Author: RR

Dietary Supplement Use during Adjuvant Chemotherapy May Increase Risk for Breast Cancer Recurrence

RR

SUMMARY: The Council for Responsible Nutrition reported that 77% of Americans consume dietary supplements. With the growing awareness regarding health, fitness and nutrition, the market size for dietary supplements is projected to hit a valuation of $349.4 billion by 2026.

Patients often use dietary supplements following a diagnosis of cancer, even though clinical recommendations discourage the use of antioxidant supplements during chemotherapy. One of the mechanisms of action of cytotoxic chemotherapeutic agents is through the generation of Reactive Oxygen Species (ROS). The use of dietary supplements during treatment, particularly antioxidants, could reduce the efficacy of cytotoxic agents. DELCaP study was conducted to address this concern.

DELCaP (Diet, Exercise, Lifestyle and Cancer Prognosis) trial is a prospective observational study, ancillary to an intergroup therapeutic clinical trial for high-risk breast cancer, conducted to evaluate associations between supplement use, particularly antioxidants during chemotherapy treatment, and breast cancer survival outcomes.

The Phase III SWOG S0221 trial evaluated the optimal dose and schedule of Anthracycline/Taxane adjuvant chemotherapy in women with high-risk early breast cancer. The current analysis involved a cohort of 1,134 of 2,014 patients enrolled in this study, who answered a baseline and follow-up questionnaires that included their use of dietary supplement at enrollment and during treatment. The authors then analyzed associations of dietary supplement use with clinical outcomes, after adjusting for clinical and lifestyle factors. Approximately 18% of patients used antioxidants such as Vitamins C, A, and E, Carotenoids or Coenzyme Q10 during treatment, whereas 44% of patients took multivitamins during chemotherapy.

It was noted from this analysis that the use of any antioxidant supplement (Vitamins A, C, and E, Carotenoids and Coenzyme Q10), both before and during adjuvant treatment was associated with an increased risk of recurrence versus no such use of supplements (HR=1.41; P=0.06). There was also a nonsignificant increased risk of overall mortality with the use of any antioxidant supplement (HR=1.40; P=0.14). There was a weaker relationship of outcomes with individual antioxidants and this may perhaps be due to the small numbers of patients. With regards to nonoxidants, Vitamin B12 use both before and during chemotherapy was significantly associated with poorer Disease Free Survival (HR=1.83; P<0.01) and Overall Survival (HR= 2.04; P<0.01). Use of iron during chemotherapy was also significantly associated with recurrence (HR=1.79; P<0.01), as was use both before and during treatment (HR=1.91; P=0.06). Results were similar for Overall Survival. Multivitamin use however was not associated with survival outcomes.

The researchers based on this analysis concluded that the use of antioxidant and nonantioxidant dietary supplements, but not multivitamins, before and during adjuvant chemotherapy may be associated with inferior treatment outcomes, in patients with early stage high risk breast cancer. They added that caution should be exercised by patients, when considering the use of supplements, other than a multivitamin, during chemotherapy, and patients should try to get their vitamins and minerals including antioxidants through food products..

Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). Ambrosone CB, Zirpoli GR, Hutson AD, et al. J Clin Oncol. 2019;38:804-814

FDA Approves ALUNBRIG® for First Line Treatment of ALK Positive Non Small Cell Lung Cancer

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SUMMARY: The FDA on May 22, 2020 approved approved ALUNBRIG® (Brigatinib) for the first-line treatment of patients with ALK-positive metastatic 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 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 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 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) and ALUNBRIG® (Brigatinib), 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 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive, and the presence of two simultaneous mutations, are rare.

