Category: Meeting Updates

Late Breaking Abstract – ASH 2016 Superior Efficacy Data with Pacritinib in Myelofibrosis

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SUMMARY: Myelofibrosis is a MyeloProliferative Neoplasm (MPN) characterized by ineffective hematopoiesis, progressive fibrosis of the bone marrow and potential for leukemic transformation. This stem cell disorder is Philadelphia Chromosome negative and manifestations include anemia, splenomegaly and related symptoms such as abdominal distension and discomfort with early satiety. Cytokine driven debilitating symptoms such as fatigue, fever, night sweats, weight loss, pruritus and bone or muscle pain can further impact an individual’s quality of life. Myelofibrosis can be primary (PMF) or secondary to Polycythemia Vera (PV) or Essential Thrombocythemia (ET). The JAK-STAT signaling pathway has been implicated in the pathogenesis of Myelofibrosis. This pathway normally is responsible for passing information from outside the cell through the cell membrane to the DNA in the nucleus, for gene transcription. Janus Kinase (JAK) family of tyrosine kinases are cytoplasmic proteins and include JAK1, JAK2, JAK3 and TYK2. JAK1 helps propagate the signaling of inflammatory cytokines whereas JAK2 is essential for growth and differentiation of hematopoietic stem cells. These tyrosine kinases mediate cell signaling by recruiting STAT’s (Signal Transducer and Activator of Transcription), with resulting modulation of gene expression. In patients with MPN, the aberrant myeloproliferation is the result of dysregulated JAK2-STAT signaling as well as excess production of inflammatory cytokines associated with this abnormal signaling. These cytokines contribute to the symptoms often reported by patients with MF. JAK2 mutations such as JAK2 V617F are seen in approximately 60% of the patients with PMF and ET and 95% of patients with PV. Unlike CML where the BCR-ABL fusion gene triggers the disease, JAK2 mutations are not initiators of the disease and are not specific for MPN. Further, several other genetic events may contribute to the abnormal JAK2-STAT signaling.

Pacritinib is a potent JAK2 inhibitor, without significant JAK1 inhibition. It additionally targets FLT3, IRAK1, and CSF1R. Preliminary studies have shown minimal myelosuppression with Pacritinib. JAKAFI® (Ruxolitinib) is a potent JAK1 and JAK2 inhibitor approved by the FDA in 2011 to treat intermediate or high-risk Myelofibrosis. It is however not indicated for patients with platelet counts under 50,000/μl, and this group represents approximately one third of Myelofibrosis patients and have limited or no treatment options. Previously published PERSIST-1 trial showed that Pacritinib significantly reduced Spleen Volume and Myelofibrosis associated symptoms, in patients with low platelet count, when compared to Best Available Therapy (excluding JAKAFI®).

PERSIST-2 is an open label, phase III study in which the safety and efficacy of Pacritinib was compared with currently available therapies, including JAKAFI®, thus expanding the definition of Best Available Therapy (BAT). A total of 311 patients with platelet counts 100,000/μl or less were randomly assigned in a 1:1:1 ratio to receive Pacritinib 200 mg BID (N=107), 400 mg QD (N=104) or Best Available Therapy (N=100). The efficacy population in the Intent To Treat group included a total of 221 patients. Approximately half of the study population had platelet counts of less than 50,000/μl. Over 40% of the patients in both the treatment groups had prior therapy with JAKAFI®. About 60-70% of the patients had a diagnoses of Primary Myelofibrosis, and half of the patients fell in the International Prognostic Scoring System (IPSS) Intermediate-2 risk category. The two coprimary endpoints were the proportion of patients achieving 35% or greater reduction in Spleen Volume (SVR) as measured by MRI or CT scan and the proportion achieving a 50% or more improvement in symptoms such as fatigue, bone pain, itching, and abdominal pain after 24 weeks of follow up. The secondary objectives were to compare Pacritinib BID and Pacritinib QD, individually to BAT.

