SUMMARY: There is now growing body of evidence suggesting superior outcomes when advanced NSCLC patients with specific genomic alterations receive targeted therapies. Following review of 127 studies by experts and input from a scientific advisory panel, The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) offered evidence-based recommendations for the molecular analysis of lung cancers for Epidermal Growth Factor Receptor (EGFR ) mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements, thereby selecting patients with lung cancer, for treatment with EGFR and ALK tyrosine kinase inhibitors. The ASCO review panel has endorsed these guidelines which specifically address the following questions:
1) Which patients should be tested for EGFR mutations and ALK rearrangements?
EGFR or ALK testing is recommended for all patients with advanced lung adenocarcinoma or tumors with an adenocarcinoma component, irrespective of clinical characteristics such as smoking history, sex, race, or other clinical factors. Tumor samples of other histologies for which an adenocarcinoma component cannot be excluded because of sampling, can be considered for testing, particularly if clinical criteria are suggestive (eg, younger age, lack of smoking history). Both primary tumors and metastatic lesions are suitable for testing. When fully excised lung cancer specimens are available, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small-cell carcinomas, or large-cell carcinomas lacking IHC (ImmunoHistoChemistry) evidence of adenocarcinoma differentiation.
2) When should a patient specimen be tested for EGFR mutation or ALK rearrangement?
Testing should be ordered at the time of diagnosis of advanced disease or recurrence. For patients with earlier stage disease who undergo surgical resection, testing at the time of diagnosis is encouraged so that molecular information is available to an oncologist at the time of recurrence, for a subset of patients who subsequently experience recurrence. Tissue should be prioritized for EGFR and ALK testing.
3) How rapidly should test results be available?
Laboratory turnaround times of 5 to 10 working days (2 weeks) for EGFR and ALK results are recommended.
4) How should specimens be processed for EGFR mutation testing?
Pathologists should use Formalin-Fixed, Paraffin-Embedded (FFPE) specimens or fresh frozen or alcohol-fixed specimens for PCR based EGFR mutation tests. EGFR and ALK testing can be performed with cytology samples, with cell blocks being preferred over smear preparations.
5) How should EGFR testing be performed?
EGFR testing should detect mutations in samples composed of as few as 50% tumor cells, although sensitivity to detect mutations in samples containing > 10% tumor cells is strongly encouraged. Sensitizing EGFR mutations with a population frequency of at least 1% should be reported. IHC for total EGFR as well as EGFR copy number analysis by FISH (Fluorescence In Situ Hybridization) is not recommended.
6) What is the role of KRAS analysis in selecting patients for targeted therapy with EGFR TKIs?
KRAS mutations are common (30%) in lung adenocarcinomas and mutually exclusive with EGFR and ALK. Testing for KRAS may be performed initially to exclude KRAS mutated tumors from EGFR and ALK testing but KRAS mutation testing is not recommended as a sole determinant of EGFR-targeted therapy.
7) What additional testing considerations are important in the setting of secondary or acquired EGFR TKI resistance?
If a laboratory performs testing on specimens from patients with acquired resistance to EGFR kinase inhibitors, such tests should be able to detect the secondary EGFR T790M mutation in as few as 5% of cells.
8) What methods should be used for ALK testing?
ALK FISH assay using dual labeled break-apart probes should be used for selecting patients for ALK TKI therapy. ALK IHC, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing. RT-PCR (Reverse Transcription–Polymerase Chain Reaction) is not recommended as an alternative to FISH, for selecting patients for ALK inhibitor therapy.
9) Are other molecular markers suitable for testing in lung cancer?
Testing for EGFR should be prioritized over other molecular markers in lung adenocarcinoma followed by testing for ALK. Testing for ROS1 and RET rearrangements may soon become a part of the guidelines.
10) How should molecular testing of lung adenocarcinomas be implemented and operationalized?
Pathology departments should establish a process wherein tissue (blocks or unstained slides) is sent to outside molecular laboratories within 3 days of receiving a request and to in house molecular laboratories within 24 hours. Results should be available within 2 weeks and reported in a format that is easily understood by oncologists and nonspecialist pathologists.
Leighl NB, Rekhtman N, Biermann WA, et al. J Clin Oncol 2014;32:3673-3679
The sentinel node is the first lymph node(s) to which cancer cells are most likely to metastasize from a primary tumor. With the introduction of intraoperative lymphatic mapping in the 1990s, Sentinel Lymph Node Biopsy (SLNB) has gained general acceptance and is the preferred procedure in appropriate circumstances. Unlike Axillary Lymph Node Dissection (ALND), SLNB is associated with a lower incidence of Lymphedema, seroma at the surgery site, paresthesias and restriction of joint movement. Nine randomized clinical trials have not shown any difference in mortality among patients who underwent ALND or SLNB for either lymph node metastases or negative sentinel lymph nodes, validating Sentinel Lymph Node Biopsy (SLNB). The American Society of Clinical Oncology (ASCO) first published guidelines on the use of SLNB for patients with early stage breast cancer in 2005, based on one randomized clinical trial. Since then, additional information from 9 randomized clinical trials and13 cohort studies pertinent to SLNB and ALND has resulted in this ASCO Clinical Practice Guideline Update.