The new approval for ALUNBRIG® was based on results from the Phase III ALTA 1L (ALK in Lung Cancer Trial of BrigAtinib in 1st Line) trial, which is a global, ongoing, randomized, open-label, comparative, multicenter study, in which investigators compared the efficacy and safety of ALUNBRIG® with XALKORI® (Crizotinib) in 275 patients with Stage IIIB/IV ALK positive, locally advanced or metastatic NSCLC, who have not received prior treatment with an ALK inhibitor, but may have received 1 prior regimen of chemotherapy or no chemotherapy in the advanced setting. Patients were randomized 1:1 to receive either ALUNBRIG® 180 mg orally once daily (N=137), with a 7-day lead-in period at 90 mg, or XALKORI® 250 mg orally twice daily (N=138). Crossover from the XALKORI® arm to receive ALUNBRIG® was permitted at BICR (Blinded Independent Review Committee)-assessed Progression Free Survival (PFS). The median age was 59 years, and 55% of patients were female. Twenty-nine percent had brain metastases at baseline with comparable pre-enrollment central nervous system (CNS) radiotherapy rates among both cohorts. Overall, 27% of patients had prior chemotherapy in the locally advanced or metastatic setting. The Primary endpoint was BIRC assessed PFS and Secondary endpoints included Objective Response Rate (ORR), Intracranial ORR, Intracranial PFS, Overall Survival (OS), safety, and tolerability.

At a median follow up of 25 months, it was noted that ALUNBRIG® reduced the risk of disease progression or death by 51% compared with XALKORI® (HR=0.49; P=0.0007), with a median PFS of 24 months as assessed by a BIRC versus 11 months for XALKORI®. The confirmed ORR as assessed by BIRC was 74% with ALUNBRIG® and 62% for XALKORI®. The median duration of response (DOR) was not reached, and 13.8 months with ALUNBRIG® and XALKORI®, respectively.

After more than two years of follow-up, ALUNBRIG® demonstrated superiority over XALKORI®, with significant anti-tumor activity observed, especially in patients with baseline brain metastases. The confirmed intracranial ORR for patients with measurable brain metastases at baseline, treated with ALUNBRIG® was 78% versus 26% for patients treated with XALKORI®. The median intracranial Duration of Response in confirmed responders with measurable brain metastases at baseline was Not Reached with ALUNBRIG® and 9.2 months with XALKORI®, respectively. The median intracranial PFS was 24 months with ALUNBRIG®, compared with 5.6 months for XALKORI®. ALUNBRIG® reduced the risk of intracranial disease progression or death by 69% in patients who had brain metastases at baseline (HR=0.31).

Additionally, patients in the ALUNBRIG® group also experienced significant improvements in Health-Related Quality of Life, with delay in the median time to worsening in Global Health Score by 27 months versus 8 months with XALKORI®, as well as delay in the time to worsening and prolonged duration of improvement in fatigue, nausea and vomiting, appetite loss, and emotional and social functioning. Further, the duration of improvement in QoL with ALUNBRIG® was Not Reached versus 12 months with XALKORI®.

It was concluded that ALUNBRIG® demonstrated a statistically and clinically significant improvement in Progression Free Survival when compared to XALKORI® in ALK inhibitor-naïve, ALK positive NSCLC, with superior efficacy especially among those with brain metastases at baseline.

Brigatinib vs crizotinib in patients with ALK inhibitor-naive advanced ALK+ NSCLC: Updated results from the phase III ALTA-1L trial. Camidge R, Kim HR, Ahn M, et al. Presented at the 2019 ESMO Asia Congress, November 23, 2019.

FDA Approves Chemotherapy-Free First Line Immunotherapy Combination in Advanced NSCLC

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SUMMARY: The FDA on May 15, 2020, approved OPDIVO® (Nivolumab) in combination with YERVOY® (Ipilimumab), as first-line treatment for patients with metastatic Non-Small Cell Lung Cancer (NSCLC), whose tumors express PD-L1(1% or more), as determined by an FDA-approved test, with no Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® is presently approved for treatment of patients with metastatic NSCLC and progression on or after Platinum-based chemotherapy. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4.

The present FDA approval was based on CheckMate-227, which is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. In Part 1 of this trial, there were 2 cohorts– Part 1a in which OPDIVO® plus low dose YERVOY® (N=396) or OPDIVO® monotherapy (N=396) was compared with chemotherapy alone (N=397), in patients whose tumors expressed PD-L1 expression of 1% or more and Part 1b in which OPDIVO® plus low dose YERVOY® (N=187) or OPDIVO® plus chemotherapy (N=177) was compared with chemotherapy alone (N=186), in patients whose tumors did not express PD-L1 (less than 1%). (In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere). It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.