It was noted that 18% of patients who received Pacritinib achieved a 35% or greater reduction in Spleen Volume from baseline to week 24, compared to 3% of those in the BAT group (P=0.001). In the patient group who received Pacritinib twice daily, 32% reported a 50% or more reduction in symptoms compared with 14% in the BAT group (P=0.01). Further, patients treated with Pacritinib required fewer red blood cell transfusions and additionally, patients who received Pacritinib twice daily had substantially greater improvement in platelet count among those who had platelets counts 50,000/μl or less at enrollment. The most common adverse events related to Pacritinib included nausea, vomiting, diarrhea, anemia, and low platelets.

The authors concluded that this is the only randomized trial to date in patients with Myelofibrosis and thrombocytopenia that enrolled patients who had prior therapy with a JAK2 inhibitor. Regardless, Pacritinib was more effective at Spleen Volume Reduction than BAT and Pacritinib given BID was even more effective than QD dosing. Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) Versus Best Available Therapy (BAT), Including Ruxolitinib (RUX), in Patients (pts) with Myelofibrosis (MF) and Platelet Counts <100,000/µl. Hoffman R, Talpaz M, Gerds AT, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract LBA-5.

Late Breaking Abstract – ESMO 2016 FASLODEX® Superior to ARIMIDEX® as Initial Therapy in Advanced Breast Cancer

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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 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy as first line treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

The superiority of ARIMIDEX® over NOLVADEX® was first established in the year 2000 following the publication of the results of a North American Multicenter Randomized Trial. In this study, ARIMIDEX® as first-line treatment in postmenopausal women with advanced breast cancer resulted in a significant increase in Time To Progression and a lower incidence of thromboembolic events and vaginal bleeding, compared to NOLVADEX®. In a previously reported phase II study (FIRST trial), first-line treatment with FASLODEX® significantly improved Time To disease Progression and Overall Survival compared with ARIMIDEX®, in patients with hormone receptor (HR) positive advanced breast cancer.

The FALCON trial is a phase III study conducted to confirm findings from the FIRST trial. This study included 462 postmenopausal women, with locally advanced or metastatic hormone receptor positive, HER2-negative, endocrine-therapy naive breast cancer. Patients were randomized to receive FASLODEX® IM at 500 mg on days 0, 1, and 28 and then every 28 days (N=230) or ARIMIDEX® 1 mg PO daily (N=232). Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was Progression Free Survival (PFS), and secondary endpoints included Overall Survival, Objective Response Rate, Clinical Benefit Rate, Duration of Response, health-related Quality of Life, and safety.

It was noted that FASLODEX® provided better disease control with a median PFS of 16.6 months compared to 13.8 months with ARIMIDEX® (P=0.048). Subgroup analysis showed that FASLODEX® was markedly superior to ARIMIDEX® in patients with non-visceral disease with a median Progression Free Survival of 22.3 months compared with 13.8 months for ARIMIDEX®. There was no significant improvement in the Overall Response Rate between the treatment groups. However, the median Duration of Response was 20.0 months with FASLODEX® compared to 13.2 months with ARIMIDEX®. Expected Duration of response and expected Duration of Clinical Benefit were in favor of FASLODEX® (11.4 vs 7.5 months; P=0.001) and (21.9 vs 17.5 months; P=0.001), respectively. There was no difference in Overall Survival at the time of this analysis. Rates of adverse events were similar in both treatment groups.

The authors concluded that FASLODEX® was superior to ARIMIDEX® as initial treatment of hormone receptor positive, endocrine therapy naive, advanced breast cancer. Patients with non-visceral and low volume disease, as well as elderly patients, may benefit the most with FASLODEX®, as this therapy is well tolerated with a low toxicity profile. FALCON: a phase III randomised trial of fulvestrant 500 mg vs. anastrozole for hormone receptor-positive advanced breast cancer. Ellis MJ, Bondarenko I, Trishkina E, et al. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA14.

ASH – 2016 Discontinuing Tyrosine Kinase Inhibitors is Feasible in Some Patients with CML

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SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

The European Stop TKI (EURO-SKI) trial was conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in Deep Molecular Response (DMR). This trial enrolled 821 patients with chronic phase CML without prior TKI failure, in DMR (BCR-ABL <0.01% on the International Scale – MR4) for at least one year, following treatment with either Imatinib, Nilotinib or Dasatinib. Following cessation of treatment with TKIs, patients were followed up testing by RQ-PCR (Real-time Quantitative Polymerase Chain Reaction) every 4 weeks for the first 6 months followed by every 6 weeks, the first year and every 3 months thereafter. Molecular recurrence was defined by the loss of the Major Molecular Response (BCR-ABL <0.1% IS – MR3) at any one point.

