Month: November 2017

Alcohol and Cancer A Statement of the American Society of Clinical Oncology

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SUMMARY: It has been estimated that in the United States, 3-4% of all cancer deaths are attributable to drinking alcohol. According to the Centers for Disease Control and Prevention, approximately 88,000 deaths were attributed to excessive alcohol use in the United States between 2006 and 2010. Alcohol consumption is an established risk factor for several malignancies, and is a potentially modifiable risk factor for cancer. The International Agency for Research on Cancer (IARC), a branch of WHO, classified alcohol as a group 1 carcinogen. The Cancer Prevention Committee of the American Society of Clinical Oncology has now provided an overview of the evidence of the links between alcohol drinking and cancer risk and cancer outcomes.

DRINKING GUIDELINES AND DEFINITIONS

The American Heart Association, American Cancer Society, and US Department of Health and Human Services all recommend that men limit intake to one to two drinks per day and women to one drink per day. People who do not currently drink alcohol should not start for any reason. A standard drink is defined as one that contains roughly 14 g of pure alcohol, which is the equivalent of 1.5 ounces of distilled spirits, 5 ounces of wine or 12 ounces of regular beer. Moderate drinking is defined at up to one drink per day for women and up to 2 drinks per day for men whereas heavy drinking is defined as 8 or more drinks per week or 3 or more drinks per day for women, and as many as 15 or more drinks per week or 4 or more drinks per day for men. Hispanics and blacks have a higher risk than whites, for developing alcohol-related liver disease. Use of alcohol during childhood and adolescence is a predictor of increased risk of alcohol related disorders later in life.

ROLE OF ALCOHOL IN CARCINOGENESIS

Alcohol is predominantly metabolized in the liver to acetaldehyde, which is a carcinogen and is responsible for many “hangover” symptoms. Acetaldehyde is then converted into harmless acetic acid radicals also known as acetyl radicals, and eliminated from the body. There is strong evidence to suggest that acetaldehyde damages DNA. Acetaldehyde generated during alcohol metabolism in the human body is eliminated by Aldehyde Dehydrogenase-2 (ALDH2). However, a genetic variant of ALDH2, which is an inactive form, exists and individuals with the inactive form of ALDH2 who consume alcohol, accumulate excessive amounts of acetaldehyde, which in turn can lead to greater susceptibility to alcohol-induced cancer. It has been noted that this high-risk genotype in prevalent in about 50% of North East Asian population and in 5–10% of blond-haired blue-eyed people of Northern European descent. Alcohol consumption in this group is more strongly associated with cancers of the upper aerodigestive tract. Breast tissue is also more susceptible to alcohol than other sites. Even moderate alcohol intake has been associated with increased levels of circulating sex hormones, which in turn can activate cellular proliferation. Alcohol consumption is associated with lower serum folate concentrations and this may play a role in the etiology of colon cancer.

ALCOHOL AND CANCER

There is a clear association between alcohol and upper aerodigestive tract cancers (larynx, esophagus, and oral cavity/pharynx), as a result of direct contact of ingested alcohol with the involved tissues.

Continued alcohol use among survivors of upper aerodigestive tract cancers is associated with a 3 fold increase in the risk of a second primary tumor in the upper aerodigestive tract. Additionally, there is a synergistic interaction between alcohol consumption and cigarette smoking. Smoking and alcohol use during and after radiation therapy have been associated with an increased risk of osteoradionecrosis of the jaw, in patients with oral and oropharyngeal cancers.

Among women with Estrogen Receptor-positive breast cancer, those consuming 7 or more drinks per week have a 90% increased risk of asynchronous contralateral breast cancer, versus those who do not consume alcohol. It is estimated that there is a 5% increase in premenopausal breast cancer per 10 grams of ethanol consumed per day and the risk is even greater at 9%, for postmenopausal breast cancer.

