant therapy, 455 patients with resected, histologically confirmed, Stage II (T3 or T4, N0, M0) colon or rectal adenocarcinoma with negative resection margins, were randomly assigned in a 2:1 ratio to have their disease managed according to ctDNA results-ctDNA-guided management group (N=302) or managed by the treating clinician according to standard clinicopathological criteria-standard management group (N=153). Plasma specimens were obtained for ctDNA analysis from all patients at week 4 and week 7 after surgery. For patients assigned to ctDNA-guided management, week 4 and week 7 specimens were analyzed concurrently, and ctDNA results were made available to the treating clinician 8 to 10 weeks after surgery. Patients with a positive ctDNA result at either week 4 or week 7 received adjuvant single-agent fluoropyrimidine or Oxaliplatin-based chemotherapy, with the treatment regimen chosen at the treating physician’s discretion. Patients with negative ctDNA results at both week 4 and week 7 were not treated with adjuvant chemotherapy. In the standard management group, all treatment decisions were based on conventional clinicopathological criteria. This trial used a ctDNA assay specifically designed for detection of Minimal Residual Disease with very high sensitivity (a variant allele frequency limit of detection as low as 0.01%), as well as serial blood samples for ctDNA analysis to decrease the risk of a false negative result. In this study, ctDNA probes were personalized on the basis of specific mutations identified in tumor tissue.

Enrolled patients had an ECOG PS of 0-2 and had to be medically eligible to receive adjuvant Oxaliplatin-based or single-agent fluoropyrimidine chemotherapy. Patients were stratified according to tumor stage (T3 or T4) and patients with evidence of macroscopic metastatic disease on CT of the chest, abdomen, and pelvis performed within 8 weeks before enrollment, presence of synchronous primary colorectal cancer, or treatment with neoadjuvant chemoradiotherapy, were excluded. Patients were enrolled within 3 weeks following surgery, and an adequate resected tumor specimen had to be provided for mutation analysis by 4 weeks after surgery. The treatment groups were well balanced, the median age of the patients was 64 years, 85% of patients had T3 disease, 15% had T4 disease, and 5% had a lymph node yield of less than 12. Clinical high risk disease was defined as one or more of the following clinicopathological risk features: T4 lesion, poor tumor differentiation, lymph node yield less than 12, lymphovascular invasion, tumor perforation, or bowel obstruction, in association with a proficient mismatch-repair tumor, which was present in 40% of patients. The Primary efficacy end point was noninferiority of ctDNA-guided management to standard management with regards to 2-year Recurrence Free Survival (RFS). A key Secondary end point was to determine whether fewer patients would receive adjuvant chemotherapy with the ctDNA-guided approach.

At a median follow up of 37 months, the 2-year RFS was 93.5% with ctDNA-guided management and 92.4% with standard management, meeting the noninferiority criterion. Further, a lower percentage of patients in the ctDNA-guided group received adjuvant chemotherapy than in the standard-management group (15% versus 28%).

The authors concluded that a ctDNA-guided approach to the treatment of Stage II colon cancer reduced adjuvant chemotherapy use without compromising Recurrence Free Survival. Studies are underway assessing the role of escalated chemotherapy in ctDNA-positive patients and deescalation of chemotherapy in ctDNA-negative patients with Stage II colorectal cancer.

Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. Tie J, Cohen JD, Lahouel K, et al. for the DYNAMIC Investigators. N Engl J Med 2022; 386:2261-2272

Late Breaking Abstract – ASCO 2022: IMBRUVICA® plus Bendamustine and Rituximab for Older Patients with Untreated Mantle Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2022, about 80,470 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation. These patients often receive less aggressive first line therapy such as Bendamustine plus Rituximab, and this regimen has demonstrated superior Progression Free Survival compared to R-CHOP, with a better safety profile. Further, the addition of Rituximab maintenance therapy after induction therapy with Bendamustine and Rituximab has shown significantly prolonged Progression Free Survival or Overall Survival in two independent observational studies.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. The 3 BTK inhibitors presently approved by the FDA for MCL include, IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019.

Single agent IMBRUVICA® is presently approved by the FDA for the treatment of MCL patients who have received at least one prior therapy. In a Phase Ib study, the addition of IMBRUVICA® to Bendamustine and Rituximab therapy was safe and effective with a Complete Response Rate of 76%, among patients with untreated, relapsed, or refractory MCL.

SHINE study is an international, randomized, double-blind, Phase III trial , in which a combination of IMBRUVICA® with Bendamustine plus Rituximab and Rituximab maintenance therapy was compared with placebo with Bendamustine plus Rrituximab and Rituximab maintenance therapy, in elderly patients with untreated Mantle Cell Lymphoma (MCL). A total of 523 previously untreated patients, 65 years of age or older, who had a centrally confirmed diagnosis of Mantle Cell Lymphoma with Cyclin D1 overexpression or translocation breakpoints at t(11;14) were randomly assigned in a 1:1 ratio to receive either to six cycles of IMBRUVICA® along with Bendamustine and Rituximab (N=261) or six cycles of placebo along with Bendamustine and Rituximab (N=262). IMBRUVICA® 560 mg or placebo was administered orally once daily. Bendamustine was administered at 90 mg/m2 IV on days 1 and 2 of each 28 day cycle along with Rituximab 375 mg/m2 IV on day 1 of each 28 day cycle. Patients in either arm who achieved a Complete or Partial Response continued to receive IMBRUVICA® or placebo daily along with Rituximab maintenance therapy at a dose of 375 mg/m2 IV every 8 weeks for up to 12 additional doses. Patients with stable disease after induction treatment could continue to receive IMBRUVICA® or placebo until disease progression or unacceptable toxicities. Both treatment groups were well balanced. The median age of the patients was 71 years and eligible patients had documented Stage II to IV disease with at least one measurable site of disease that was at least 1.5 cm in the longest diameter. Patients were excluded if stem-cell transplantation was planned or if they had known CNS involvement. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Objective Response Rate, Complete Response Rate, Overall Survival and Safety.