It was noted that after stopping TKI therapy, 62% showed no evidence of molecular recurrence at 6 months, and 52% showed no recurrence at 24 months. Patients who had taken a TKI for more than 5.8 years before stopping, were significantly less likely to experience relapse within the first 6 months and had a Molecular Relapse Free Survival at 6 months of 65.5% compared with 42.6% for those on treatment for 5.8 years or less. Further, each additional year of TKI therapy increased a patient’s chances of maintaining Major Molecular Response successfully at 6 months by 16%, after TKI therapy was discontinued. Most of the patients who experienced molecular recurrence were able to regain their previous remission level, after resuming TKI therapy and none of the patients in the study had progression to advanced stage.

The authors concluded that stopping TKI therapy of CML patients appeared safe and feasible in over 50% of the patients and longer duration of therapy with TKIs (5.8 years or more) prior to stopping therapy with TKIs, was associated with a higher probability of Molecular Recurrence Free Survival. Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial. Mahon F-X, Richter J, Guilhot J, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 787.

Neoadjuvant Chemotherapy in Advanced Ovarian Cancer – ASCO Clinical Practice Guideline

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SUMMARY: The American Cancer Society estimates that over 22,280 women will be diagnosed with ovarian cancer in the United States for 2016 and over 14,240 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. For the past 40 years, primary cytoreductive surgery followed by chemotherapy has been the standard approach, for women with advanced epithelial ovarian cancer. The benefit of neoadjuvant chemotherapy followed by interval debulking surgery was recognized in the early 1990’s, especially when treating those with advanced age, stage and associated comorbidities. An Expert Panel from the Society of Gynecologic Oncology and the American Society of Clinical Oncology conducted a systematic review of the literature and the primary evidence for these recommendations is based on four phase III clinical trials. The following recommendations are meant to provide guidance to Health Care Providers regarding the use of neoadjuvant chemotherapy and interval cytoreduction among women with stage IIIC or IV epithelial ovarian cancer. The following clinical questions were addressed:

What clinical evaluations should be performed in all women with suspected or newly diagnosed stage IIIC or IV epithelial ovarian cancer?

Recommendation 1.1. All women with suspected stage IIIC or IV invasive epithelial ovarian cancer should be evaluated by a gynecologic oncologist prior to initiation of therapy to determine whether they are candidates for primary cytoreductive surgery.

Recommendation 1.2. A primary clinical evaluation should include a CT scan of the abdomen and pelvis with Oral and IV contrast and chest imaging (CT preferred), to evaluate the extent of disease and feasibility of surgical resection. The use of other tools to refine this assessment may include laparoscopic evaluation or additional radiographic imaging such as PET scan or MRI.

Which patient and disease factors should be used as criteria for identifying patients who are not suitable for primary cytoreductive surgery?

Recommendation 2.1. Women who have a high perioperative risk profile, or a low likelihood of achieving cytoreduction to less than 1 cm, ideally to no visible disease, should receive neoadjuvant chemotherapy.

Recommendation 2.2. Decisions that women are not eligible for medical or surgical cancer treatment, should be made after consultation with a gynecologic oncologist and/or a medical oncologist with gynecologic expertise.

How do neoadjuvant chemotherapy and primary cytoreductive surgery compare with respect to progression-free survival, overall survival, and perioperative morbidity and mortality in women who are fit for primary cytoreduction and have potentially resectable disease, and how should this information be used to select initial treatment?

Recommendation 3.1. For women who are fit for primary cytoreductive surgery, with potentially resectable disease, either neoadjuvant chemotherapy or primary cytoreductive surgery may be offered, based on data from phase III randomized, controlled trials that demonstrate neoadjuvant chemotherapy is noninferior to primary cytoreductive surgery with respect to Progression Free and Overall Survival. Neoadjuvant chemotherapy is associated with less peri- and postoperative morbidity and mortality and shorter hospitalizations, but primary cytoreductive surgery may offer superior survival in selected patients.

Recommendation 3.2. For women with a high likelihood of achieving cytoreduction to less than 1 cm (ideally to no visible disease) and with acceptable morbidity, primary cytoreductive surgery is recommended over neoadjuvant chemotherapy.

