Month: February 2018

Molecular Testing in Lung Cancer – Guideline Update

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 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.Management-of-NSCLC-based-on-Histology-and-Genomics

The College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology convened an expert panel in 2013 and had published evidence-based guideline to set standards for the molecular analysis of lung cancers and to guide treatment decisions with targeted therapies. With the availability of new medical information and technological advances, this expert panel which comprised of pathologists, oncologists, pulmonologists, and laboratory scientists, issued an evidence based update which included 18 new recommendations, along with 3 updated recommendations from the 2013 guideline, asking 5 key questions.

Key Question 1: Which new genes should be tested for lung cancer patients?

a) ROS1 testing must be performed on all lung adenocarcinoma patients, irrespective of clinical characteristics.

b) ROS1 ImmunoHistoChemistry (IHC) may be used as a screening test in lung adenocarcinoma patients; however, positive ROS1 IHC results should be confirmed by a molecular or cytogenetic method.

c) BRAF, RET, ERBB2 (HER2), KRAS and MET molecular testing are currently not indicated as a routine stand-alone assay, outside the context of a clinical trial. It is appropriate to include molecular testing for these genes, as part of larger testing panels performed either initially or when routine EGFR, ALK, and ROS1 testing are negative.

Key Question 2: What methods should be used to perform molecular testing?

a) ImmunoHistoChemistry (IHC) is an equivalent alternative to Fluorescence In Situ Hybridization (FISH) for ALK testing.

b) Multiplexed genetic sequencing panels are preferred over multiple single-gene tests, to identify other treatment options beyond EGFR, ALK, and ROS1.

c) Laboratories should ensure test results that are unexpected, discordant, equivocal or otherwise of low confidence, are confirmed or resolved, using an alternative method or sample.

Key Question 3: Is molecular testing appropriate for lung cancers that do not have an adenocarcinoma component?

a) Physicians may use molecular biomarker testing in tumors with histologies other than adenocarcinoma when clinical features indicate a higher probability of an oncogenic driver.

Key Question 4: What testing is indicated for patients with targetable mutations who have relapsed on targeted therapy?

a) In lung adenocarcinoma patients who harbor sensitizing EGFR mutations and have progressed after treatment with an EGFR-targeted TKI, physicians must use EGFR T790M mutational testing when selecting patients for third-generation EGFR-targeted therapy.

b) Laboratories testing for EGFR T790M mutation in patients with secondary clinical resistance to EGFR-targeted kinase inhibitors should deploy assays capable of detecting EGFR T790M mutations in as little as 5% of viable cells.

c) There is currently insufficient evidence to support a recommendation for or against routine testing for ALK mutational status for lung adenocarcinoma patients with sensitizing ALK mutations, who have progressed after treatment with an ALK-targeted Tyrosine Kinase Inhibitor (TKI).

Key Question 5: What is the role of testing for circulating cell-free DNA for lung cancer patients?

a) There is currently insufficient evidence to support the use of circulating cfDNA molecular methods for the diagnosis of primary lung adenocarcinoma.

b) In some clinical settings in which tissue is limited and/or insufficient for molecular testing, physicians may use a cfDNA assay to identify EGFR mutations.

c) Physicians may use cfDNA methods to identify EGFR T790M mutations in lung adenocarcinoma patients with progression or secondary clinical resistance to EGFR-targeted TKI; testing of the tumor sample is recommended if the plasma result is negative.

d) There is currently insufficient evidence to support the use of circulating tumor cell molecular analysis for the diagnosis of primary lung adenocarcinoma, the identification of EGFR or other mutations, or the identification of EGFR T790M mutations at the time of EGFR TKI resistance.