The study met its Primary endpoint and at a median follow up of 84.7 months, the median PFS was 80.6 months in the IMBRUVICA® group and 52.9 months in the placebo group (HR for disease progression or death=0.75; P=0.01). The Complete Response Rate was 65.5% in the IMBRUVICA® group and 57.6% in the placebo group (P=0.06). The Overall Survival was similar in the two treatment groups. Grade 3 or 4 adverse events during treatment were 81.5% in the IMBRUVICA® group and 77.3% in the placebo group and the most common Grade 3 and 4 adverse events were rash, pneumonia, and atrial fibrillation.

The authors concluded that treatment with IMBRUVICA® in combination with standard chemoimmunotherapy significantly prolonged Progression Free Survival, and may be a new treatment option for elderly patients with newly diagnosed Mantle Cell Lymphoma, who may not be candidates for intensive chemotherapy or Autologous Stem Cell Transplantation.

Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. Wang ML, Jurczak W, Jerkeman M, et al. June 3, 2022. DOI: 10.1056/NEJMoa2201817.
DOI: 10.1200/JCO.2022.40.17_suppl.LBA7502 Journal of Clinical Oncology 40, no. 17_suppl (June 10, 2022) 

FDA Approves OPDIVO® Combination for Advanced Esophageal Carcinoma

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SUMMARY: The FDA on May 27, 2022, approved OPDIVO® (Nivolumab) in combination with Fluoropyrimidine and Platinum-based chemotherapy, as well as OPDIVO® in combination with YERVOY® (Ipilimumab) for the first-line treatment of patients with advanced or metastatic esophageal Squamous Cell Carcinoma. The American Cancer Society estimates that in 2022, about 20,640 new cases of esophageal cancer will be diagnosed in the US and about 16,410 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases.

Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. It has been noted that approximately 50% of patients with advanced esophageal Squamous Cell Carcinoma express tumor-cell Programmed Death Ligand 1 (PD-L1) greater than 1%. In the ATTRACTION-3 multicentre, Phase III trial, treatment with OPDIVO® was associated with a significant improvement in Overall Survival, compared with chemotherapy, in previously treated patients with advanced esophageal Squamous Cell Carcinoma, regardless of PD-L1 expression. In the CheckMate 649 Phase III trial involving patients with gastric, gastroesophageal junction, or esophageal adenocarcinoma, first-line treatment with OPDIVO® plus chemotherapy resulted in a significant Overall Survival (OS) and Progression Free Survival (PFS) benefit, as compared with chemotherapy alone, as well as durable Objective Response Rate (ORR), with an acceptable safety profile.

CheckMate 648 is a global, open-label, Phase III trial in which the efficacy and safety of both an Immune Checkpoint Inhibitor in combination with chemotherapy and a dual Immune Checkpoint Inhibitor combination was evaluated in previously untreated patients with advanced esophageal Squamous Cell Carcinoma. The researchers herein reported the results for OPDIVO® plus chemotherapy and for OPDIVO® plus YERVOY® (Ipilimumab) as compared with chemotherapy alone. In this study, 970 patients with previously untreated, unresectable, advanced, recurrent or metastatic esophageal Squamous Cell Carcinoma were randomly assigned 1:1:1 to receive OPDIVO® plus chemotherapy (N=321), OPDIVO® plus YERVOY® (N=325), or chemotherapy alone. Patients in the OPDIVO® plus chemotherapy group received OPDIVO® 240 mg IV every 2 weeks and chemotherapy consisted of Fluorouracil 800 mg/m2 IV Days 1-5 and Cisplatin 80 mg/m2 IV on Day 1, given every 4 weeks. The OPDIVO® plus YERVOY® group received OPDIVO® 3 mg/kg IV every 2 weeks plus YERVOY® 1 mg/kg IV every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. Patients could receive OPDIVO® or OPDIVO® plus YERVOY® for a maximum of 2 years. Demographic and baseline clinical characteristics were balanced across the treatment groups and in patients with tumor-cell PD-L1 expression of 1% or greater (49% of patients in each treatment group had tumor-cell PD-L1 expression of 1% or greater). The Primary end points were Overall Survival (OS) and Progression Free Survival (PFS), as determined by Blinded Independent Central Review (BICR), with hierarchical testing performed first in patients with tumor-cell PD-L1 expression of 1% or greater and then in the overall population. The Secondary end points included Objective Response Rate (ORR), which was also assessed by BICR.