Recommendation 3.3. For women who are fit for primary cytoreductive surgery but are deemed unlikely to have cytoreduction to less than 1 cm (ideally to no visible disease) by a gynecologic oncologist, neoadjuvant chemotherapy is recommended over primary cytoreductive surgery. Neoadjuvant chemotherapy is associated with less peri and postoperative morbidity and mortality and shorter hospitalizations.

What additional clinical evaluations should be performed in women with suspected or newly diagnosed stage IIIC or IV epithelial ovarian cancer before neoadjuvant chemotherapy is delivered?

Recommendation 4. Before neoadjuvant chemotherapy is delivered, all patients should have histologic confirmation (core biopsy preferred) of an invasive ovarian, fallopian tube, or peritoneal cancer. In exceptional cases, when a biopsy cannot be performed, cytologic evaluation combined with a serum CA-125 to carcinoembryonic antigen (CEA) ratio more than 25 is acceptable, to confirm the primary diagnosis and exclude a non-gynecologic cancer.

What is the preferred chemotherapy regimen for women with stage IIIC or IV epithelial ovarian cancer who will receive neoadjuvant chemotherapy?

Recommendation 5. For neoadjuvant chemotherapy, a Platinum-Taxane doublet is recommended. However, alternative regimens, containing a Platinum agent, may be selected based on individual patient factors.

Among women treated with neoadjuvant chemotherapy, does the timing of interval cytoreduction or the number of chemotherapy cycles after interval cytoreduction affect the safety or efficacy of treatment?

Recommendation 6. Randomized, controlled trials tested surgery following three or four cycles of chemotherapy in women who had a response to neoadjuvant chemotherapy or stable disease. Interval cytoreductive surgery should be performed after up to four cycles of neoadjuvant chemotherapy for women with a response to chemotherapy or stable disease. Alternative timing of surgery has not been prospectively evaluated but may be considered based on patient-centered factors.

What are the treatment options for patients with progressive disease on neoadjuvant chemotherapy?

Recommendation 7. Patients with progressive disease on neoadjuvant chemotherapy have a poor prognosis. Options include alternative chemotherapy regimens, clinical trials, and/or discontinuation of active cancer therapy and initiation of end-of-life care. In general, there is little role for surgery, and it is not typically advised, unless for palliation such as relief of bowel obstruction. Neoadjuvant Chemotherapy for Newly Diagnosed, Advanced Ovarian Cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline. Wright AA, Bohlke K, Armstrong DK, et al. Journal of Clinical Oncology 2016;34:3460-3473

VYXEOS® – A Novel First Line Treatment for High Risk Acute Myeloid Leukemia

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SUMMARY: The American Cancer Society estimates that in 2016, 19,950 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 10,430 patients will die of the disease. Acute Myeloid Leukemia in general is a disease of the elderly and the average age of a patient with AML is about 66 years. AML can be considered as a group of heterogeneous diseases with different clinical behavior and outcomes. In general, only 40% of patients younger than 60 years of age survive more than 5 years and 5 year survival for those who relapse after achieving a complete remission (CR) is dismal. Treatment with conventional chemotherapy regimens in elderly patients with secondary AML (sAML) have resulted in poor outcomes. Even though rapid development of new agents against genetic and epigenetic targets is underway, modifications and reformulations of conventional chemotherapy have demonstrated improved outcomes in patients with AML.

CPX-351 (VYXEOS®) is a liposomal formulation of a fixed combination of Cytarabine and Daunorubicin in a 5:1 molar ratio, developed using a platform known as “CombiPlex”. In vitro studies have demonstrated that this ratio maximizes synergy with the lowest level of antagonism and results in preferential uptake of the drug into leukemic cells. In a randomized, open label phase II trial involving patients with or without secondary AML (sAML), CPX-351 improved the composite CR (CRc) rate (Complete Remission and CR with incomplete blood count recovery – CRi) when compared to conventional induction chemotherapy with Daunorubicin and Cytarabine. Those patients with a higher rate of CRc (CR + CRi) had a statistically significant 6 month survival benefit. In another study of AML patients in first relapse, CPX-351 improved median Overall Survival (OS) in poor-risk patients when compared to investigator’s choice of salvage regimens.