A recent meta-analysis of cohort studies among 209,597 cancer survivors showed an 8% increase in overall mortality and a 17% increased risk for recurrence in the highest versus lowest alcohol consumers and these numbers were statistically significant.

The benefit of alcohol consumption on cardiovascular health likely has been overstated and nondrinkers have lower rates of coronary heart disease and stroke than even light drinkers. Given the increase in the risk of cancer even with low levels of alcohol consumption, the net effect of alcohol is harmful. Alcohol consumption should therefore not be recommended to prevent cardiovascular disease or all-cause mortality.

In conclusion, alcohol is a well-established risk factor for the development of certain cancers and further research is needed to understand the effects of alcohol exposure on the efficacy of chemotherapy, immunotherapy and radiation treatment. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. LoConte NK, Brewster AM, Kaur JS, et al. DOI: 10.1200/JCO.2017.76.1155 Journal of Clinical Oncology – published online before print November 7, 2017

FDA Grants Approval to CALQUENCE® for Mantle Cell Lymphoma

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SUMMARY: The FDA on October 31, 2017, granted accelerated approval to CALQUENCE® (Acalabrutinib) for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate, following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease.

Normal B-cell activation and proliferation is dependent on B-cell receptor (BCR) signaling. This signaling is also important for initiation and progression of B-cell lymphoproliferative disorders. Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Following binding of antigen to the B-Cell Receptor, kinases such as Syk (Spleen Tyrosine Kinase), Lyn (member of the Src family of protein tyrosine kinases) and BTK (Bruton’s Tyrosine Kinase) are activated, with subsequent propagation through PI3K/Akt, MAPK, and NF-κB pathways. This results in B-cell activation and proliferation. Three previously approved agents by the FDA for MCL include, IMBRUVICA® (Ibrutinib), REVLIMID® (Lenalidomide) and VELCADE® (Bortezomib).

CALQUENCE® is a novel, irreversible, second-generation BTK inhibitor, designed to be more potent and selective than IMBRUVICA®. Unlike IMBRUVICA®, CALQUENCE® has reduced off-target activity on EGFR, TEC, etc., which may lead to less untoward toxicities such as bleeding, rash, and atrial fibrillation. The approval of CALQUENCE® was based on ACE-LY-004 study, which is a Phase II, open label, single-arm clinical trial, in which 124 adult patients with Relapsed or Refractory MCL were enrolled. Patients had a confirmed diagnosis of MCL, 93% of the patients had an ECOG PS of 1 or less, median number of prior treatments were 2, which included stem cell transplant for 18% of patients, and 24% of the patients were refractory to their most recent prior treatment. Those treated with a prior BTK inhibitor were excluded from this study. The median age was 68 years. CALQUENCE® was administered orally at 100 mg twice daily until progressive disease or unacceptable toxicity. The Primary endpoint was Objective Response Rate (Complete Response + Partial Response) and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.

At a median follow up of 15.2 months, the Objective Response Rate was 81% with a Complete Response rate of 40% and Partial Response rate of 41%. The median Duration of Response was not yet reached at the time of analysis, with ongoing responses at 20+ months. The response rates were consistent across prespecified subgroups of age, tumor bulk of 10 cm or more and number and types of prior treatment. The median time to best response was 1.9 months. The median Duration of Response (DOR) was not reached and the 12-month DOR was 72%. The median PFS and OS were not reached, whereas the 12-month PFS and OS rates were 67% and 87% respectively. The most common toxicities of any grade included cytopenias, headache, diarrhea, fatigue, myalgia and bruising.

It was concluded that for patients with Relapsed/Refractory Mantle Cell Lymphoma, CALQUENCE® given as a single agent resulted in a high and durable Objective Response Rate as well as Complete Response Rate, with a favorable safety profile. CALQUENCE® is a new treatment option for this aggressive malignancy. Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study. Wang M, Rule S, Zinzani PL, et al. 59th Annual Meeting & Exposition Atlanta, GA. December 9-12, 2017. #155

CALQUENCE® (Acalabrutinib)

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The FDA on October 31, 2017 granted accelerated approval to CALQUENCE® for treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. CALQUENCE® is a product of AstraZeneca Pharmaceuticals Inc. under license of Acerta Pharma BV.