2013 Statements VERSUS 2017 Statements

a) 2013 – Cytologic samples are also suitable for EGFR and ALK testing, with cell blocks being preferred over smear preparations VERSUS 2017 – Pathologists may use either cell blocks or other cytologic preparations as suitable specimens for lung cancer biomarker molecular testing.

b) 2013 – Laboratories should use EGFR test methods that are able to detect mutations in specimens with at least 50% cancer cell content, although laboratories are strongly encouraged to use (or have available at an external reference laboratory) more sensitive tests that are able to detect mutations in specimens with as little as 10% cancer cells VERSUS 2017 – Laboratories should use, or have available at an external reference laboratory, clinical lung cancer biomarker molecular testing assays that are able to detect molecular alterations in specimens with as little as 20% cancer cells.

c) 2013 – IHC for total EGFR is not recommended for selection of EGFR TKI therapy VERSUS 2017 – It is strongly recommended that laboratories should not use total EGFR expression by IHC testing to select patients for EGFR-targeted TKI therapy.

Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Lindeman NI, Cagle PT, Aisner DL et al. [published online January 22,2018]. Arch Pathol Lab Med . doi: 10.5858/arpa.2017-0388-CP

OPDIVO® and YERVOY® Combination Improves Survival in Metastatic Colorectal 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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%).

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and when sporadic, the DNA MisMatchRepair gene is MLH1. Defective MisMatchRepair can also manifest as a germline mutation occurring in 1 of the 4 MisMatchRepair genes which include MLH1, MSH2, MSH6, PMS2. This produces Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC), an Autosomal Dominant disorder and is the most common form of hereditary colon cancer, accounting for 35% of the MSI colorectal cancers. MSI tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to PD-1 blockade with immune checkpoint inhibitors.Testing-for-MSI-and-MMR-Deficiency

MSI (Micro Satellite Instability) testing is performed using a PCR based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MisMatchRepair genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). MLH1 gene is often lost in association with PMS2. NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer.

CheckMate 142 is a large, multi-center, open label, phase II trial which evaluated the efficacy and safety of PD-1 inhibitor treatment in patients with dMMR/MSI-H metastatic colorectal cancer. This study evaluated the benefit of OPDIVO® alone or in combination YERVOY® in this patient population. The rationale behind combining OPDIVO® a PD-1 inhibitor and YERVOY®, a CTLA-4 inhibitor, was based on the synergy between these two agents, to promote T-cell antitumor activity, thereby improving upon single-agent activity of OPDIVO®. The study enrolled 119 patients who received OPDIVO® as a single agent at 3 mg/kg IV every 2 weeks or OPDIVO® 3 mg/kg plus YERVOY® 1 mg/kg every 3 weeks for 4 doses, followed by OPDIVO® 3 mg/kg every 2 weeks. Treatment was continued until disease progression or unacceptable toxicities. The Primary endpoint was Objective Response Rate (ORR) and exploratory endpoints included Safety, Progression Free Survival (PFS), Overall Survival (OS) and efficacy in biomarker-defined populations. This study was not designed to compare the outcomes in these two treatment cohorts. Based on initial data from CheckMate-142, the FDA in July 2017 granted accelerated approval to OPDIVO® for the treatment of patients with MisMatch Repair deficient (dMMR) and MicroSatellite Instability-High (MSI-H) metastatic CRC, that has progressed, following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan.

This review provides an update on outcomes with monotherapy and immunotherapy combination. In the OPDIVO® monotherapy group which included 74 patients, the updated analysis at 21 months showed a response rate was 34%, with 9% being complete responses, and the disease control rate was 62%. The median duration of response has not been reached in the overall cohort of patients and among those responding, 64% had responses lasting at least 1 year. Longer follow up resulted in deepening response rates. The median Progression Free Survival (PFS) for the entire cohort was 6.6 months. Clinical Benefit was seen regardless of PD-L1 expression, BRAF mutation status, KRAS mutation status, and clinical history of Lynch Syndrome.

In the combination immunotherapy group, the median follow up was 13.4 months and the authors of this analysis, André, et al., compared the results of this cohort with those of the OPDIVO® monotherapy group, for the same 13.4 month median follow up period. The most common prior therapies included Fluoropyrimidine (99%), Oxaliplatin (93%) and Irinotecan (73%). Of the 119 patients who received this combination immunotherapy, 76% had 2 or more prior lines of therapy. The Objective Response Rate with a combination of OPDIVO® and YERVOY® was 55%, with 3.4% Complete Responses, and the Disease Control Rate was 80%. About 78% of the patients had reduction in tumor burden with combination immunotherapy. The median time to response was 2.8 months and the median Duration of Response has not yet been reached. Among patients who responded to the combination, 94% had ongoing responses at the time of data cutoff and 63% of the cohort receiving combination immunotherapy remained on treatment. These responses were noted regardless of PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome. The PFS and Overall Survival with combination immune checkpoint inhibitor therapy at 12 months were 71% and 85%, respectively. There were statistically significant and clinically meaningful improvements in quality-of-life measurements as well.