On the basis of these studies, the authors conducted a randomized, open-label, phase III trial of first-line CPX-351 in patients with high-risk sAML. Enrolled patients (N=309) were stratified based on AML type (therapy-related AML, AML with a history of MDS with and without prior Hypo Methylating Agent therapy, AML with a history of CMML, or de novo AML with MDS karyotype) and age (60-69 yrs or 70-75yrs). Patients were randomized in a 1:1 ratio to receive either CPX-351 (N=153) 100 units/m2, days 1, 3, 5 or the standard 7+3 (Cytarabine 100 mg/m2/day x 7 days, Daunorubicin 60 mg/m2 days 1, 2, 3) induction therapy (N=156). Both treatment groups were well balanced. The primary end point was Overall Survival (OS) and secondary endpoints included Event Free Survival (EFS), independent blinded assessment of CR+CRi, and 60-day mortality.

The final analysis began after a minimum follow up of 13.7 months. Patients in the CPX-351 group had a significant improvement in Overall Survival compared with standard treatment (HR=0.69; P=0.005; median OS, 9.56 versus 5.95 months). Additionally, there was a significant improvement in Event Free Survival for the CPX-351 group compared to standard therapy (HR=0.74; P=0.021), as well as CR+CRi response (47.7% versus 33.3%; P=0.016) and 60-day mortality (13.7% versus 21.2%). The Complete Remission rates alone were 37.3% and 25.6%, in favor of CPX-351 (P=0.04). Grade 3-5 Adverse Events were similar in frequency and severity in both arms (92% versus 91%) and similar numbers of patients underwent transplantation in both treatment groups.

The authors concluded that treatment with CPX-351 (VYXEOS®) significantly improved Overall Survival, Event Free Survival and Response Rates, without an increase in 60-day mortality or Adverse Events, in elderly patients with high risk secondary AML, when compared with standard induction therapy. CPX-351 reduced the risk of death by 31%. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Lancet JE, Uy GL, Cortes JE, et al. J Clin Oncol 34, 2016 (suppl; abstr 7000).

Proton Beam Therapy May Improve Survival Compared to Conventional Radiation in Stage II and III NSCLC Patients

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SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016 about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Even though Photon-based external beam radiation plus concurrent chemotherapy is the current standard of care for patients with unresectable stage III NSCLC, Proton beam therapy is emerging as an alternative to conventional Photon beam therapy for many cancer types. Radiation Therapy involves the use of X-Rays, Gamma rays and charged particles for cancer treatment. External beam radiation therapy is most often delivered using a linear accelerator in the form of Photon beams (either X-rays or Gamma rays). Photons have no mass and are packets of energy of an electromagnetic wave. Electrons and Protons are charged particles and Electrons are considered light particles whereas Protons are considered heavy particles. Electron beams are used to irradiate skin and superficial tumors, as they are unable to penetrate deep into the tissues. 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.

It has remained unclear whether Proton beam therapy improves Overall Survival (OS) in patients with NSCLC. To address this question, the authors conducted a retrospective analysis using the National Cancer Data Base (NCDB) and analyzed outcomes and predictors associated with Proton beam therapy for NSCLC. This analysis included 140,383 patients with stage I to stage IV NSCLC, treated with thoracic radiation from 2004-2012, of whom 59% had stage II and III disease. Of these patients, 140,035 were treated with Photon beam therapy and 348 with Proton beam therapy. The median age was 68 yrs, 57% were males, 85% were Caucasian, 27% were treated at academic centers and 78% in metropolitan areas. To reduce treatment selection bias, propensity score matching method was implemented.

It was noted that patients were less likely to receive Proton beam therapy in community or comprehensive community centers compared to academic centers (P< 0.001). Further, patients who received Proton beam therapy were more likely to have a higher education and income. On multivariate analysis, it was noted that the risk for death was greater with use of Photon beam therapy compared to Proton beam therapy (HR=1.46; P<0.001). Among patients with stage II and III disease, 5 year OS was superior with Proton beam therapy compared with Photon beam therapy (22.3% versus 15%; P=0.01). Patients with stage II and III disease who received Photon beam therapy had worse OS both in multivariate (HR=1.19; P=0.06) and univariate (HR=1.23; P=0.02) analyses, compared with Proton beam therapy. Proton beam therapy was associated with better 5 year OS compared to Photon beam therapy (23% vs. 14%; P=0.02), on propensity matched analysis. The median OS was 11 months with Photon therapy compared to 19 months with Proton therapy.

