The FDA on October 24, 2016 approved KEYTRUDA® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors express PD-L1, as determined by an FDA-approved test. This is the first FDA approval of a checkpoint inhibitor for first-line treatment of Lung cancer. This approval also expands the indication in second-line treatment of Lung cancer to include all patients with PD-L1-expressing NSCLC. KEYTRUDA® is a product of Merck & Co., Inc.
Author: RR
LARTRUVO® (Olaratumab)
The FDA on October 19, 2016 granted accelerated approval to LARTRUVO® for the treatment of patients with Soft Tissue Sarcoma (STS) not amenable to curative treatment with radiotherapy or surgery and with a histologic subtype for which an Anthracycline-containing regimen is appropriate. LARTRUVO® is a product of Eli Lilly and Company.
TECENTRIQ® (Atezolizumab)
The FDA on October 18, 2016 approved TECENTRIQ® for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) whose disease progressed during or following Platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations, prior to receiving TECENTRIQ®. TECENTRIQ® is a product of Genentech, Inc.
TARCEVA® (Erlotinib)
The FDA on October 18, 2016 modified the indication for TARCEVA® for treatment of Non Small Cell Lung Cancer, to limit use to patients whose tumors have specific Epidermal Growth Factor Receptor (EGFR) mutations. TARCEVA® is a product of Astellas Pharm Global Development Inc.
OPDIVO® (Nivolumab)
The FDA on September 13, 2016 modified the dosage regimen for OPDIVO®, which is currently approved for Renal Cell Carcinoma, metastatic Melanoma, and Non Small Cell Lung Cancer. The currently approved recommended dosage regimens were modified to 240 mg intravenously (IV) every two weeks. OPDIVO® is marketed by Bristol-Myers Squibb company.
Postmastectomy Radiotherapy ASCO Guideline Update
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The update of the American Society of Clinical Oncology guideline concerning use of PostMastectomy RadioTherapy (PMRT) published in 2001, was developed by an expert panel following review of relevant literature published between January 2001 and July 2015 and further included a meta-analysis of 22 clinical trials published in 2014. Even though the use of PMRT has been widely accepted for patients with four or more positive lymph nodes, the role of PMRT for those with one to three positive nodes still remains controversial. This update addresses the issues at large and provides guidelines to help Health Care Providers and patients make informed decisions.
Clinical Question 1
Is PMRT indicated in patients with T1-2 tumors with one to three positive axillary lymph nodes who undergo Axillary Lymph Node Dissection (ALND)?
Recommendation 1a: The panel unanimously agreed that the available evidence shows that PMRT reduces the risks of locoregional failure, any recurrence, and breast cancer mortality for patients with T1-2 breast cancer and one to three positive lymph nodes. However, one has to weigh the risk and benefit with PMRT and individualize therapy. Patients with low tumor burden, favorable tumor characteristics, comorbidities, or coexisting conditions and limited life expectancy, may not be appropriate candidates for PMRT, as its potential toxicities outweigh the absolute benefit of PMRT.
Recommendation 1b: The decision to use PMRT should be made in a multidisciplinary fashion through discussion among providers from all treating disciplines, early in a patient’s treatment course, soon after surgery or before or soon after the initiation of systemic therapy.
Recommendation 1c: Decision making must fully involve the patients, so that they are able to weigh the risk/benefits of PMRT, with the best information provided by the treating Health Care Provider.
Clinical Question 2
Is PMRT indicated in patients with T1-2 tumors and a positive Sentinel Node Biopsy (SNB) who do not undergo completion ALND?
Recommendation: Patients with T1-2 tumors with positive sentinel lymph node biopsy, who choose not to have Axillary Lymph Node Disection, should receive PMRT only if there is already sufficient information to justify its use, without needing to know that additional axillary nodes are involved. SNB is generally performed at the time of mastectomy for this patient group, with omission of ALND if the nodes are negative. If the sentinel nodes are positive, ALND is performed. There is increasing controversy about whether ALND is always necessary, if there is limited disease in the affected sentinel nodes. This practice is based on extrapolation of data from randomized trials of patients treated exclusively or predominantly with breast-conserving surgery and whole-breast irradiation or breast plus axillary irradiation.
Clinical Question 3
Is PMRT indicated in patients presenting with clinical stage I or II cancers who have received NeoAdjuvant Systemic Therapy (NAST)?
Recommendation: Patients with axillary nodal involvement that persists after NAST, such as less than a complete pathologic response, should receive PMRT. Observational data suggest a low risk of locoregional recurrence for patients who have clinically negative nodes and receive NAST or who have a complete pathologic response in the lymph nodes with NAST.