After a minimum follow up period of 13 months, Overall Survival was significantly longer with OPDIVO® plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (15.4 months versus 9.1 months; HR=0.54; P<0.001) and in the overall population (13.2 months versus 10.7 months; HR=0.74; P=0.002). These findings suggested a 46% and 26% lower risk of death respectively with OPDIVO® plus chemotherapy, than with chemotherapy alone. Overall Survival was also significantly longer with OPDIVO® plus YERVOY® than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (13.7 months versus 9.1 months; HR=0.64; P=0.001) and in the overall population (12.7 months versus 10.7 months; HR=0.78; P=0.01).

There was a significant improvement in Progression Free Survival seen with OPDIVO® plus chemotherapy over chemotherapy alone, among patients with tumor-cell PD-L1 expression of 1% or greater (HR=0.65; P=0.002). This PFS benefit was not seen with OPDIVO® plus YERVOY®, as compared with chemotherapy. The incidence of Grade 3 or 4 treatment-related Adverse Events was 47% with OPDIVO® plus chemotherapy, 32% with OPDIVO® plus YERVOY® and 36% with chemotherapy alone.

Treatment with either OPDIVO®-based regimens resulted in a higher Complete Response rate, as well as in more durable responses, than chemotherapy alone. Of the three treatment regimens, OPDIVO® plus chemotherapy led to the highest Objective Response Rate and OPDIVO® plus YERVOY® resulted in the longest median Duration of Response.

It was concluded that first-line treatment of advanced esophageal Squamous Cell Carcinoma with either OPDIVO® plus chemotherapy or OPDIVO® plus YERVOY®, resulted in a significantly longer Overall Survival benefit and durable responses, than chemotherapy alone.

Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. Doki Y, Ajani JA, Kato K, et al. N Engl J Med 2022;386:449-462

Consider Guideline-Recommended Biomarker Testing as an Integral Component of NSCLC Care

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The NSCLC Landscape Has Evolved Significantly Due Largely to the Growing Number of Actionable Mutations1

Despite advancements in standard-of-care, advanced non-small cell lung cancer (NSCLC) continues to burden patients, with poor survival outcomes.2,3 NSCLC has been identified as the leading cause of cancer death worldwide with an estimated 1.8 million deaths in 2020.2 As the number of targeted therapies and approved companion diagnostics continues to grow, mortality and survival rates have begun to improve.3 With the addition of KRAS G12C, there are 9 actionable molecular biomarkers (as of February 2022) and more than 20 targeted therapies approved for use in advanced NSCLC.1,4 Guidelines recommend biomarker testing for all eligible patients at diagnosis of advanced NSCLC regardless of characteristics such as smoking history, race, or histology.5,6 Unfortunately, real-world evidence shows that far too many patients fail to receive the comprehensive biomarker testing.7

Adherence to Guidelines Can Improve Patient Outcomes8

As targeted therapies are approved, guidelines continue to update their recommendations on biomarker testing.5 As of March 2022, NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC recommend broad molecular testing of actionable and emerging biomarkers for eligible patients with advanced or metastatic NSCLC (Figure 1).5 Similarly, the American Society of Clinical Oncology (ASCO) endorsed the 2018 College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) guidelines, recommending comprehensive cancer panel testing for genetic biomarkers.9,10

Figure 1: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC5,*,†Advanced-Non-Squamous-NSCLC*The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.5†The NCCN Guidelines® for NSCLC recommend broad molecular testing to identify rare driver variants for which targeted therapies may be available to ensure patients receive the most appropriate treatment.5‡KRAS G12C and EGFR exon 20 mutations are used to determine subsequent (ie, second-line and beyond) therapy using targeted agents or other novel agents.5 §The definition of high-level MET amplification is evolving and may differ according to the assay used for testing. For NGS-based results, a copy number greater than 10 is consistent with high-level MET amplification.5 **For oncogenic or likely oncogenic HER2 mutations, refer to definitions at oncokb.org.5

Although adherence to guideline-recommended biomarker testing is associated with improved patient outcomes, real-world EMR data reveals suboptimal biomarker testing rates.8,11 In a retrospective study,†† 81% of patients with metastatic NSCLC did not receive testing for ALK, EGFR, ROS1, and BRAF before initiation of first-line treatment, despite availability of targeted therapies.11 Moreover, only 28% of patients received testing for all four genetic biomarkers and PD-L1 during the study period.11 In another retrospective study, less than 50% of patients with metastatic NSCLC received testing for all five biomarkers (EGFR, ALK, ROS1, BRAF, PD-L1) (Figure 2).7

Beyond the underutilization of biomarker testing, there remains an even greater need to increase broad molecular testing among racial and ethnic minority groups in the US.12,13 In one retrospective study, Black/African American patients with advanced NSCLC had significantly lower rates of testing with NGS assays (39.8%) compared with White patients (50.1%) (Figure 3).12

††A retrospective study assessing real-world biomarker testing patterns in patients with de novo mNSCLC (N=2,257) in the community oncology setting using the US Oncology Network electronic health records between January 1st, 2017 and September 31st, 2019 with follow-up through December 31st, 2019.11

Figure 2: MYLUNG Consortium™ EMR Analysis of Patients With Metastatic NSCLC7,‡‡MYLUNG-Consortium‡‡A retrospective, observational study assessing real-world biomarker testing patterns in patients with metastatic NSCLC(N=3,474) from community oncology practices within the US Oncology Network community practices between 2018 and 2020.7
Figure 3: EMR Analysis of Biomarker Testing in Patients With Advanced/Metastatic NSCLC12,§§
EMR-Analysis-of-Biomarker-Testing§§From a retrospective cohort study of patients with advanced/metastatic: NSCLC (N=14,768) from ~800 sites of care identified via the Flatiron Electronic Health Record Database between 2017 and 2020. Of this study cohort, patients included White (n=9,793), Black/African American (n=1,288), and non-squamous NSCLC (n=10,333).