The authors concluded that in this retrospective database analysis, thoracic radiation with Proton beam therapy was associated with better survival rates for patients with stage II and III NSCLC. An ongoing randomized phase III trial (NRG Oncology 1308) involving stage III NSCLC patients is evaluating if chemotherapy and Proton beam therapy is superior to chemotherapy and Photon beam therapy. National Cancer Data Base analysis of proton versus photon radiotherapy in non-small cell lung cancer (NSCLC). Behera M, OConnell KA, Liu Y, et al. J Clin Oncol 34, 2016 (suppl; abstr 8501)

Long Term Survival in Advanced Renal Cell Carcinoma with OPDIVO®

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SUMMARY: The American Cancer Society estimates that about 62,700 new cases of kidney cancer will be diagnosed in the United States in 2016 and over 14,000 patients will die from this disease. The understanding of the Immune checkpoints has lead to the development of novel immunotherapies. Immune checkpoints or gate keepers 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 may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. 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 PD-1(Programmed cell Death-1), etc. Following inhibition of PD-1 by specific antibodies, T cells are unleashed, resulting in T cell proliferation and activation with subsequent therapeutic responses. OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

OPDIVO® was approved by the FDA in November 2015, for the treatment of advanced Renal Cell Carcinoma in patients who have received prior anti-angiogenic therapy. This approval was based on a randomized, open-label, phase III study (CheckMate 025), in which previously treated patients with advanced clear cell RCC, were randomly assigned to receive either OPDIVO® or AFINITOR® (N Engl J Med 2015; 373:1803-1813). It was noted that the median Overall Survival (OS) in the OPDIVO® group was 25 months and 19.6 months in the AFINITOR® group, and this meant a 27% reduction in the risk of death with OPDIVO® (HR=0.73; P=0.002). This survival benefit was seen with a minimum follow up of 14 months.

The authors in this publication reported the long term OS results from phase I and II OPDIVO® studies, leading to CheckMate 025 phase III study. In the phase I open-label study, 34 patients with advanced Renal Cell Carcinoma, with ECOG Performance Status of 2 or less and who had prior systemic treatment with 1-5 regimens, received OPDIVO® at a dose of 1 or 10 mg/kg every 2 weeks (J Clin Oncol 2015;33:2013-2020). At a minimum follow up of 50.5 months, the Objective Response Rate (ORR) was 29% and the median Duration of Response was 12.9 months. The 3 and 5 year OS rates were 41% and 34% respectively. In the phase II study, 167 patients with advanced Renal Cell Carcinoma with KPS of 70% or more and who had prior treatment with 1-3 regimens in the metastatic setting, received OPDIVO® at a dose of 0.3, 2, or 10 mg/kg every 3 weeks (J Clin Oncol 2015;33:1430–37). At a minimum follow up of 38 months, ORR was 21% and the median Duration of Response was 22 months. The 3 year OS rate was 35% and 4 year OS rate was 29%. Long-term survival was observed in MSKCC good, intermediate and poor-risk patients, as well as in patients with excellent or reduced Karnofsky Performance Status.

The authors concluded that with this longest follow up data reported to date with any anti-PD-1/PD-L1 agent in advanced Renal Cell Carcinoma, about 33% of patients treated with OPDIVO® are alive at 5 years in the phase I study and at 3 years in the phase II study. Potential predictors of long term survival with OPDIVO® are being explored, in this previously treated patient population. Long-term overall survival (OS) with nivolumab in previously treated patients with advanced renal cell carcinoma (aRCC) from phase I and II studies. McDermott DF, Motzer RJ, Atkins MB, et al. J Clin Oncol 34, 2016 (suppl; abstr 4507)