Clinical Question 4
Should Regional Nodal Irradiation (RNI) include both the Internal Mammary (IMNs) and supraclavicular-axillary apical nodes when PMRT is used in patients with T1-2 tumors with one to three positive axillary nodes?
Recommendation: Radiation Therapy should generally be administered to both the IMNs and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast, when PMRT is used for patients with positive axillary lymph nodes.
Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update. Recht A, Comen EA, Fine RE, et al. Published online before print September 19, 2016, doi:10.1200/JCO.2016.69.1188
DARZALEX® Combination Demonstrates Impressive Efficacy in Relapsed or Refractory Myeloma
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,330 new cases will be diagnosed in 2016 and 12,650 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®).
Daratumumab (DARZALEX®) is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. Previously published phase I and II studies involving patients with relapsed or refractory multiple myeloma demonstrated promising efficacy of DARZALEX® when given as a single agent, as well as when given along with Lenalidomide (REVLIMID®) and Dexamethasone.
The authors now report the results of a prespecified interim analysis of a phase III trial of DARZALEX®, REVLIMID® and Dexamethasone in patients with relapsed or refractory multiple myeloma. In this randomized, open-label, multicenter, phase III study, 569 patients who had relapsed or refractory multiple myeloma were assigned in a 1:1 ratio to receive either DARZALEX®, REVLIMID® and Dexamethasone (Daratumumab group, N=286) or REVLIMID® and Dexamethasone (Control group, N=283). Patients refractory to REVLIMID® were excluded. Patients in the Daratumumab group received DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter. Both treatment groups received REVLIMID® 25 mg PO on days 1-21 of each cycle and Dexamethasone 40 mg PO weekly. The primary end point was Progression Free Survival (PFS). Secondary end points included the time to disease progression, Response Rate, time to response, duration of response, Overall Survival (OS) and percentage of patients with results below the threshold for Minimal Residual Disease. Minimal Residual Disease status was evaluated for patients who had a Complete Response by Next-Generation sequencing assay of bone marrow.
At a median follow-up of 13.5 months, the PFS at 12 months was 83.2% in the Daratumumab group compared to 60.1% in the control group (HR=0.37; P<0.001). The Overall Response Rate was significantly higher in the Daratumumab group than in the control group (92.9% versus 76.4%, P<0.001) and further, there was a higher rate of Complete Response or better (43.1% vs. 19.2%, P<0.001). In the Daratumumab group, 22.4% of the patients had results below the threshold for Minimal Residual Disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001), and those with results below the threshold for Minimal Residual Disease had improved outcomes. The most common grade 3 or 4 adverse events were cytopenias. Approximately 48% of the patients in the Daratumumab group experienced grade 1 or 2 infusion-related reactions.
The authors concluded that the addition of DARZALEX® to REVLIMID® and Dexamathasone significantly improves Progression Free Survival among patients with relapsed or refractory multiple myeloma. This impressive efficacy data may warrant the use of this triplet combination for first relapse, in this group of patients, provided their disease is not refractory to REVLIMID®. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. Dimopoulos MA, Oriol A, Nahi H, et al. for the POLLUX Investigators. N Engl J Med 2016;375:1319-1331
CDK4 and CDK6 Inhibitor ABEMACICLIB Highly Effective in Refractory Hormone Receptor Positive Breast Cancer
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 80% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6), phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation.
Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. The FDA granted breakthrough designation for Abemaciclib based on a phase I trial in which this agent demonstrated significant single agent activity in refractory Hormone Receptor (HR) positive metastatic breast cancer. MONARCH 1 is a single arm phase II study which evaluated the single-agent activity of Abemaciclib in heavily pretreated patients with HR-positive, HER2-negative metastatic breast cancer. This trial included 132 patients with HR-positive, HER2-negative metastatic breast cancer, whose disease progressed on or after endocrine therapy and chemotherapy. Patients had received a median of 3 lines of prior therapy for advanced disease and this included a median of 2 lines of chemotherapy. Approximately 50% of the patients had received FASLODEX® (Fulvestrant), 70% of patients had received Taxane based chemotherapy and 55 % of patients had received XELODA® (Capecitabine), in the metastatic setting. Abemaciclib was administered at 200 mg PO daily on a continuous schedule every 12 hours until disease progression. The median age was 58 yrs, 90% of the patients had visceral disease and 85% had at least 2 sites of metastatic disease. The primary endpoint was Objective Response Rate (ORR) and secondary endpoints included Duration of Response, Progression Free Survival (PFS), Overall Survival (OS), Clinical Benefit Rate (Complete Response plus Partial Response plus Stable Disease) and safety.