Collectively, these findings highlight the disparity in proactive disease management across different patient populations.7,11,12

Considerations Across the Biomarker Testing Journey

There are several different methods in which eligible patients can be tested for actionable genetic alterations, each with unique considerations as indicated below (Figure 4).

Figure 4: Comparing Biomarker Testing Methods and Sample Types
Comparing-Biomarker-Testing-Methods***Data from a review of common molecular assays for biomarker testing that analyzed common detected variants, sensitivities, and turnaround time.6 †††cfDNA refers to all circulating DNA (largely non-malignant), while ctDNA refers to the tumor-related component of cfDNA.15 ‡‡‡Data from a prospective study that enrolled patients with previously untreated metastatic NSCLC undergoing SOC tissue genotyping and comprehensive cfDNA analysis, with turnaround time defined as the number of days between test order date and the retrieval of test results.16

While tissue biopsy remains the “gold standard” in NSCLC, it may not be feasible (insufficient tissue) or pragmatic (urgent need to begin treatment) in all patients.17 Plasma ctDNA demonstrates complementary results to tissue-based assays and can be considered a valid tool for genotyping of newly diagnosed patients with advanced NSCLC.15 In a prospective study of patients with previously untreated, non-squamous metastatic NSCLC from 2016 to 2018, guideline-recommended biomarkers with FDA-approved therapies (EGFR Exon 19 deletion and L858R, ALK fusion, ROS1 fusion, BRAF V600E) showed ≥ 98.2% concordance between tissue and liquid-based testing.16 While concordance is high for any single test, high concordance for full panels will be required for liquid biopsies to become standard; additionally, negative results on liquid biopsy still require validation with tissue testing.16,17

Liquid biopsy may offer improvements in sample acquisition and small tissue samples and provides less invasive procedures and shortened turnaround times.17 Other considerations for maximizing the tissue journey include the use of comprehensive testing, rapid on-site evaluation (ROSE), and implementing reflex testing protocols with the help of a multidisciplinary team (MDT).17

Delays in Biomarker Testing Results May Impact Treatment Plan Decisions18

Longer turnaround times for molecular testing compared with turnaround times for PD-L1 testing by IHC may result in the initiation of immunotherapy before molecular testing results are received.18 Waiting for complete biomarker test results prior to initiating therapy can allow doctors to make the most informed decisions surrounding a patient’s treatment journey.18

Consider Comprehensive Biomarker Testing as an Important Part of Your Treatment Plan8

As the NSCLC landscape continues to progress with the increasing number of actionable biomarkers, there is a growing need for proactive and comprehensive molecular testing.7,17 Although real-world data has shown significant underuse of biomarker testing, rates can be improved with diligent observation of expanding guidelines and recommendations by expert panels and associations.7,8 In the coming years, clinicians may consider evolving institutional protocols, including enabling reflex testing, and work as an MDT to ensure biomarker testing is performed on all eligible patients with advanced NSCLC.17

[Abbreviations]
AA, African American; ALK, anaplastic lymphoma kinase; BRAF, proto-oncogene B-Raf; cfDNA, cell-free DNA; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; EMR, electronic medical record; ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma viral oncogene homolog; MET, mesenchymal-to-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; NSCLC, non-small cell lung cancer; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PD-L1, programmed cell death ligand 1; RET, rearranged during transfection; ROS1, c-ros oncogene 1; SOC, standard-of-care.

[References]
1. Majeed U, et al. J Hematol Oncol. 2021;14:108.
2. Sung H, et al. CA Cancer J Clin. 2021;71:209-249.
3. Siegel RL, et al. CA Cancer J Clin. 2021;71:7-33.
4. Food and Drug Administration. www.fda.gov. Accessed October 6, 2021.
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.3.2022. ©National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed March 16, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
6. Pennell NA, et al. Am Soc Clin Oncol Educ Book. 2019;39:531-542.
7. Robert NJ, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 102.
8. John A, et al. Adv Ther. 2021;38:1552-1566.
9. Hanna N, et al. J Clin Oncol. 2017;35:3484-3515.
10. Lindeman NI, et al. Arch Pathol Lab Med. 2018;142:321-346.
11. Nadler ES, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 9079.
12. Bruno DS, et al. Presented at: The American Society of Clinical Oncology Annual Meeting; June 4–8, 2021; Virtual Meeting. Abstract 9005.
13. Hann KEJ, et al. BMC Public Health. 2017;17:503.
14. Pennell NA, et al. JCO Precis Oncol. 2019;3:1-9.
15. Rolfo C, et al. J Thorac Oncol. 2021;16:1647-1662.
16. Leighl NB, et al. Clin Cancer Res. 2019;25:4691-4700.
17. Gregg JP, et al. Transl Lung Cancer Res. 2019;8:286-301.
18. Smeltzer MP, et al. J Thorac Oncol. 2020;15:1434-1448.