Anthracycline Regimen Superior in High Risk Early Stage Breast Cancer

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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 superiority of Anthracycline based chemotherapy regimens for the treatment of breast cancer was demonstrated in the mid 1980’s. The Early Breast Cancer Trialists Collaborative Group (EBCTCG) overview analysis published in the Lancet in 1998 concluded that there was a 12% proportional reduction in the risk of recurrence and 11% proportional reduction in mortality with Anthracycline containing regimens versus non-Anthracycline containing chemotherapy regimens. There is however a small risk of cardiotoxicity even with cumulative doses of Doxorubicin of less than 550 mg/m2. Jones and colleagues in 2009 published the results of US Oncology Research Trial 9735 which compared TC with AC and concluded that TC is superior to AC chemotherapy regimen and would be a reasonable option for both younger and older patients requiring chemotherapy, who are hormone receptor positive or negative with either node negative disease or have 1-3 positive lymph nodes.

The ABC (Anthracyclines in early Breast Cancer) adjuvant phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49) done in sequence, were developed by USOR and NSABP to determine if a regimen of TC for 6 cycles was non-inferior to combination regimens of Doxorubicin/Cyclophosphamide with Docetaxel or Paclitaxel (TaxAC), in patients with resected, high risk, HER2-negative breast cancer. The final analysis set from these collective trials known as ABC included 4130 patients, of whom 2078 patients were randomized to TC and 2052 patients to TaxAC. The treatment groups were well balanced. Sixty nine percent (69%) were hormone receptor positive, 41% were node negative and 51% had high grade tumors. The Primary Endpoint was invasive Disease Free Survival (iDFS) and the median follow up was 3.2 years.

At the time of pre-planned analysis with 399 invasive Disease Free Survival events, the 4 year DFS was significantly higher with TaxAC (90.7%) compared to 88.2% with TC (P=0.04). TaxAC provided little or no added benefit in hormone receptor positive and node negative patients. There was some benefit for patients with hormone receptor positive disease with 1-3 positive lymph nodes and those with hormone receptor negative disease with negative nodes. The most benefit was seen with TaxAC in patients with hormone receptor positive disease with 4 or more positive lymph nodes and in those with hormone receptor negative disease with positive nodes. The 4 year Overall Survival was comparable in both treatment groups although longer follow up is needed.

It can be concluded based on these findings that in early stage breast cancer, Anthracycline containing regimens are superior to non-Anthracycline regimens in patients with triple negative breast cancer and for those hormone receptor positive patients with 4 or more positive lymph nodes. There may be some benefit in select group of hormone receptor positive patients with 1-3 positive lymph nodes and in some patients with node negative, hormone receptor negative disease. Non-Anthracycline regimen such as TC is appropriate in node negative, hormone receptor positive patients. Interim joint analysis of the ABC (anthracyclines in early breast cancer) phase III trials (USOR 06-090, NSABP B-46I/USOR 07132, NSABP B-49 [NRG Oncology]) comparing docetaxel + cyclophosphamide (TC) v anthracycline/taxane-based chemotherapy regimens (TaxAC) in women with high-risk, HER2-negative breast cancer. Blum JL, Flynn PJ, Yothers G, et al. J Clin Oncol 34, 2016 (suppl; abstr 1000)

Late Breaking Abstract – ASCO 2016 Biosimilar of HERCEPTIN® Equally Effective and Safe

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SUMMARY: A Biosimilar product is a biological product that is approved based on its high similarity to an already approved biological product (also known as reference product). Biological products are made from living organisms including humans, animals and microorganisms such as bacteria or yeast and are manufactured through biotechnology, derived from natural sources or produced synthetically. Biological products have larger molecules with a complex structure than conventional drugs (also known as small molecule drugs). Unlike biological products, conventional drugs are made of pure chemical substances and their structures can be identified. A generic drug is a copy of brand name drug and has the same active ingredient and is the same as brand name drug in dosage form, safety and strength, route of administration, quality, performance characteristics and intended use. Therefore, brand name and the generic drugs are bioequivalent. The Affordable Care Act in 2010 created an abbreviated licensure pathway for biological products that are demonstrated to be “Biosimilar” to, or “interchangeable” with an FDA-licensed (FDA approved) biological product (reference product). The Biosimilar must show that it has no clinically meaningful differences in terms of safety and effectiveness from the reference product. A Biosimilar product can only be approved by the FDA if it has the same mechanism of action, route of administration, dosage form and strength as the reference product, and only for the indications and conditions of use that have been approved for the reference product. Biosimilars are not as easy to manufacture as generics (copies of brand name drugs) because of the complexity of the structure of the biologic product and the process used to make a biologic product. The facilities where Biosimilars are manufactured must also meet the FDA’s standards.