The CDC updated their recommendations in 2008 and recommended HBV screening for patients receiving cytotoxic chemotherapy or immunotherapy. The American Society of Clinical Oncology in 2010 rendered a Provisional Clinical Opinion (PCO) suggesting that there was insufficient evidence to recommend routine screening for HBV in cancer patients, but screening may be considered for patient populations at high risk or for those who are to receive highly immunosuppressive therapies including anti-CD20 monoclonal antibody therapy such as RITUXAN® (Rituximab). According to the International recommendations, HBV reactivation is defined as the detection of serum HBV DNA of 10 IU/mL or more, by a real-time polymerase chain reaction–based assay. Because of the ambiguity regarding HBV reactivation in lymphoma patients receiving immunosuppressive therapy, the authors conducted a prospective trial to determine the frequency and factors predictive of HBV reactivation in HBsAg-negative, anti-HBc–positive patients treated with RITUXAN® based chemotherapy regimens. In this observational study, 260 patients with hematologic malignancies who were HBsAg-negative, anti-HBc–positive, with undetectable serum HBV DNA (< 10 IU/mL) and treated with RITUXAN® containing chemotherapy, were prospectively monitored every 4 weeks for up to 2 years. Patients were started on BARACLUDE® (Entecavir), when HBV reactivation (serum HBV DNA of 10 IU/mL or more), was documented.
The cumulative rate of HBV reactivation over the 2 year observation period was high at 41.5%. The HBV reactivation occurred at a median of 23 weeks after RITUXAN® treatment and the median HBV DNA level at reactivation was 43 IU/mL. Undetectable antibody level to HBsAg (anti-HBs; < 10 mIU/mL) at baseline, prior to treatment with RITUXAN®, was the only significant risk factor that was strongly associated with HBV reactivation (P=0.009). Patients with negative baseline antibody level to HBsAg (anti-HBs) had a significantly higher 2-year cumulative rate of HBV reactivation, compared with those who had positive baseline antibody level to HBsAg (68.3% vs 34.4%; P=0.012). All patients had normal ALT when HBV reactivation occurred and except for one patient, were HBsAg negative. More importantly, all patients with HBV reactivation were successfully treated with BARACLUDE®. The authors concluded that HBsAg-negative, anti-HBc–positive lymphoma patients, receiving RITUXAN® based chemotherapy regimens experience a high rate of HBV reactivation, with this rate even significantly higher in patients with negative baseline antibody level to HBsAg. Periodic monitoring for HBV reactivation can enable early detection and intervention,thereby avoiding HBV related morbidities and mortality. Seto W, Chan T, Hwang Y, et al. JCO 2014;32:3736-3743
This latest approval was based on the results of an international, randomized, open-label phase III trial in which 487 patients with stage II to IV MCL, who were ineligible or not considered for Bone Marrow Transplantation, received VR-CAP (N = 243) or R-CHOP (N = 244). VR- CAP is essentially R-CHOP with the Vincristine replaced by VELCADE®. So, VR-CAP regimen consisted of VELCADE® administered IV at 1.3 mg/m2 on days 1, 4, 8, and 11, RITUXAN® (Rituximab) 375 mg/m2 IV given on day 1, Cyclophosphamide 750 mg/m2 IV on day 1, Doxorubicin 50 mg/m2 IV on day 1 and Prednisone at 100 mg/m2 PO on days 1 to 5 of a 21 day cycle for 6-8 cycles. R-CHOP regimen was exactly similar except that Vincristine 1.4 mg/m2 (max 2 mg) IV was administered on day 1 of each cycle instead of VELCADE®. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Time To Progression (TTP), Time To Next Treatment (TTNT), Overall Survival (OS) and safety. Patients received a median of 6 cycles and after a median follow up of 40 months, patients in the VR-CAP group demonstrated a significantly longer median PFS (25 months vs. 14 months; HR=0.63;P<0.001) with a 37% relative improvement in the PFS compared to those who were treated with standard R-CHOP. Patients in the VR-CAP group also had a higher overall response rate (88 vs 85%) and a higher rate of complete response (44% vs. 34%). The most common adverse reactions occurring in 20% or more of patients receiving the VR-CAP regimen were neutropenia, leukopenia, anemia, thrombocytopenia, lymphopenia, peripheral neuropathy, pyrexia, nausea and diarrhea. Infections were reported for 31% of patients in the VR-CAP group compared to 23% of the patients in the R-CHOP group. The authors concluded that VR-CAP significantly prolonged PFS and consistently improved secondary efficacy endpoints, compared to R-CHOP, in newly diagnosed, Bone Marrow Transplant ineligible Mantle Cell Lymphoma patients with manageable toxicity. Proteosome inhibition with a VELCADE® based chemotherapy regimen has opened the doors for more effective therapies for Mantle Cell Lymphoma patients. Cavalli F, Rooney B, Pei L, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8500)</s
Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. This was a Grade: B recommendation which meant that the USPSTF recommends the service and there is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. This therefore meant that clinicians offer or provide this service to these high risk individuals.