USA-510-80864 02/22

FDA Approves KYMRIAH® for Relapsed or Refractory Follicular Lymphoma

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SUMMARY: The FDA on May 27, 2022, granted accelerated approval to KYMRIAH® (Tisagenlecleucel) for adult patients with Relapsed or Refractory Follicular Lymphoma after two or more lines of systemic therapy. The American Cancer Society estimates that in 2022, about 80,470 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,250 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 22% of all NHLs are Follicular Lymphomas (FL).

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

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen. KYMRIAH® (genetically engineered T-cells) seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

The present FDA approval was based on the ELARA trial, which is an international, multicenter, single-arm, open-label trial in which the efficacy and safety of KYMRIAH® was investigated in adult patients with Relapsed/Refractory Follicular Lymphoma, after at least two prior therapies. A total of 97 patients received KYMRIAH® (0.6-6×108 CAR+ viable T cells) after lymphodepleting chemotherapy. Bridging therapy was permitted followed by disease assessment prior to KYMRIAH® infusion. Eligible patients had Grades 1-3A Relapsed/Refractory Follicular Lymphoma who had progressed on 2 or more lines of systemic therapy, (including an anti-CD20 antibody and an alkylating agent) or relapsed after Autologous hematopoietic Stem Cell Transplant. The median patient age was 57 years, 85% had Stage III-IV disease, 60% had a FLIPI score 3 or more, 65% had bulky disease, and 42% had LDH above the upper limit of normal. The median number of prior therapies was 4, 78% of patients were refractory to their last treatment and 60% progressed within 2 years of initial anti-CD20 based therapy. The Primary endpoint was Complete Response Rate (CRR) by central review per Lugano 2014 criteria. Secondary endpoints included Overall Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), Safety, and cellular kinetics.

In the primary efficacy analysis, with a median follow up 10.6 months, the Overall Response Rate was 86% with a Complete Response Rate of 66%. The response rates were comparable among key high risk subgroups. The median Duration of Response was Not Reached, with 75% of responders still in response at 9 months. At a median follow up of 17 months, the response rates were maintained and the 12-month PFS was 67% and 9 month Duration of Response was 76%. For patients who had a Complete Response, the 12-month PFS was 86% and the estimated Duration of Response was 87%. Approximately 48% of patients experienced Cytokine Release Syndrome (CRS) within eight weeks of infusion, with no patients experiencing CRS of Grade 3 or higher.

It was concluded that after a median follow up of 17 months, KYMRIAH® demonstrated high Response Rates, as well as durable responses, with remarkable safety profile, thus providing a new treatment option for this difficult-to-treat patient group of patients with Relapsed or Refractory Follicular Lymphoma.

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study. Thieblemont C, Dickinson M, Martinez-Lopez J, et al. Presented in an oral session at the 63rd American Society of Hematology Annual Meeting & Exposition (ASH) 2021:(Abstract #131).

IMFINZI® in Combination with Chemotherapy Improves Overall Survival in Advanced Biliary Tract Cancer

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SUMMARY: Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Patients with advanced bile tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by bile tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival, has been increasingly explored.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMFINZI® in combination with Gemcitabine and Cisplatin showed encouraging antitumor activity in a Phase II study, among patients with advanced bile tract cancers.

TOPAZ-1 is a double-blind, multicenter, global, Phase III trial conducted to evaluate the efficacy of first line immunotherapy given along with Gemcitabine and Cisplatin in patients with advanced metastatic biliary tract cancer. In this study, a total of 685 previously untreated patients with unresectable, locally advanced, recurrent or metastatic biliary tract cancer were randomized 1:1 to receive IMFINZI® (Durvalumab) 1500 mg IV every 3 weeks (N=341) or placebo (N=344), along with Gemcitabine 1000 mg/m2 IV and Cisplatin 25 mg/m2 IV given on Days 1 and 8, every 3 weeks for up to 8 cycles, followed by IMFINZI® 1500 mg IV every 4 weeks or placebo, until disease progression or unacceptable toxicity. Patients with recurrent disease more than 6 months following curative surgery or adjuvant therapy were also included. The median patient age was 64 years and approximately 50% of patients had an ECOG Performance Status of 0. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versus gallbladder cancer). Approximately 56% had intrahepatic cholangiocarcinoma, followed by gallbladder cancer (25%) and extrahepatic cholangiocarcinoma (19%). The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety.

The Primary endpoint was met at the first interim analysis and treatment with IMFINZI® plus Gemcitabine and Cisplatin significantly improved Overall Survival compared with placebo plus chemotherapy, with a 20% reduction in the risk of death (HR=0.80; P=0.021). Progression Free Survival was also greatly improved with chemoimmunotherapy vs chemotherapy alone (HR=0.75; P=0.001). The Objective Response Rate was was 26.7% in the IMFINZI® plus chemotherapy group and 18.7% in the placebo plus chemotherapy group. Grade 3 or 4 treatment-related adverse events were almost similar in both treatment groups (62.7% versus 64.9%), and treatment discontinuation due to adverse events was 8.9% in the IMFINZI® plus chemotherapy group and 11.4% in the placebo plus chemotherapy group.