OPDIVO® was administered at 3 mg/kg every 2 weeks, and in the combination arm, YERVOY® was administered at 1 mg/kg every 6 weeks. When administered with chemotherapy, OPDIVO® was administered at 360 mg every 3 weeks. Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or administered for 2 years for immunotherapy. There were two Co-primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). The minimum follow up for the Primary endpoint was 29 months. Both Part 1a and Part 1b groups met their Primary endpoints.

In the Part 1a cohort with PD-L1 expression of 1% or more, the Overall Survival was significantly longer with OPDIVO® plus YERVOY®, compared to chemotherapy. The median Overall Survival was 17.1 months in the Immunotherapy combination group compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007), with a 2-year OS rates of 40.0% and 32.8%, respectively. Progression Free Survival, Objective Response Rates and Duration of Response were all greater with OPDIVO® plus YERVOY® combination, compared to chemotherapy. The median Progression Free Survival (PFS) was 5.1 months in the OPDIVO® plus YERVOY® group and 5.6 months in the platinum-doublet chemotherapy group (HR=0.82). Confirmed Overall Response Rate (ORR) was 36% and 30% respectively. Median Duration of Response was 23.2 months in the OPDIVO® plus YERVOY® group and 6.2 months in the platinum-doublet chemotherapy group. In the Part 1b cohort with PD-L1 expression of less than 1%, Overall Survival benefit was again observed with the OPDIVO® plus YERVOY® combination, compared with chemotherapy, with a median duration of 17.2 months with OPDIVO® plus YERVOY® and 12.2 months with chemotherapy. Among all the patients in the trial, the median duration of OS was 17.1 months with OPDIVO® plus YERVOY® and 13.9 months with chemotherapy. Grade 3 and 4 treatment-related Adverse Events across all patients was 33% in those treated with OPDIVO® plus YERVOY® combination and 36% with chemotherapy.

It was concluded that first-line treatment of patients with advanced NSCLC, with a combination of two immunotherapy drugs, improves Overall Survival, compared to chemotherapy, independent of the PD-L1 expression level, and offers a chemotherapy-free first line treatment option for a subset of NSCLC patients, leaving chemotherapy for later lines of therapy.

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. N Engl J Med. 2019;381:2020-2031.

FDA Approves RUBRACA® for BRCA-Mutated Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on May 15, 2020, granted accelerated approval to RUBRACA® (Rucaparib) for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic Castration-Resistant Prostate Cancer (mCRPC), who have been treated with Androgen Receptor-directed therapy and a taxane-based chemotherapy. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 191,930 new cases of prostate cancer will be diagnosed in 2020 and 33,330 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. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly bind to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibit translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

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. The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1, PARP2 and PARP3. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination (HR) pathway. Homologous Recombination is a type of genetic recombination, and 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, BRCA2 and ATM genes. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins therefore repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy.

Recently published data has shown that deleterious germline and/or somatic mutations in BRCA1, BRCA2, ATM, or other Homologous Recombination DNA-repair genes, are present in about 25% of patients with advanced prostate cancer, including mCRPC. Mutations in BRCA1 and BRCA2 also account for about 20-25% of hereditary breast cancers, about 5-10% of all breast cancers, and 15% of ovarian cancers. 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). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. HRD therefore indicates an important loss of DNA repair function. PARP 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. In the presence of a PARP inhibitor, there is synthetic lethality because of the loss of both repair pathway genes, leading to cell death. Thus PARP inhibitors are only harmful to cancer cells.MOA-of-RUBRACA