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, 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 central nervous system 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 such as Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL) and Non Hodgkin lymphoma (NHL), such as Diffuse Large B-Cell Lymphoma (DLBCL). Previously published studies have shown significant responses with CAR T-cell therapy in patients with relapsed and refractory B-cell ALL. But the durability of remission has remained unclear.
The primary end point was Progression Free Survival (PFS) and secondary end points included Objective Response Rate (ORR), Overall Survival (OS), safety, and patient reported outcomes. The combination of AVASTIN® plus chemotherapy resulted in a 62% reduction in the risk of progression compared to those who received chemotherapy alone, with a median PFS of 6.8 months for the AVASTIN® plus chemotherapy group versus 3.4 months for the single agent chemotherapy group (HR=0.38, P<0.0001) and thus met the primary endpoint of this clinical trial. This PFS benefit was seen consistently across all subgroups including the subgroup of patients with ascites. The ORR was 27.3% with the AVASTIN® combination versus 11.8% with single agent chemotherapy (P =0.001). The median OS was 16.6 months for the AVASTIN® combination versus 13.3 months for the single agent chemotherapy group (HR=0.85; P < .17). The lack of statistical significance in the OS has been attributed to cross over of 40% of patients, initially randomized to the chemotherapy alone group, who upon progression received AVASTIN®. There was a 15% improvement in abdominal and GI symptoms as reported by patients, with the AVASTIN® combination, compared to chemotherapy alone. On exploratory analyses it was noted that the addition of AVASTIN® to TAXOL® resulted in the most benefit, with a 5.7 month improvement in median PFS (9.6 versus 3.9 months), a 23% improvement in the overall response rate (53% versus 30%) and a 9.2 month improvement in median OS (22.4 versus 13.2 months) compared to single agent TAXOL®. This benefit was seen in spite of the fact that 97% of the patients in the TAXOL® group had received this agent with previous chemotherapy regimens. These findings suggest that patients who have received prior treatment with TAXOL® may benefit from AVASTIN® plus weekly TAXOL®. The most common adverse reactions (greater than or equal to 15%) in patients treated with AVASTIN® plus chemotherapy were neutropenia, peripheral neuropathy, hypertension and GI perforation occurred in 1.7% of these patients. This low perforation rate has been attributed to the exclusion of patients with rectosigmoid involvement by pelvic examination or bowel involvement on CT scan as well as those with clinical symptoms of bowel obstruction. The authors concluded that AVASTIN® in combination with chemotherapy significantly improved Progression Free Survival and Objective Response Rates in patients with Platinum Resistant Recurrent Ovarian Cancer. Pujade-Lauraine E, Hilpert F, Weber B, et al. J Clin Oncol 2014;32:1302-1308
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. Survival of cancer cells in the human body may be to a significant extent, related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being 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 doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. The authors in this randomized study, compared the efficacy of YERVOY® (Ipilimumab) plus Sargramostim with YERVOY® alone, for treatment of metastatic melanoma. The rationale for this study was based on the synergy that was noted between YERVOY® and GM-CSF in preclinical models. The first immune checkpoint protein to be clinically targeted was CTLA-4. YERVOY® is a fully human IgG1monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA- 4 and counteracts immune regulatory cells. YERVOY® has been shown to prolong overall survival in patients with previously treated, unresectable or metastatic melanoma. GM-CSF is a cytokine that enhances the antitumor activity of T and B lymphocytes by activating the antigen presenting dendritic cells and recruiting macrophages. It however can induce negative regulatory immune responses.
