Historically, all brain metastases were treated with surgery and/or radiotherapy.

Now, investigators are looking to separate the treatment approach by the primary tumor type, with many targeted therapies, immunotherapies, and combinations under investigation for the treatment of patients with melanoma-associated brain metastases (MBM).

For primary melanoma, treatment with radiation in the frontline is not suggested as results from studies have shown varying benefits from initial treatment with radiation and it has been suggested that primary melanoma may be radioresistant.

However, for brain metastases, radiation is recommended.

Surgical resection is usually performed on patients with a single, symptomatic brain metastasis.

When the tumors are resectable, surgery has a significant benefit over radiotherapy. The results of a retrospective study of 686 patients with MBM showed a median overall survival (OS) of 8.7 months for patients undergoing surgery compared with 3.4 months with radiotherapy alone.

Among patients who received both, the median OS was 8.9 months (P <.001). Of those who received surgery, most only had 1 brain metastasis.

Beyond a single metastasis or an inaccessible tumor, radiation therapy is the go-to treatment modality with either whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS).

While WBRT does tend to show a benefit in local control, its role is being questioned due to the associated deficits in memory and learning.

The phase III Alliance trial of 213 patients with 1 to 3 brain metastases, most commonly from a lung primary cancer, treated with SRS with or without additional WBRT showed that intracranial tumor control with SRS plus WBRT was 84.9% at 1 year compared with 50.5% with SRS alone (P <.001).

However, patients treated with the combination showed more frequent neurocognitive deterioration than the SRS-alone arm in terms of immediate recall (31% vs 8%, respectively; P = .007), delayed recall (51% vs 20%; P = .002), and verbal fluency (19% vs 2%, P = .02). An OS benefit was not noted from the addition of WBRT. Efforts are ongoing to mitigate these effects by avoiding the hippocampus during radiation, as few metastases occur near the hippocampus, or by adding memantine (Namenda), an NMDA receptor antagonist.

SRS is considered the best approach for achieving local control of 1 to 3 small brain lesions, and is increasingly being recommended due to the negative effects of WBRT.

Existing targeted agents are increasingly being investigated to see if they can improve the prognosis for patients with MBM as they have for patients without metastases.

-targeted therapies vemurafenib (Zelboraf) and dabrafenib (Tafinlar) have both been tested as

mutations are common in patients with melanoma and are frequently tested for.

V600-mutant melanoma metastatic to the brain, whose metastases were unresectable and previously treated, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0-5.5) and the median OS was 5.3 months (95% CI, 3.9-6.6) with vemurafenib therapy.

Partial responses (PRs) were noted at both intracranial and extracra- nial sites in 10 patients (24%), and stable disease was seen in 9 (38%). Seven of 19 patients experienced more than 30% intra- cranial tumor regression. The benefit was similar to that seen in patients with melanoma without brain metastases. Patients who responded poorly tended to have activation mutations in

A phase II study of vemurafenib looked at patients with melanoma with previously treated or untreated brain metastases.

Of the 90 patients in the untreated cohort, 2 achieved an intracranial complete response and 14 achieved PRs, for a best overall response rate of 18%. The median PFS in the brain was 3.7 months in the untreated cohort and 4 months in the previously treated cohort. The median OS was 8.9 months in cohort 1 and 9.6 months in cohort 2. No significant central nervous system toxicities were noted.

In the phase II BREAK-MB trial, 172 patients with

V600-mutated metastatic melanoma were treated with dabrafenib, separated into a cohort for patients whose brain metastases were untreated and a cohort for patients with recurrent disease following treatment for their brain metastases.

In the first cohort, 39.2% (95% CI, 28.0%-51.2%) of patients with V600E mutations and 6.7% (95% CI, 0%-31.9%) of patients with V600K mutations experienced an overall intracranial response. In the second cohort, 30.8% (95% CI, 19.9%-43.4%) of patients with V600E mutations and 22.2% (95% CI, 6.4%-47.6%) of patients with V600K mutations experienced a response. Frequent serious adverse events (AEs) included pyrexia; intracranial hemorrhage, 1 of which was treatment-related; and squamous-cell carcinoma (6% each).

Checkpoint inhibitors have been incorporated into treatment for patients with melanoma and could be beneficial for patients with MBM. In a nonrandomized phase II trial, patients with untreated or progressive brain metastases from either melanoma (n = 18) or nonsmall cell lung cancer were treated with the PD-1 inhibitor pembrolizumab (Keytruda).