It was concluded that in patients with advanced biliary tract cancers, IMFINZI® in combination with Gemcitabine and Cisplatin significantly improved Overall Survival and Progression Free Survival with manageable safety, when compared to chemotherapy alone, and should therefore be considered first line standard-of- care for this patient group.

A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (gemcis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Oh D-Y, He AR, Qin S, et al. J Clin Oncol. 2022;40(suppl 4):378. DOI:10.1200/JCO.2022.40.4_suppl.378.

Mutations of STK11/KRAS Genes and Efficacy of Immunotherapy in NSCLC

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SUMMARY: The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

TECENTRIQ® (Atezolizumab) is an anti-PDL1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors and thus enabling the activation of T cells. AVASTIN® (Bevacizumab) is a biologic antiangiogenic antibody, directed against Vascular Endothelial Growth Factor (VEGF), and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors has been shown to result in endothelial cell proliferation and new blood vessel formation. Combining TECENTRIQ® and AVASTIN® is supported by the following scientific rationale. AVASTIN® in addition to its established anti-angiogenic effects, may further enhance the ability of TECENTRIQ® to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

IMpower150 is a multicenter, open-label, randomized, Phase III study, conducted to evaluate the efficacy and safety of TECENTRIQ® in combination with Carboplatin and Paclitaxel with or without AVASTIN®, in patients with Stage IV, treatment naïve, non-squamous NSCLC. This study enrolled 1,202 patients, who were randomized (1:1:1) to receive either TECENTRIQ® along with Carboplatin and Paclitaxel (ACP-Group A), TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel (ABCP-Group B), or AVASTIN® plus Carboplatin and Paclitaxel (BCP-Group C – control arm). During the treatment-induction phase, patients in Group A received TECENTRIQ® 1200 mg IV along with Carboplatin AUC 6 and Paclitaxel 200mg/m2 IV on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, patients received maintenance treatment with TECENTRIQ® on the same dose schedule until disease progression. Patients in Group B received AVASTIN® 15 mg/kg IV, along with TECENTRIQ®, Carboplatin and Paclitaxel IV, Day 1 of a 3-week treatment cycle for 4 or 6 cycles followed by maintenance treatment with the TECENTRIQ® and AVASTIN® until disease progression. Patients in the control Group C received AVASTIN® plus Carboplatin and Paclitaxel every 3 weeks for 4 or 6 cycles followed by AVASTIN® maintenance treatment until disease progression. Among randomized patients with tumors demonstrating no ALK and EGFR mutations, ABCP was associated with significant improvements in Progression Free Survival (PFS) and Overall Survival (OS), compared with BCP, in an updated OS analysis. ABCP also prolonged OS and PFS compared with BCP in an exploratory subgroup analysis of patients with EGFR-sensitizing mutations.

The Serine‐Threonine Kinase 11 (STK11) gene is located on the short arm of chromosome 19 and germline STK11 mutations are often detected in Peutz‐Jeghers syndrome, an Autosomal Dominant disorder resulting in mucocutaneous hyperpigmentation, hamartomas throughout the gastrointestinal tract, and a predisposition for breast, lung, pancreas, and gastrointestinal malignancies including cancers of the colon and small bowel. Both STK11 (also called LKB1) and KEAP1 mutation occur in about 17% of NSCLC (adenocarcinomas), respectively, and correlates with poor outcome with immune checkpoint inhibitors or immune checkpoint inhibitors plus chemotherapy. Although immune checkpoint inhibitors with or without chemotherapy have demonstrated survival benefit in patients with KRAS mutated tumors, it remains unclear how co-occurring STK11, KEAP1, and TP53 mutations affect outcomes following immune checkpoint blockade.

The authors in this publication conducted a retrospective exploratory analysis of the efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel), in patients with KRAS mutations and co-occuring STK11, KEAP1, or TP53 mutations, from the IMpower150 nonsquamous NSCLC patient population. Mutation status was determined by circulating tumor DNA Next-Generation Sequencing.

Among the KRAS mutated population, there was numerical improvement in median OS with ABCP compared to BCP (19.8 vs 9.9 months; HR=0.50), as well as PFS (8.1 vs 5.8 months; HR=0.42) respectively. The median OS with ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was 11.7 vs 9.9 months (HR=0.63), and PFS was 4.8 vs 5.8 months (HR=0.80), when compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel). When compared to BCP, the ABCP group showed numerically greater survival than the ACP group among KRAS mutated patients. These results were consistent with reported survival improvements with immune checkpoint inhibitors in KRAS-mutant NSCLC.

In KRAS mutant patients across PD-L1 subgroups, OS and PFS were longer with ABCP when compared with BCP, but in PD-L1-low and PD-L1-negative subgroups, OS with ACP was similar to BCP. Conversely, in KRAS wild type patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups.

KRAS was frequently comutated with STK11, KEAP1, and TP53 and these subgroups conferred different prognostic outcomes. Within the KRAS mutated population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-wild type and/or KEAP1wild type. In KRAS mutated patients with co-occurring STK11 and/or KEAP1 mutations (44.9%) or TP53 mutations (49.3%), survival was longer with ABCP than with ACP or BCP.