In this phase II randomized clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG), patients with unresectable stage III or IV melanoma (N = 245), who had received at least 1 prior therapy and with no central nervous system metastases were randomized to receive either YERVOY® along with Sargramostim (N=123) or YERVOY® alone (N=122). Patients in the combination group (Group A) received YERVOY®10 mg/kg, IV on day 1 along with Sargramostim 250 μg given subcutaneously, on days 1 thru 14 of a 21day cycle, every 3 weeks for four cycles followed by YERVOY® maintenance every 12 weeks. Patients in Group B received YERVOY® alone. Treatment was continued until disease progression or uncontrolled toxicities. The primary endpoint was comparison of length of Overall Survival (OS). Secondary end points included Progression Free Survival (PFS), response rate, safety, and tolerability. With a median follow up of 13.3 months, the median OS for the combination of YERVOY® plus Sargramostim was 17.5 months vs 12.7 months for YERVOY® alone. The one year survival rate for YERVOY® plus Sargramostim was 68.9% compared to 52.9% for YERVOY® alone (HR=0.64; P=0.01). The median PFS was similar and was 3.1 months in both study groups. The explanation for similar PFS in both treatment groups may be due to both YERVOY® and Sargramostim bringing about inflammatory changes at the tumor sites, which in turn could be misinterpreted as disease progression, on radiological studies. The authors commented that PFS may not be an appropriate endpoint in immunotherapy trials. Grade 3 to 5 adverse events were less in the combination group (44.9%) compared to 58% for single agent YERVOY® (P=0.04). The authors concluded that treatment of unresectable stage III or IV melanoma patients with YERVOY® plus Sargramostim resulted in significantly longer overall survival with lower toxicities, compared to YERVOY® alone. Hodi SF, Lee S, McDermott DF, et al. JAMA 2014;312:1744-1753
The RAINBOW study is an international, placebo-controlled, double-blind, phase III trial in which 665 patients with metastatic gastroesophageal junction or gastric adenocarcinoma, who had disease progression on or within 4 months after first-line platinum and fluoropyrimidine-based combination therapy, were included. Patients were randomly assigned to receive TAXOL® (Paclitaxel) 80 mg/m2 given on D1, 8, 15 along with Placebo (N=335) or the same dose and schedule of TAXOL® given along with CYRAMZA® at 8 mg/kg IV every 2 weeks (N=330), of a 28 day cycle. Treatment was continued until disease progression or unacceptable toxicities were noted. The primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and Time To Progression (TTP). The median OS for the combination of CYRAMZA® and TAXOL® was 9.6 months compared to 7.4 months for Placebo and TAXOL® (HR=0.81; P=0.017), resulting in a 19% reduction in the risk of death with the CYRAMZA® and TAXOL® combination. The secondary endpoints favored the CYRAMZA® and TAXOL® combination as well. The median PFS was 4.4 months and 2.9 months (HR=0.64; P<0.001), ORR was 28% and 16% (P<0.0001) and median TTP was 5.5 months and 3 months with the CYRAMZA® and TAXOL® combination vs Placebo and TAXOL® combination respectively. As one would expect, treatment related adverse events were seen more frequently in the CYRAMZA® and TAXOL® combination group. Significant were neutropenia, hypertension, fatigue and asthenia, diarrhea and epistaxis. The incidence of febrile neutropenia in the two treatment groups was however comparable (3.1% vs 2.4%). The authors concluded that the combination of CYRAMZA® and TAXOL® combination significantly improved both Progression Free and Overall Survival and also resulted in significantly improved disease control rates, in patients with metastatic gastroesophageal junction or gastric adenocarcinoma. Wilke H, Van Cutsem E, Oh SC, et al. J Clin Oncol 32, 2014 (suppl 3; abstr LBA7)
The different types of external beam radiation treatments include 3-Dimensional Conformal Radiation Therapy (3D-CRT) meant to deliver radiation to very precisely shaped target areas, IMRT or Intensity Modulated Radiation Therapy which allows different areas of a tumor or nearby tissues to receive different doses of radiation, Image Guided Radiation Therapy (IGRT) which allows reduction in the planned volume of tissue to be treated as changes in a tumor size are noted during treatment, Stereotactic RadioSurgery (SRS) which can deliver one or more high doses of radiation to a small tumor, Stereotactic Body Radiation Therapy (SBRT) or CYBERKNIFE® which is similar to SRS but also takes the normal motion of the body into account while treating malignancies involving the lung and liver and Proton Beam therapy. Proton beams unlike Photons, enter the skin and travel through the tissues and deposit much of their energy at the end of their path (known as the Bragg peak) and deposit less energy along the way. This is unlike Photons which deposit energy all along the path through the tissues and the deposited dose decreases with increasing depth. As a result, with Proton beam therapy, normal tissues are exposed to less radiation compared with Photons. Despite this advantage, tissue heterogeneity such as organ motion, tumor volume changes during treatment can have a significant negative impact on target coverage for Proton beam therapy and can result in damage to the surrounding tissues and potential complications. The authors in this review discussed the clinical applications of Proton therapy in Adult and Pediatric malignancies. Pediatric patients with malignancies have greater benefit with Proton beam therapy, with a statistically significant lower risk of secondary malignancies and less damage to the developing tissues and organs, compared to Photon therapy (External Beam Radiation Therapy). This clinical benefit may be less so in adult malignancies in spite of superior dosimetry, compared to external beam radiation, as adults are less prone to secondary malignancies compared to children.