These data from the CheckMate-142 study support the use of OPDIVO® as a single agent or in combination with YERVOY®, for the treatment of patients with previously treated DNA MisMatch Repair-Deficient/MicroSatellite Instability-High (MSI-H) metastatic CRC.

1. Overman MJ, Bergamo F, McDermott RS, et al. Nivolumab in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): Long-term survival according to prior line of treatment from CheckMate-142. Overman MJ, Bergamo F, McDermott RS, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 554)

2. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): First report of the full cohort from CheckMate-142. André T, Lonardi S, Wong M, et al. J Clin Oncol 36, 2018 (suppl 4S; abstr 553)

ADCETRIS® with Chemotherapy for the Frontline Treatment of Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2018, about 8,500 new cases of Hodgkin lymphoma will be diagnosed and about 1,050 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).WHO-Classification-of-Hodgkin-Lymphoma

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (stage III to stage IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

ADCETRIS® (Brentuximab vedotin) is an antibody-drug conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. ADCETRIS® is presently approved by the FDA for the treatment of Classical Hodgkin lymphoma, after failure of Autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates. It is also approved for Classical Hodgkin lymphoma at high risk of relapse or progression, as auto-HSCT consolidation.

In a previously published phase I study, ADCETRIS® in combination with AVD (A+AVD) resulted in a Complete Response rate of 96% and a 5 year Overall Survival rate of 100%. Based on these finding, ECHELON-1 study was conducted, which is an international, open-label, randomized, multicenter, phase III trial, comparing A+AVD with ABVD, as frontline therapy in patients with stage III or IV Classical Hodgkin lymphoma.

This study included 1334 previously untreated patients with stage III or IV Classical Hodgkin lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously, on days 1 and 15 of each 28-day cycle, for up to 6 cycles. The Primary end point was “modified” Progression Free Survival (mPFS), which, in addition to disease progression or death, included less than Complete Response after the completion of frontline chemotherapy, based on independently assessed PET results. PET scan interpretation was based on Deauville score (The Deauville score is a 5-point scale on which higher scores indicate greater uptake of FDG glucose at involved sites on PET). Patients were stratified according to International Prognostic Score (IPS) risk group (low risk vs. intermediate risk vs. high risk). A PET scan was performed at the end of the second cycle of treatment (PET2) and patients were offered alternative frontline therapy at the discretion of the treating physician, for patients with a PET Deauville score of 5. Secondary end points included Overall Survival.

At a median follow up of 24.6 months, the 2 year modified PFS in the A+AVD and ABVD groups were 82.1% and 77.2% respectively ( HR=0.77; P=0.04). All Secondary end points also trended in favor of A+AVD. Further, the benefit of A+AVD was noted across all prespecified subgroups, including those with involvement of more than one extranodal site, patients with a high IPS risk score and stage IV disease. Additionally, a higher proportion of the patients treated with A+AVD had negative PET2 results than those treated with ABVD (89% versus 86%). There was however a higher incidence of neutropenia in the A+AVD group, but this was alleviated with G-CSF prophylaxis. There was a higher incidence of peripheral neuropathy in the A+AVD group as well, and this improved or resolved over time. Pulmonary toxicity was lower in patients receiving A+AVD compared to those receiving ABVD.

The authors concluded that at 2 years, among patients with advanced stage Hodgkin lymphoma, A+AVD had superior efficacy when compared to ABVD, with a lower combined risk of progression, death or incomplete response and subsequent use of anticancer therapy. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. Connors JM, Jurczak W, Straus DJ, et al., for the ECHELON-1 Study Group. N Engl J Med 2018; 378:331-344