YESCARTA® (Axicabtagene ciloleucel)

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The FDA on October 18, 2017 granted regular approval to YESCARTA®, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including Diffuse Large B-Cell Lymphoma (DLBCL) Not Otherwise Specified, Primary Mediastinal large B-cell Lymphoma, high-grade B-cell lymphoma, and DLBCL arising from Follicular lymphoma. YESCARTA® is a product of Kite Pharma, Inc.

OPDIVO® and YERVOY® Combination Improves Overall Survival in Advanced Melanoma

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SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins 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® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy to show prolonged Overall Survival (OS) among patients with advanced melanoma, in randomized phase III trials. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies, which bind to the PD-1 receptor and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY®, in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA®, have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.

CheckMate 067 is a phase III study which enrolled treatment naïve patients with advanced melanoma, and the authors in a previous publication reported significantly longer PFS and higher rates of ORR with OPDIVO® plus YERVOY® and with OPDIVO® alone, compared with single agent YERVOY®. In this publication, the authors provided the first analysis of 3-year OS data from the CheckMate 067 trial. In this double-blind, phase III study, patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two primary end points were PFS and OS in the OPDIVO® plus YERVOY® group and in the OPDIVO® group versus the YERVOY® group.

The median OS at a minimum follow up of 36 months, had not been reached in the OPDIVO® plus YERVOY® group and was 37.6 months in the OPDIVO® group, compared with 19.9 months in the YERVOY® group (Hazard Ratio for death with OPDIVO® plus YERVOY® versus YERVOY®=0.55 (P<0.001); Hazard Ratio for death with OPDIVO® versus YERVOY®=0.65 (P<0.001). The OS at 3 years in the OPDIVO® plus YERVOY® group was 58% and in the OPDIVO® group was 52%, as compared with 34% in the YERVOY® group. Grade 3 or 4 treatment-related toxicities, as expected were higher in the OPDIVO® plus YERVOY® group at 59% compared with 21% in the OPDIVO® group, and 28% in the YERVOY® group.

It was concluded that in patients with previously untreated advanced melanoma, significantly longer Overall Survival can be achieved with OPDIVO® plus YERVOY® combination therapy or with OPDIVO® alone, compared with single agent YERVOY®. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. N Engl J Med 2017; 377:1345-1356

Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer with Excellent Prognosis

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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 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The lifetime risk of developing ColoRectal Cancer (CRC) is about 1 in 20 (5%). The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.

The initial evaluation of patients with metastatic ColoRectal Cancer (CRC) includes Molecular diagnostic testing including testing for extended RAS (RAt Sarcoma) and RAF (Rapid Accelerated Fibrosarcoma) mutations. Next-Generation Sequencing (NGS) allows expanded mutational testing for RAS which includes KRAS, NRAS and HRAS. RAS mutations are predictive of resistance to EGFR targeted therapy. NGS is able to detect approximately 20% of the patients who were originally classified as having KRAS Wild-Type (WT) metastatic CRC but were subsequently found to have KRAS or NRAS mutations, thus predicting resistance to EGFR targeted therapy.

Approximately 10% of CRCs detected by NGS harbor BRAF V600E mutation and the detection of BRAF V600E mutation is recognized as a marker of poor prognosis in patients with metastatic CRC. RAS and BRAF V600E mutations occur in a mutually exclusive fashion. Patients with this molecular subtype of CRC are older than age 60 years, more frequently female, have a right-sided tumor with high-grade histology, and often have MicroSatellite Instability (MSI-H). These patients often have peritoneal metastasis and despite chemotherapeutic intervention have a shortened overall survival. These tumors have limited response to EGFR targeted therapy and current guidelines recommend against the use of anti-EGFR antibodies in BRAF V600E-mutated mCRC.