Responses were achieved in 4 patients with melanoma (22%; 95% CI, 7%-48%). Grade &ge;3 treatment-related or serious AEs included colitis, pneumonitis, fatigue, and grade 4 hyperkalemia (6% each). Significant neurological AEs from the melanoma cohort included transient grade 3 cognitive dysfunction and grade 1-2 seizures.

In a phase II study of ipilimumab (Yervoy), a CTLA-4 checkpoint inhibitor, 14 of 72 patients achieved disease control in the brain, including 2 patients whose brain tumors were symptomatic and who were receiving corticosteroids.

Activity was more frequent in patients whose metastases were small and asymptomatic.

inhibition and radiotherapy have separately shown benefit among patients with MBM, the combination is also being tested in these patients, as

inhibitors may have the ability to increase radiosensitivity in melanoma.

A study of 52 patients with MBM treated with SRS with or without

inhibitor therapy showed increased local control for patients receiving combination therapy over radiotherapy alone.

mutations who were treated with the combination showed a local control rate of 85.0% at 1 year compared with 67.1% in

wild-type patients treated with the combination.

-mutant patients treated with SRS alone had a 1-year local control rate of 51.5% (P = .0077). However, the OS rate and rate of distant brain failure did not vary significantly.

In another study of patients treated with SRS with or without a

inhibitor, the median survival times were greater among patients with

mutations treated with the combination compared with wild-type patients (P <.01) and patients with

Increased potential neurotoxicity from this combination is of concern. Individual cases of radiation necrosis and intracranial hemorrhage following therapy have been noted, although overall rates are unknown.

To mitigate these effects, the ECOG group recommends holding

inhibitor therapy for &ge;1 day before and after SRS and for &ge;3 days before and after fractionated radiosurgery.

Patients with melanoma have demonstrated strong responses to

inhibition combined with a MEK inhibitor to reduce resistance to

-targeted therapy. A trial of patients with metastatic melanoma, although not focused on patients with MBM, demonstrated an objective response rate of 64% from dabrafenib and trametinib (Mekinist) compared with 51% from vemurafenib monotherapy (P <.001) in patients with a

The phase II NIBIT-M1 study of ipilimumab with fotemustine showed clinical activity in patients with metastatic melanoma, including in those with MBM.

Ten patients with asymptomatic brain metastases (50%) achieved disease control, including 5 whose metastases became undetectable by imaging.

Radiotherapy combined with immunotherapy is also considered as radiotherapy could increase the permeability of the blood-brain barrier for checkpoint inhibitors. The results of retrospective studies of patients treated with ipilimumab and radiotherapy have shown that the combination is more effective than radiotherapy alone in patients with brain metastases.

A retrospective analysis of 2 studies examined 26 patients with MBM who were also treated with SRS within 6 months of receiving nivolumab therapy.

Local brain metastasis control at 1 year following SRS treatment was 85% overall. Patients with unresected metastases showed a median OS of 11.8 months from the date of SRS therapy and 12 months from the date of nivolumab initiation. Neurotoxicity was experienced in 1 case of grade 2 headaches following SRS. No other treatment-related neurotoxicities were reported.

A retrospective study of patients with MBM compared outcomes of 96 patients treated with 1 of 5 combination approaches with SRS: antiPD-1 therapy (n = 21), anti&ndash;CTLA-4 therapy (n = 25),

and MEK inhibitors (n = 12), and SRS with chemotherapy (n = 20).

Patients were included in the analysis if their metastases were unresected and had received single-fraction SRS within 3 months of systemic or cytotoxic therapy.

Distant MBM control rates were 38%, 21%, 8%, 20%, and 5%, respectively (P = .008) at 1 year. No significant differences in local control were noted between the treatment arms (P = .25).

Following treatment with radiotherapy, systemic PFS rates at 1 year were 41%, 27%, 12%, 39%, and 5%, for combination therapy with antiPD-1 therapy, anti&ndash;CTLA-4 therapy,

and MEK inhibitors, and chemotherapy, respectively (P = .04). At 1 year, the OS rates following SRS were 48%, 41%, 24%, 65%, and 10%, respectively (P = .01).

The comparison demonstrates that combination therapy with

and MEK inhibitors and SRS, a PD-1 inhibitor and SRS, or with a CTLA-4 inhibitor and SRS all provide increased benefits in patients with MBM. Each of these combination approaches significantly improved OS rates on both univariate and multivariate analyses compared with chemotherapy.

The authors noted that systemic treatment combined with radiation was well tolerated with no significant neurotoxicites reported.