An interim analysis was performed at 8 months by when 35.6% of patients had received at least 8 cycles of Abemaciclib. The ORR was 17.4%, the Clinical Benefit Rate lasting for 6 months or more was 42.4%. The median time to response was 3.7 months and the median Duration of Response was 8.6 months. The median PFS was 5.7 months. The most common adverse events were diarrhea, fatigue, nausea, decreased appetite, abdominal pain and treatment discontinuation rate was infrequent at 6.8%.
It was concluded that CDK4 and CDK6 inhibitor, Abemaciclib, has significant antitumor activity in patients with refractory, HR-positive, HER2-negative metastatic breast cancer, for whom chemotherapy is the only option. Studies are underway combining Abemaciclib with FASLODEX®, for postmenopausal patients with HR-positive, HER2-negative, locally advanced or metastatic breast cancer who had progressed on 1 prior endocrine therapy (MONARCH-2 trial), as well as combining Abemaciclib with a nonsteroidal Aromatase Inhibitor in an earlier setting (MONARCH-3 trial), for patients with HR-positive, HER2-negative, locoregionally recurrent or metastatic breast cancer. MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. Dickler MN, Tolaney SM, Rugo HS, et al. J Clin Oncol 34, 2016 (suppl; abstr 510)
Adjuvant Therapy with YERVOY® Improves Overall Survival in Stage III Melanoma
SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in the greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78%, whereas those with stage IIIB and stage IIIC disease have a disease-specific survival rates of 59% and 40% respectively. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins (“gate keepers”) and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.
YERVOY® is a fully human immunoglobulin G1 monoclonal antibody, that blocks Immune checkpoint protein/receptor CTLA-4. YERVOY® was approved by the FDA in 2015 as adjuvant therapy for patients with malignant melanoma based on a phase III trial (EORTC 18071) in which adjuvant YERVOY® was compared with placebo in patients with resected stage III melanoma. At a median follow-up of 2.7 years, adjuvant YERVOY® was associated with significantly prolonged Recurrence Free Survival compared with placebo (HR=0.75; P=0.001). In this study, YERVOY® was dosed at 10 mg/kg and this dose was chosen based on a phase II trial that evaluated YERVOY® administered at three dose levels – 0.3 mg/kg, 3 mg/kg and 10 mg/kg. This trial demonstrated that the 10 mg/kg dose had the greatest efficacy for treatment of advanced melanoma, but had more toxicity.
The authors have now reported the efficacy of adjuvant therapy with YERVOY® in patients with high-risk stage III melanoma after complete lymph node dissection, at a median follow up of 5.3 years. EORTC 18071 is a randomized, double-blind, phase III trial in which patients who had undergone complete resection of stage III cutaneous melanoma were randomly assigned in a 1:1 ratio to receive YERVOY® at a dose of 10 mg/kg (N=475) or placebo (N=476), every 3 weeks for four doses and then every 3 months for up to 3 years or until disease recurrence or unacceptable toxicities. The Primary end point was Recurrence Free Survival and Secondary end points included Overall Survival, distant metastasis-free survival and safety.
At a median follow up of 5.3 years, the 5-year Recurrence Free Survival was 40.8% in the YERVOY® group compared with 30.3% in the placebo group (HR for recurrence or death = 0.76; P<0.001) and the 5-year Overall Survival was 65.4% in the YERVOY® group compared with 54.4% in the placebo group (HR for death = 0.72; P=0.001). The later meant a 28% reduction in the risk of death. The distant metastasis-free survival rate at 5 years was 48.3% in the YERVOY® group compared with 38.9% in the placebo group (HR for death or distant metastasis = 0.76; P=0.002). Grade 3 or 4 adverse events occurred in 54.1% of the patients in the YERVOY® group compared to 26.2% in the placebo group, and this was significant. Grade 3 or 4 Immune-related adverse events occurred in 41.6% of the patients in the YERVOY® group compared to 2.7% in the placebo group.
It was concluded that adjuvant therapy with YERVOY® at a dose of 10 mg/kg for high-risk stage III melanoma, significantly improves Recurrence Free Survival, Overall Survival, and distant metastasis-free survival, when compared to placebo. Given the potentially severe toxicities with this dose level of YERVOY®, the risks and benefits of this treatment has to be discussed with the patients and this treatment option should be reserved for experienced centers. Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. Eggermont AM, Chiarion-Sileni V, Grob J-J, et al. October 8, 2016DOI: 10.1056/NEJMoa1611299
ASCO Guidelines on Adjuvant Targeted Therapy for HER2-Positive Breast Cancers
SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their life time. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 20-25% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2. HERCEPTIN® binds to subdomain IV of the HER2 extracellular domain and blocks the downstream cell signaling pathways (PI3K-AKT pathway) and induces Antibody Dependent Cellular Cytotoxicity (ADCC). Adjuvant chemotherapy in combination with HERCEPTIN® has been shown to reduce the relative risk of relapse by 52% and relative risk of death by 33%. ASCO has established a process for adapting clinical practice guidelines of other organizations and this summary of the practice recommendations were adapted from the Cancer Care Ontario evidence based clinical practice guidelines, for the adjuvant treatment of HER2-positive early breast cancers.