The significance of non-V600 BRAF mutations detected by NGS however has remained unclear. The authors in this multicenter, retrospective cohort study, pooled NGS data from three large US reference laboratories and attempted to establish the clinical characteristics of patients with non-V600 BRAF mutations. Using NGS databases from the Mayo Clinic (MC), The University of Texas MD Anderson Cancer Center (MDACC), and Foundation Medicine (FM) from 2013-2016, patients with non-V600 BRAF mutations from these three institutions were identified and pooled for the primary analysis. Out of a total of 9,643 patients with metastatic CRC who underwent NGS testing, 208 patients with non-V600 BRAF mutations and 133 patients with V600E BRAF mutations, were identified. This study also included 249 patients with Wild-Type BRAF metastatic CRC, for comparative analysis , identified from the same NGS database, from the Mayo Clinic.

It was noted that the prevalence rate of any BRAF mutation was 10%, non-V600 BRAF mutations occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Of particular clinical interest, compared with those with V600E BRAF mutations, patients harboring a non-V600 BRAF mutation were significantly younger, more frequently male, and presented with left-sided MicroSatellite-Stable (MSS) tumors. Additionally, non-V600 BRAF-mutated tumors were mostly low grade and did not often metastasize to the peritoneum. The median Overall Survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and Wild-Type BRAF metastatic CRC (60.7 vs 11.4 vs 43.0 months, respectively; P<0.001) and in multivariable analysis, non-V600 BRAF mutation was independently associated with improved Overall Survival (HR=0.18; P<0.001).

This study concluded that Non-V600 BRAF mutations in metastatic ColoRectal Cancer (CRC), which accounted for 22% of all BRAF mutations identified by NGS, is a clinically distinct subtype of CRC, with an excellent prognosis and aggressive chemotherapeutic intervention could be avoided for this group of patients. Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. Jones JC, Renfro LA, Al-Shamsi HO, et al. J Clin Oncol 2017;35: 2624-2630

ASCO Clinical Practice Guideline Update for Stage IV Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. ASCO published the last clinical practice guideline update on systemic therapy for patients with Stage IV Non Small Cell Lung Cancer (NSCLC), in 2015. With the many advances in the management of these patients and availability of new practice changing evidence since the last publication, the latest ASCO guideline has been revised. The ASCO NSCLC Expert Panel updated their recommendations based on a systematic review of 14 randomized controlled trials from February 2014 to December 2016 and six nonrandomized studies on systemic therapy. This guideline is applicable to patients who had received molecular testing for EGFR/ALK/ROS1, as well as Programmed Death Ligand 1 (PD-L1), and clinicians know the test results.

Guideline Question: What systemic therapy treatment options should be offered to patients with Stage IV NSCLC, depending on the subtype of the patient’s cancer?

Target Population: Patients with Stage IV NSCLC.

Target Audience: Oncology care providers (including primary care physicians, specialists, nurses, social workers, and any other relevant member of a comprehensive multidisciplinary cancer care team), patients, and their caregivers.

Key Points:

1) There is no cure for patients with Stage IV NSCLC.

2) Decisions regarding chemotherapy should not be made based on age alone.

Recommendations: First Line Treatment for Patients

Patients with Non-Squamous Cell Carcinoma without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a Performance Status (PS) of 0 or 1 (and appropriate PS of 2):

1) With high PD-L1 expression (Tumor Proportion Score [TPS] 50% or more) and no contraindications, single-agent Pembrolizumab is recommended.

2) With low PD-L1 expression (TPS less than 50%), a variety of combination cytotoxic chemotherapies (with or without Bevacizumab, if patients are receiving Carboplatin and Paclitaxel) are recommended.

3) There is insufficient evidence to recommend Bevacizumab in combination with Pemetrexed plus Carboplatin.

4) Other checkpoint inhibitors, combination checkpoint inhibitors, or immune checkpoint therapy with chemotherapy are not recommended.