As many of these trials were retrospective, further study is required to determine the true value of these approaches and which is best for patients with MBM.

Ajithkumar T, Parkinson C, Fife K, Corrie P, Je eries S. Evolving treatment options for melanoma brain metastases. Lancet Oncol. 2015;16(13):e486-e497. doi: 10.1016/S1470-2045(15)00141-2.

Chowdhary M, Patel KR, Danish HH, Lawson DH, Khan MK. BRAF inhibitors and radiotherapy for melanoma brain metastases: potential advantages and disadvantages of combination therapy. Onco Targets Ther. 2016;9:7149-7159. doi: 10.2147/OTT.S119428.

Fife KM, Colman MH, Stevens GN, et al. Determinants of outcome in melanoma patients with cere- bral metastases. J Clin Oncol. 2004;22(7):1293-1300.

Brown PD, Asher AL, Ballman KV, et al. NCCTG N0574 (Alliance): a phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol. 2015;(suppl; abstr LBA4).

Chukwueke U, Batchelor T, Brastianos P. Management of brain metastases in patients with melano- ma. J Oncol Pract. 2016;12(6):536-542. doi: 10.1200/JOP.2016.011882.

Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF (V600) muta- tion-positive melanoma with symptomatic brain metastases: nal results of an open-label pilot study. Eur J Cancer. 2014;50(3):611-621. doi: 10.1016/j.ejca.2013.11.002.

McArthur GA, Maio M, Arance A, et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicentre study. Ann Oncol. 2017;28(3):634-641. doi: 10.1093/annonc/mdw641.

Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mu- tant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087-1095. doi: 10.1016/S1470-2045(12)70431-X.

Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non- small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-la- bel, phase 2 trial. Lancet Oncol. 2016;17(7):976-983. doi: 10.1016/S1470-2045(16)30053-5.

Margolin K, Ernsto MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13(5):459-465. doi: 10.1016/S1470-2045(12)70090-6.

Ly D, Bagshaw HP, Anker CJ, et al. Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J Neurosurg. 2015;123(2):395- 401. doi: 10.3171/2014.9.JNS141425.

Xu Z, Lee CC, Ramesh A, et al. BRAF V600E mutation and BRAF kinase inhibitors in conjunction with stereotactic radiosurgery for intracranial melanoma metastases. J Neurosurg. 2017;126(3):726-734. doi: 10.3171/2016.2.JNS1633.

Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM. Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative On- cology Group (ECOG). Int J Radiat Oncol Biol Phys. 2016;95(2):632-646. doi: 10.1016/j.ijrobp.2016.01.038.

Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with com- bined dabrafenib and trametinib. N Engl J Med. 2015;372(11):30-39. doi: 10.1056/NEJMoa1412690.

Di Giacomo AM, Ascierto PA, Pilla L, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 2012;13(9):879-886. doi: 10.1016/S1470-2045(12)70324-8.

Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain metastases treated with ste- reotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27(3):434-441. doi: 10.1093/annonc/mdv622.

Ahmed KA, Abuodeh YA, Echevarria MI, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhib- itor, or conventional chemotherapy. Ann Oncol. 2016;27(12):2288-2294. doi: 10.1093/annonc/mdw417.

Articles

Clinical Articles

Outcomes have significantly improved for patients with melanoma in the wake of newer targeted treatments. Yet, brain metastases from melanoma remain a significant unmet need, with up to 60% of patients with advanced melanoma developing brain metastases.

Systemic Therapy Under Consideration for Melanoma-Associated Brain Metastases

SUITABILITY REQUIREMENTS FOR RADIATION TARGETS

"When we're treating, we really want to define what the target is," said Kilian E. Salerno, MD, director of breast radiation and soft tissue/melanoma radiation, Roswell Park Cancer Institute. Targets for radiation in breast cancer include whole-breast irradiation, partial-breast irradiation (PBI), radiation to the chest wall, and regional nodal irradiation (RNI).

A meta-analysis from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) informed the need for radiation therapy following surgery in the guidelines, showing that radiation therapy reduced the incidence of locoregional recurrence, overall recurrence, and breast cancer mortality in patients with &ge; 4 positive nodes.

In women treated with whole-breast irradiation, an appropriate margin under the latest guidelines is 2mm in women with ductal carcinoma in situ (DCIS) and no tumor on ink for women with stage I-II invasive carcinoma.