It was concluded that this analysis supported previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. Even though the clinical efficacy of ABCP (TECENTRIQ® and AVASTIN® along with Carboplatin and Paclitaxel) and ACP (TECENTRIQ® along with Carboplatin and Paclitaxel) was favorable compared with BCP (AVASTIN® plus Carboplatin and Paclitaxel) in these mutational subgroups, survival benefits were greater in the KRAS mutated and KEAP1 and STK11 wild type population versus KRAS mutated and KEAP1 and STK11 mutated population, suggesting both prognostic and predictive value of mutational analysis. The researchers added that these results suggest that TECENTRIQ® in combination with AVASTIN® and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with KRAS mutations co-occurring with STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS- mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial. West JH, McCleland M, Cappuzzo, F, et al. J Immunother Cancer. 2022 Feb;10(2):e003027. doi: 10.1136/jitc-2021-003027.

IMFINZI® Plus Tremelimumab Significantly Improves Overall Survival in Advanced Hepatocellular Carcinoma

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SUMMARY: The American Cancer Society estimates that for 2022, about 41,260 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US and 30,520 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis and only 7% of patients with advanced disease survive five years. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. Tremelimumab is a human monoclonal antibody that targets and blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In a Phase II study, a single priming dose of Tremelimumab added to IMFINZI® (STRIDE regimen), showed encouraging clinical activity and limited toxicity in patients with unresectable HepatoCellular Carcinoma (HCC), suggesting that a single exposure to Tremelimumab may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicentre, global, Phase III study conducted in 190 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. In this study, 1,171 patients with Stage III or IV unresectable hepatocellular carcinoma who had received no prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue), were randomly assigned to receive either the STRIDE regimen which consisted of a single priming dose of Tremelimumab 300 mg IV added to IMFINZI® (Durvalumab) 1500 mg IV, followed IMFINZI® 1500 mg IV by every 4 weeks (N= 393), IMFINZI® monotherapy given at the same dose and schedule (N = 389) or NEXAVAR® (Sorafenib) 400 mg orally BID (N=389). Enrolled patients had ECOG performance status of 0 or 1 and Child-Pugh A disease and could not have main portal vein thrombosis. Patients were stratified based on macrovascular invasion (Yes versus No), etiology of liver disease (Hepatitis B virus versus Hepatitis C virus versus others), and ECOG Performance Status (0 versus 1). The Primary endpoint was Overall Survival (OS) for STRIDE regimen versus NEXAVAR® and key Secondary endpoints included OS for IMFINZI® monotherapy versus NEXAVAR®, Objective Response Rate and Progression Free Survival (PFS) for STRIDE and IMFINZI® monotherapy.

The Primary objective of this study was met at the time of data cutoff. At a median follow up of 16.1 months of treatment with the STRIDE regimen, there was a 22% reduction in the risk of death for patients who received the STRIDE regimen compared to NEXAVAR® alone (HR=0.78; P=0.0035). The median OS with the STRIDE regimen was 16.4 months, compared with 13.8 months with NEXAVAR®, and the 3 year OS rate was 30.7% versus 20.2 % respectively. The Overall Response Rate for the combination STRIDE regimen was 20.1% compared to 5.1% for NEXAVAR®

IMFINZI® monotherapy met the objective of OS non-Inferiority to NEXAVAR® (HR=0.86; 96% CI, 0.73–1.03) and the median OS after 16.5 months of median follow up was 16.6 months with IMFINZI® monotherapy versus 13.8 months with NEXAVAR®, and the 3 year OS rate was 24.7% versus 20.2 % respectively. The Overall Response Rate with IMFINZI® monotherapy was 17% compared to 5.1% for NEXAVAR®. The Secondary endpoint of PFS was not superior in either investigational study group relative to the NEXAVAR® control arm.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody Tremelimumab, to another checkpoint inhibitor, IMFINZI®. This combination regimen (STRIDE) demonstrated superior efficacy and a favorable benefit-risk profile when compared with NEXAVAR® and should be considered a novel , first-line standard of care systemic therapy, for patients with unresectable Hepatocellular Carcinoma.

Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. Abou-Alfa GK, Chan SL, Kudo M, et al. J Clin Oncol. 2022;40(suppl 4):379. doi:10.1200/JCO.2022.40.4_suppl.379

Factors Associated with Mortality among Cancer Patients with COVID-19 Infection Compared with Those without Cancer

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SUMMARY: The SARS-CoV-2 Coronavirus (COVID-19) induced pandemic first identified in December 2019 in Wuhan, China, has contributed to significant mortality and morbidity in the US, and the numbers of infected cases continue to increase worldwide. As of May 15, 2022, over ONE million individuals have died from COVID-19 in the USA. Majority of the patients present with treatment-resistant pyrexia and respiratory insufficiency, with some of these patients progressing to a more severe systemic disease and multiple organ dysfunction.

Patients with cancer are immunocompromised from either the underlying disease or therapy and are susceptible to infections with respiratory viruses. This is even more relevant with the emergence of the COVID-19 pandemic, and numerous studies have been conducted to understand the impact of infection with COVID-19 and outcomes in patients with cancer, infected with COVID-19, with discordant results. The understanding of possible risks, complications and outcomes of COVID-19 infection among cancer patients is important for patients and families, as well as health care systems.