RUBRACA® is an oral, small molecule inhibitor of Poly-Adenosine diphosphate [ADP] Ribose Polymerase (PARP), presently approved by the FDA for ovarian, fallopian tube or primary peritoneal cancers. This recent FDA approval for prostate cancer patients was based on TRITON2, which is an ongoing international, multicenter, open-label, single arm, Phase II trial, in patients with BRCA-mutated mCRPC, who had been treated with Androgen Receptor-directed therapy and taxane-based chemotherapy. In this study, 115 mCRPC patients with either germline or somatic BRCA mutations were enrolled, of whom 62 patients had measurable disease at baseline. Patients received RUBRACA® 600 mg orally twice daily and concomitant GnRH analog or had prior bilateral orchiectomy. Treatment was continued until disease progression or unacceptable toxicity. The median age was 73 years, majority of patients had an ECOG performance status of 0 or 1, 18% of patients had lung metastases, 21% had liver metastases, 24% had metastases to lymph nodes alone and 40% had 10 or more bone lesions at baseline. The major efficacy outcomes of the study were Objective Response Rate (ORR) and Duration of Response (DOR) in the 62 patients with measurable disease. The median duration of follow up was 13.1 months

The confirmed ORR was 44% and the median DOR was not evaluable. Fifty six percent (56%) of patients with confirmed Objective Responses had a DOR of 6 months or more.

It was concluded that RUBRACA® demonstrates promising efficacy in patients with mCRPC with deleterious BRCA mutations. TRITON3 study is evaluating RUBRACA® versus physician’s choice of second-line AR-directed therapy or Docetaxel, in chemotherapy-naïve patients with mCRPC and alterations in BRCA1/2, who progressed on one prior AR-directed therapy.

ESMO 2019: Preliminary Results from the TRITON2 Study of Rucaparib in Patients with DNA Damage Repair-deficient mCRPC: Updated Analyses. Abida W, Campbell D, Patnaik A, et al. 2019 ESMO Annual Meeting, #ESMO19, 27 Sept – 1 Oct 2019 in Barcelona, Spain.

LYNPARZA® (Olaparib)

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The FDA on May 19, 2020 approved LYNPARZA® for adult patients with deleterious or suspected deleterious germline or somatic Homologous Recombination Repair (HRR) gene-mutated metastatic Castration-Resistant Prostate Cancer (mCRPC), who have progressed following prior treatment with Enzalutamide or Abiraterone. LYNPARZA® is a product of AstraZeneca Pharmaceuticals, LP.

TECENTRIQ® (Atezolizumab)

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The FDA on May 18, 2020, approved TECENTRIQ® for the first-line treatment of adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained 50% or more of tumor cells [TC 50% or more] or PD-L1 stained Tumor-Infiltrating Immune Cells [IC] covering 10% or more of the tumor area [IC 10% or more]), with no EGFR or ALK genomic tumor aberrations. TECENTRIQ® is a product of Genentech Inc.

QINLOCK® (Ripretinib)

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The FDA on May 15, 2020 approved QINLOCK® for adult patients with advanced GastroIntestinal Stromal Tumor (GIST), who have received prior treatment with 3 or more kinase inhibitors, including GLEEVEC® (Imatinib). QINLOCK® is a product of Deciphera Pharmaceuticals, LLC.

RUBRACA® (Rucaparib)

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The FDA on May 15, 2020 granted accelerated approval to RUBRACA® for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic Castration-Resistant Prostate Cancer (mCRPC), who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. RUBRACA® is a product of Clovis Oncology, Inc.

OPVIDO® (Nivolumab) plus YERVOY® (Ipilimumab)

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The FDA on May 15, 2020 approved the combination of OPDIVO® plus YERVOY® as first-line treatment for patients with metastatic Non-Small Cell Lung Cancer, whose tumors express PD-L1 (1% or more), as determined by an FDA-approved test, with no Epidermal Growth Factor Receptor (EGFR) or Anaplastic Lymphoma Kinase (ALK) genomic tumor aberrations. Both OPDIVO® and YERVOY® are products of Bristol-Myers Squibb Co.

POMALYST® (Pomalidomide)

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The FDA on May 14, 2020, expanded the indication of POMALYST® to include treating adult patients with AIDS-related Kaposi Sarcoma, after failure of highly active antiretroviral therapy, and Kaposi Sarcoma in adult patients who are HIV-negative. POMALYST® is a product of Celgene Corporation.