Guideline Question: What is the optimal use of cytotoxic chemotherapy and Human Epidermal growth factor Receptor 2 (HER2) – directed therapy?
Target Population: Female patients who are being considered for, or who are receiving, systemic therapy after definitive surgery for early invasive breast cancer, defined largely as invasive cancer stages I to IIA (T1N0-1, T2N0).
RECOMMENDATIONS
Use of an Anthracycline-Taxane Regimen
1) An adjuvant chemotherapy regimen containing Anthracycline-Taxane is considered the optimal strategy for high risk patients, if they are able to tolerate this regimen.
2) For patients with high-risk disease who will not receive a Taxane, an optimal-dose Anthracycline three-drug regimen (cumulative dose of doxorubicin ≥ 240 mg/m2 or epirubicin ≥ 600 but no higher than 720 mg/m2) that contains Cyclophosphamide, is recommended. The cumulative dose of Doxorubicin in two-drug regimens should not exceed 240 mg/m2.
3) The addition of Gemcitabine or Capecitabine to an Anthracycline-Taxane regimen is not recommended for adjuvant chemotherapy.
Capecitabine in Patients 65 Years of Age and Older
In patients age 65 years or older, Capecitabine is not recommended as an adjuvant chemotherapy option in lieu of standard regimens like Doxorubicin plus Cyclophosphamide (AC) or Cyclophosphamide, Methotrexate, and Fluorouracil (CMF with oral cyclophosphamide).
CMF as an Alternative to AC
For patients in whom Anthracycline-Taxane is contraindicated, CMF (with oral cyclophosphamide) is an acceptable chemotherapy alternative to AC. The ASCO panel recommends classic CMF (oral cyclophosphamide days 1 to 14 with IV Methotrexate-Fluorouracil days 1 and 8, repeated every 28 days for six cycles) as the default adjuvant CMF regimen. However, the panel also recognizes IV CMF regimen given every 21 days.
Acceptable Adjuvant Chemotherapy Regimens for Patients with Higher-Risk Early-Stage Breast Cancer
1) FEC (Fluorouracil, Epirubicin, and Cyclophosphamide) × 3 → T (Docetaxel) × 3 (superior to FEC × 6)
2) AC × 4 → T × 4 (superior to AC × 4)
3) Docetaxel, Doxorubicin, and Cyclophosphamide × 6 (superior to Fluorouracil, Doxorubicin, and Cyclophosphamide × 6)
4) AC × 4 → paclitaxel (P) administered weekly
5) Dose-Dense AC → P (every 2 weeks)
Adjuvant Regimen When an Anthracycline Is Not Preferred
1) Docetaxel plus Cyclophosphamide (TC) × 4 is recommended as an alternative to AC × 4
2) Classic CMF with oral Cyclophosphamide for six cycles. The panel also recognizes IV CMF regimen given every 21 days.
Patient Selection and Adjuvant Trastuzumab Therapy
Only patients with HER2-positive breast cancer (overexpressed based on ImmunoHistoChemistry (IHC 3+) or amplified based on in situ hybridization [ISH ratio ≥ 2.0 or average HER2 copy number ≥ 6.0]), should be offered adjuvant Trastuzumab.
Trastuzumab Plus Chemotherapy
1) Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer greater than 1 cm in size.
2) Trastuzumab therapy can be considered in small, node-negative tumors (1 cm or less).
3) Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen.
4) The administration of Trastuzumab concurrently with the Anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity.
5) Trastuzumab should be preferentially administered concurrently (not sequentially) with a non-Anthracycline chemotherapy regimen.
6) Less cardiotoxicity is seen with TCH (Docetaxel, Carboplatin, and Trastuzumab) than with AC→TH (Doxorubicin and Cyclophosphamide→Docetaxel and Trastuzumab), and TCH is recommended for patients at higher risk for cardiotoxicity.
7) Even though there is no phase III evidence for the addition of Trastuzumab to some chemotherapy regimens, such as TC, those regimens might be in use and are reasonable options, particularly to mitigate cardiotoxicity in certain patients.
Duration of Trastuzumab Therapy and Cardiac Function Assessment
Patients should be offered 1 year total of adjuvant Trastuzumab, with regular assessments of cardiac function during that period.
Selection of Optimal Adjuvant Chemotherapy Regimens for Early Breast Cancer and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. Denduluri N, Somerfield MR, Eisen A, et al. J Clin Oncol 2016;34:2416-2427