The researchers conducted this study to assess the differences in clinical outcomes between cancer patients with SARS-CoV-2 infection and patients without cancer but with SARS-CoV-2 infection, and also to identify cancer patients at a high risk for poor outcomes. This systematic review and meta-analysis included 81 studies involving 61, 532 patients with cancer. Among 58 849 patients with available data, 52% were male median age ranged from 35- 74 years. Data was extracted from the PubMed, Web of Science, and Scopus databases until June 14, 2021. The main outcomes and measures were the difference in mortality between cancer patients with SARS-CoV-2 infection and control patients, as well as the difference in outcomes for various tumor types and cancer treatments. Majority of patients represented were from the US, UK, Italy, France and China.

In age and sex-matched analysis, the Relative Risk (RR) of mortality from COVID-19 among cancer patients compared to those without cancer was 1.69 (P<0.001). The risk of mortality among cancer patients versus those without cancer decreased with increasing age (Odds Ratio = 0.96; P=0.03). The researchers hypothesized that the reasons for this finding were likely associated with the type of cancer, the intensity of treatments, or behavioral factors such as increased social mixing among patients younger than 50 years, compared to that of an older population.

When mortality and Case Fatality Rate were analyzed by cancer type, the pooled Case Fatality Rate for patients with lung cancer and SARS-CoV-2 infection was 30% and the Relative Risk of mortality in those patients with lung cancer compared with other cancer types was significantly higher at 1.68 (P<0.001). This was followed by hematologic cancer with a pooled Case Fatality Rate for patients with hematologic cancer and SARS-CoV-2 infection of 32%, and the Relative Risk of mortality in patients with hematologic cancer and SARS-CoV-2 infection compared with those with solid malignant neoplasms was 1.42 (P<0.001). Breast cancer (RR, 0.51; P<0.001) and gynecological cancer (RR, 0.76; P=0 .009) were associated with a significantly lower risk of death.

When Case Fatality Rate was analyzed by treatment type, chemotherapy was associated with the highest overall pooled Case Fatality Rate of 30%, and endocrine therapy was associated with the lowest at 11%. Radiotherapy was associated with a Case Fatality Rate of 23%, Immunotherapy, as well as surgery within 3 months of a COVID-19 diagnosis in patients with cancer was associated with a Case Fatality Rate of 19% and targeted therapy was associated with a rate of 18%.

The authors from this analysis concluded that patients with cancer and SARS-CoV-2 infection had a higher risk of death, than patients without cancer. Risk factors associated with poor outcomes from COVID-19 included younger age, lung cancer, and hematologic malignancies.

Differences in Outcomes and Factors Associated With Mortality Among Patients With SARS-CoV-2 Infection and Cancer Compared With Those Without CancerA Systematic Review and Meta-analysis. Khoury E, Nevitt S, Madsen WR, et al. JAMA Netw Open. 2022;5(5):e2210880. doi:10.1001/jamanetworkopen.2022.10880

Long Term Disease Free Survival Benefits with Adjuvant OPDIVO® in Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analyses have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

OPDIVO®(Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group, as well as adjuvant treatment of patients with urothelial carcinoma who are at high risk of recurrence after undergoing radical resection.

CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. The mean age was 65.3 years and both treatment groups were well balanced. Approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant Cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS), Overall Survival and Safety.

The authors in this publication reported the DFS outcomes, with 5 additional months of follow up, in all randomized patients. Patients with high-risk, muscle-invasive urothelial carcinoma continued to experience clinically meaningful improvements in Disease Free Survival (DFS), with a median DFS of 22.0 months among those receiving OPDIVO® (95% CI, 17.7-36.9) compared with 10.9 months (95% CI, 8.3-14.0) among those receiving placebo (HR=0.70; 95% CI, 0.57-0.85). The DFS probability at 12 months was 63.5% with OPDIVO® versus 46.9% with placebo. The DFS benefit was even more significant in patients with PD-L1 expression of 1% or more and was Not Reached in the OPDIVO® group versus 8.4 months in the placebo group (HR, 0.53; 95% CI, 0.38-0.75). The DFS probability at 12 months was 67.6% with OPDIVO® versus 46.3% with placebo. The DFS benefits was observed with OPDIVO® among most subgroups analyzed, including age, sex, ECOG PS, nodal status and use of prior Cisplatin-based chemotherapy.

NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival (DMFS) were also improved with OPDIVO® when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more.

It was concluded that with longer follow up, OPDIVO® continued to show clinically meaningful improvement in Disease Free Survival among patients with high-risk muscle-invasive urothelial carcinoma, when compared to placebo, both in all randomized patients, as well as patients with PD-L1 expression of 1% or more. OPDIVO® also improved NonUrothelial Tract Recurrence-Free Survival (NUTRFS) and Distant Metastasis-Free Survival when compared to Placebo. The authors added that these results support adjuvant OPDIVO® as a Standard of Care for high risk muscle-invasive urothelial carcinoma patients after radical surgery.

Galsky M, Witjes JA, Gschwend JE, et al. Disease-free survival with longer follow-up from the CheckMate 274 trial of adjuvant nivolumab in patients after surgery for high-risk muscle-invasive urothelial carcinoma. J Urol. 2022;207(suppl 5):e183. doi:10.1097/JU.0000000000002536.01