The preferred method of delivering radiation therapy, according to the NCCN, is hypofractionation, which employs a shorter treatment course that uses larger doses per fraction. Hypofractionation achieves local control and breast cosmesis that is at least equivalent to that achieved with conventional fractionation, said Salerno.

&ldquo;I hope that we move away from this concept of standard fractionation being conventional because I would argue that for breast radiation, hypofractionation is standard as well,&rdquo; Salerno said. The recommendation is to deliver a total of 40 to 42 Gy in daily fractions for whole-breast radiotherapy or 34 to 38.

Gy given in twice-daily fractions for accelerated PBI (APBI).

The guidelines for suitability of APBI accept the updated American Society for Radiation Oncology criteria,

which stipulate that patients &ge;50 years with invasive DCIS measuring &le;2 cm (T1 disease) with negative margin widths of &ge;2 mm, no lymphovascular invasion, ER-positive status, and negative for a BRCA mutation, and patients with a low or intermediate nuclear grade screen-detected DCIS measuring &le;2.5 cm with negative margin widths of &ge;3 mm, are both eligible for APBI.

Whether or not to treat with RNI is based on assessment of an individual&rsquo;s risk for recurrence using nomograms or recurrence scores, said Salerno. RNI was found to improve locoregional disease-free survival (DFS), distant DFS, and breast cancer mortality, with 10 years&rsquo; median follow-up in women who underwent breast conservation surgery in the MA.

and EORTC22922 studies. The rate of regional and distant recurrences was reduced in both studies; however, an improvement was not seen in overall survival.

In general, RNI is recommended for patients with &ge;4 positive nodes or locally advanced disease and should be strongly con- sidered for patients with 1 to 3 positive nodes.

The latest version of the NCCN breast cancer guidelines incorporates the use of genomic expression profiling to assist in adjuvant treatment decision making in women with hormone receptor (HR) positive, HER2-negative breast cancer.

Genomic profiling has been found to successfully predict the benefit of endocrine therapy, as was demonstrated in the TAILORx study, said Lee S. Schwartzberg, MD. The study utilized the 21-gene recurrence score (Oncotype DX) to determine the risk of recurrence.

Patients with a score &le;11 had a lower risk of their breast cancer returning. The study found that patients with breast cancer whose tumors had a favorable gene-expression profile had very low rates of recurrence at 5 years following treatment with endocrine therapy.

The 21-gene recurrence score has also been found to be prognostic in women with node-positive cancer, although its predictive value in this group remains uncertain, said Schwartzberg, executive director, West Cancer Center and chief, Division of Hematology/Oncology, University of Tennessee Health Science Center.

Genomic profiling can also be used to select candidates for chemotherapy. In the MINDACT study of patients with node-negative breast cancer, those with a high clinical risk and low genomic risk, per the 70-gene signature (MammaPrint), who did not receive adjuvant chemotherapy had a rate of distant metastasis-free survival of 94.7%.

Evidence also points to genomic classifiers being prognostic for late relapse, which is common in ER-positive patients, Schwartzberg added. The EBCTCG group found that distant recurrence rates kept increasing after 5 years of tamoxifen exposure.

The updated guidelines state that for patients with HR-positive, HER2-negative, node-negative breast cancer whose tumors are >0.5 cm, the 21-gene recurrence score assay should be considered. For a low recurrence score (<18), adjuvant endocrine therapy alone is recommended. For an intermediate recurrence score (18 to 30), adjuvant endocrine therapy or chemotherapy followed by endocrine therapy is acceptable. A high recurrence score (&ge;31) merits both adjuvant endocrine therapy and chemotherapy. The guidelines mention in the footnotes that the 21-gene recurrence assay can be considered in select patients with 1 to 3 positive nodes, and that other genomic expression profiling assays are prognostic, but are supported by less evidence to predict response to chemotherapy.

Overcoming resistance to endocrine therapy has been an emphasis of clinical research. The NCCN guidelines have adopted partnering strategies in which targeted agents are added to endocrine therapy in an effort to combat resistance, said William J. Gradishar, MD.

The recognition that breast cancer is cyclin-dependent has led to the development of agents that act on the cyclin D/CDK4/6/INK4-Rb pathway. With the advent of CDK4/6 inhibitors, everolimus (Afinitor) has now been shifted to a later line of therapy.

Biomarker development is essential to help determine which patients stand to benefit from CDK4/6 inhibition and everolimus, said Gradishar, deputy director, Robert H. Lurie Comprehensive Cancer Center and interim chief, Division of Hematology/Oncology, Northwestern University&rsquo;s Feinberg School of Medicine. However, the various CDK4/6 inhibitors &ldquo;should not be assumed to be exactly the sameclinically, pharmacodynamically, or kinetically,&rdquo; he said.