Heritage is a double-blind, randomized phase III trial in which the efficacy and safety of Myl-1401O, a Biosimilar, was compared with HERCEPTIN®. The randomization included 500 patients treated at 95 sites worldwide, with centrally confirmed, measurable HER2 positive metastatic breast cancer, who had not received prior chemotherapy or HERCEPTIN® for their metastatic disease. Patients received either Myl-1401O or HERCEPTIN® along with TAXOTERE® (Docetaxel) or TAXOL® (Paclitaxel) administered every 3 weeks for a minimum of 8 cycles (24 weeks), with the antibody therapy continued, until disease progression. Both antibodies were administered with a loading dose of 8 mg/kg and a maintenance dose of 6 mg/kg every 3 weeks. Approximately 44% of the enrolled patients had hormone receptor positive disease and 84% received TAXOTERE®. The final analysis included 458 patients of whom 230 were in the Myl-1401O group and 228 were in the HERCEPTIN® group. The Primary endpoint was Overall Response Rate (ORR) at 24 weeks and Secondary endpoints include Progression Free Survival (PFS), Overall Survival (OS) and Safety.

The ORR after 24 weeks of treatment was 69.6% for the Myl-1401O group and 64% for the HERCEPTIN® group and this was not statistically significant. The median PFS had not yet been reached. Safety data in both treatment groups were comparable and there was no significant change in cardiac function from baseline to Week 24 in either group. The dose-normalized maximum concentration and Area Under the Curve, were similar for both antibodies.

The authors concluded that this study is one of the first trials of Biosimilars in oncology to demonstrate similar results and they added that MYL-1401O is equivalent to HERCEPTIN®, when given in combination with a Taxane, as first line therapy, for patients with HER2 positive metastatic breast cancer. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin. Rugo HS, Barve A, Waller CF, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA503)

Late Breaking Abstract – ASCO 2016 Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

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Late Breaking Abstract – ASCO 2016: Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

SUMMARY: The FDA approved the first “Liquid Biopsy” test on June 1, 2016 for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene. On the heels of this approval, Zill and colleagues reported the results of the largest liquid biopsy study ever conducted thus far. It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful, as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma, also called liquid biopsy, can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The authors in this study utilized Next Generation Sequencing (NGS) of circulating tumor DNA (ctDNA), isolated from plasma specimens (liquid biopsy specimens) of 15,191 patients of whom 37% had advanced lung cancer, 14% had breast cancer, 10% had colorectal cancer and 39% had other malignancies. Seventy genes were targeted and accuracy of ctDNA sequencing was assessed by comparing with matched tissue tests for 386 patients and frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects such as data from The Cancer Genome Atlas (TCGA).

It was noted that the ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% and the accuracy increased to 98% when blood and tumor were collected less than six months apart. Pearson Correlation between sets of data is a measure of how well these sets are related. Between 0.5 and 1.0 is considered high correlation. Pearson correlation for TP53 gene was 0.94, for KRAS was 0.99 and for PIK3CA was 0.99.

The researchers commented on the clinical outcome benefits using liquid biopsy, in four distinct groups:

1) Testing for actionable mutations (ALK fusion, EGFR or BRAF activating mutations in lung; ERBB2 amplification in gastric cancer) in cases with insufficient tissue quantity.

2) Testing for actionable resistance mutations (MET amplification or EGFR T790M in lung cancer), at the time of progression.

3) Genomic evolution upon progression such as ERBB2-amplified metastatic breast cancer in patients with triple negative primary tumor.

4) Tumors with genotypes that need more extensive driver mutation testing such as BRAF V600E in lung.

The authors concluded that there is a high correlation between ctDNA plasma samples and tissue testing with the exception of resistance mutations such as EGFR T790M mutation which evolve while on anti-EGFR inhibitor therapy and consequently may not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation. Patients who received treatment based on ctDNA findings also experienced better clinical outcomes. Zill OA, Mortimer S, Banks KC, et al Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016;34(suppl; abstr LBA11501).