5) With PS of 2, combination or single agent therapy or palliative care alone may be used.

Patients with Squamous Cell Carcinoma without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with a PS of 0 or 1 (and appropriate PS of 2):

1) With high PD-L1 expression (TPS 50% or more) and no contraindications, single agent Pembrolizumab is recommended.

2) With low PD-L1 expression (TPS less than 50%), a variety of combination cytotoxic chemotherapies are recommended.

3) Other checkpoint inhibitors, combination checkpoint inhibitors, or immune checkpoint therapy with chemotherapy are not recommended.

4) With PS of 2, combination or single agent therapy or palliative care alone may be used.

5) With Squamous NSCLC treated with Cisplatin and Gemcitabine, the Panel neither recommends for nor recommends against the addition of Necitumumab to chemotherapy.

With sensitizing EGFR mutations, Afatinib, Erlotinib, or Gefitinib is recommended.

With ALK gene rearrangements, Crizotinib is recommended. 

With ROS1 rearrangement, Crizotinib is recommended. 

Recommendations: Second Line Treatment for Patients

Without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with PS of 0 or 1 (and appropriate PS of 2):

1) In patients with high PD-L1 expression (TPS 1% or more), no contraindications, who received first line chemotherapy and have not received prior immune therapy, single agent Nivolumab, Pembrolizumab, or Atezolizumab is recommended.

2) In patients with negative or unknown tumor PD-L1 expression (TPS less than 1%), no contraindications and who received first line chemotherapy, single agent Nivolumab, or Atezolizumab, or a variety of combination cytotoxic chemotherapies are recommended.

3) Other checkpoint inhibitors, combination checkpoint inhibitors, and immune checkpoint therapy with chemotherapy are not recommended.

4) In patients who received an immune checkpoint inhibitor as first line therapy, a variety of combination cytotoxic chemotherapies are recommended.

5) In patients with contraindications to immune checkpoint inhibitor therapy after first line chemotherapy, Docetaxel is recommended.

6) In patients with non-Squamous Cell Carcinoma who have not previously received Pemetrexed, Pemetrexed is recommended.

With sensitizing EGFR mutations:

1) In patients with disease progression after first line therapy with an EGFR Tyrosine Kinase Inhibitor (TKI) and the presence of the T790M resistance mutation, Osimertinib is recommended. If T790M mutation is not present, a platinum doublet is recommended.

2) In patients who received an EGFR-TKI in the first-line setting, had an initial response, and subsequently experienced slow or minimal disease progression at isolated sites, EGFR-TKI with local therapy to the isolated sites is an option.

With ROS1 rearrangement:

1) In patients who have not received prior Crizotinib, Crizotinib is recommended.

2) In patients who have received prior Crizotinib, platinum-based therapy in the second line with or without Bevacizumab is recommended.

With BRAF mutations:

1) In patients without prior immune checkpoint therapy and high PD-L1 expression (TPS more than 1%), single agent Atezolizumab, Nivolumab, or Pembrolizumab is recommended.

2) In patients who have received prior immune checkpoint therapy, Dabrafenib alone or in combination with Trametinib in third line, is an option.

Recommendations: Third Line Treatment for Patients

1) In patients without a tumor EGFR-sensitizing mutation or ALK or ROS1 gene rearrangement and with non-Squamous Cell Carcinoma and PS of 0 or 1 (and appropriate PS of 2), who received chemotherapy with or without Bevacizumab and immune checkpoint therapy, single agent Pemetrexed or Docetaxel are options.

2) In patients with tumor EGFR-sensitizing mutation(s) who have received at least one first-line EGFR-TKI and prior platinum-based chemotherapy, there are insufficient data to recommend immunotherapy in preference to chemotherapy.

Recommendations: Fourth Line Treatment for Patients

Patients and clinicians should consider and discuss experimental treatment, clinical trials, and continued best supportive (palliative) care.

Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Hanna N, Johnson D, Temin S, et al. J Clin Oncol 2017;35:3484-3515

KEYTRUDA® Improves Overall Survival in Advanced Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Patients with urothelial carcinoma are currently treated in the first line setting with a platinum based chemotherapy regimen. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The FDA approved KEYTRUDA® (Pembrolizumab) in May 2017 for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA subsequently in July 2017 granted an accelerated approval to frontline KEYTRUDA® for patients with locally advanced or metastatic urothelial carcinoma, who are not eligible for cisplatin-containing chemotherapy. KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-045 trial is an open-label, multicenter, phase III study in which 542 patients with advanced urothelial carcinoma who had progressed on prior therapies were randomly assigned to receive KEYTRUDA® or investigator's choice of Paclitaxel, Docetaxel, or Vinflunine. Eligible patients had histologically or cytologically confirmed urothelial carcinoma and had progressed on no more than 2 prior systemic therapies, including a platinum based regimen. Patients were randomly assigned in a 1:1 ratio to receive KEYTRUDA® 200 mg every 3 weeks (N=270) or investigator's choice of Paclitaxel 175 mg/m2 , Docetaxel 75 mg/m2, or Vinflunine 320 mg/m2, every 3 weeks (N=272). The primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS), and the secondary endpoints included Objective Response Rate (ORR) and Safety. Efficacy was assessed in all patients as well as in patients with a PD-L1 Combined Positive Score (CPS) of 10% or more. (CPS is the percentage of PD-L1-expressing tumor and inflammatory cells).

In an updated analysis, with a median follow up of 22.5 months for both treatment groups, the median OS with KEYTRUDA® was 10.3 months compared with 7.4 months with chemotherapy (HR=0.70; P=0.0003) and among patients with a Combined Positive Score of 10% or more, the OS was 8.0 versus 5.2 months respectively (HR=0.58; P=0.003). The OS benefit was noted regardless of age, liver metastases, hemoglobin, visceral disease, and choice of chemotherapy. The 18 month OS rate was 33.2% with KEYTRUDA® versus 19.7% with chemotherapy. There was however no significant difference in the median PFS between the two treatment groups. The ORR was 21.1% with KEYTRUDA® and 11.0% with chemotherapy and the responses with KEYTRUDA® were more durable than with chemotherapy. The median response duration of response was not reached in the KEYTRUDA® group versus 4.4 months in the chemotherapy group. Treatment-related Adverse Events of any grade occurred in 62% of patients in the KEYTRUDA® group and 91% of patients in the chemotherapy group. Discontinuation due to toxicities occurred in 7.1% versus 12.5% of KEYTRUDA® vs chemotherapy patients, respectively.

It was concluded that KEYTRUDA® is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses. Pembrolizumab (pembro) versus paclitaxel, docetaxel, or vinflunine for recurrent, advanced urothelial cancer (UC): mature results from the phase 3 KEYNOTE-045 trial. De Wit R, Vaughn DJ, Fradet Y, et al. Annals of Oncology (2017) 28 (suppl_5): v605-v649. 10.1093/annonc/mdx440

FDA Approves VERZENIO® for Hormone Receptor Positive, HER2-Negative Breast Cancer

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The FDA in September 2017, approved VERZENIO® (Abemaciclib) in combination with FASLODEX® (Fulvestrant) for women with Hormone Receptor positive (HR-positive), HER2-negative, advanced or metastatic breast cancer, with disease progression following endocrine therapy. In addition, VERZENIO® was approved as monotherapy for women and men with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy and prior chemotherapy, in the metastatic setting. The approval of VERZENIO® in combination with FASLODEX® was based on MONARCH 2 study which showed that a combination of VERZENIO® plus FASLODEX® significantly improved Progression Free Survival and Objective Response Rates, with a tolerable safety profile, in patients with Hormone Receptor-positive and HER 2-negative metastatic breast cancer, who had progressed while receiving endocrine therapy.