Findings from the PALOMA trials showed consistent clinical bene t across all 3 trials with palbociclib (Ibrance). Based on these findings, the updated guidelines now include palbociclib/letrozole and palbociclib/fulvestrant (Faslodex) as options for endocrine therapy for postmenopausal women with recurrent or stage IV disease, with a category 1 recommendation for the palbociclib/letrozole regimen in HER2-negative patients.

The guideline updates also noted that women who are postmenopausal at diagnosis can be considered for an additional 5 years of an aromatase inhibitor, for a total treatment duration of 10 years. This consideration lies in the observation of very late recurrences of ER-positive disease. &ldquo;Even out to 20 years, you see a progressive increase in recurrence rates,&rdquo; Gradishar said. Yet due to the conflicting nature of the data, the recommendation was not quali ed as category 1 in the updated guidelines.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2017. NCCN website. https://www.nccn.org/professionals/physician_gls/ pdf/breast.pdf. Accessed April 10, 2017.

Correa C, Harris EE, Leonardi MC, et al. Accelerated partial breast irradiation: Executive sum- mary for the update of an ASTRO evidence-based consensus statement. Pract Radiat Oncol. 2017;7(2):73-79. doi: 10.1016/j.prro.2016.09.007.

Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 study investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316. doi: 10.1056/NEJMoa1415340.

Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014. doi: 10.1056/NEJMoa1510764.

Cardoso F, van&rsquo;t Veer LJ, Bogaerts J, et al; MINDACT Investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.

An overview of updated guidelines for the management of invasive breast cancer, issued by the National Comprehensive Cancer Network.

Prognostic Indicators Incorporated Into Breast Cancer Guidelines

The National Comprehensive Cancer Network (NCCN) published its first set of guidelines for myeloproliferative neoplasms (MPNs) in October 2016 and is already looking to update and expand these guidelines to match the need for direction in diagnosing and treating patients with MPNs.

The guidelines initially focused on diagnosing each of the MPNs and treatment options for patients with myelofibrosis, as that was the disease type with the greatest unmet need, Ruben A. Mesa, MD, explained in an interview with

following his presentation at the 2017 NCCN Annual Conference.

&ldquo;The myeloproliferative neoplasms were probably one of the most significant of the hematologic malignancies that did not yet have NCCN guidelines,&rdquo; said Mesa, a professor of medicine and chair of hematology at Mayo Clinic in Phoenix, Arizona, and chair of the panel for the NCCN guidelines on MPNs. &ldquo;The guidelines are very helpful in terms of improving quality of care by providing more homogeneity of care in the United States, trying to bring in current evidence regarding treatment that can be utilized, as well as clarifying the role of a variety of things, ranging from transplantation to therapies.&rdquo;

The guidelines look to explain the criteria for diagnosing each of the MPNs, including the World Health Organization&rsquo;s recent update to the classi cation of MPNs, and risk assessment. Yet the current edition of the guidelines only included treatment options for patients with myelofibrosis. Treatment guidelines for patients with polycythemia vera or essential thrombocythemia are expected in the update, which Mesa remarked is expected in the summer of this year.

The myelofibrosis guidelines incorporate scoring systems for risk stratification, including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS), and the DIPSS-Plus. Mesa also noted that the guidelines endorse the 2013 International Working Group for Myelofibrosis Research and Treatment and European LeukemiaNet consensus response criteria, as well as the scoring system for total symptom burden.

&ldquo;In myelofibrosis, there are clinical improvement criteria that can stand alone. You can have reduction in splenomegaly that counts as a response. What that leads to for clinical decision making is more subtle, and like all of these guidelines, they are married to clinical experience and expertise in terms of the character of response and how that balances against any negatives that come with the treatment in terms of side effects or toxicities as well as expense,&rdquo; he said.

The guidelines also describe the prognostic significance of several common mutations in patients with primary myelofibrosis. Patients with an

W515L/K mutation, for example, have a higher risk of thrombosis compared with patients who have a

mutation, and they usually have an intermediate prognosis. Those who do not have

mutations have an inferior prognosis compared with patients with these driver mutations, with lower leukemia-free and overall survival rates. Patients with

mutations are associated with a greater risk for transformation to acute myeloid leukemia.

For patients with low-risk asymptomatic myelofibrosis, the guidelines recommend either observation for signs and symptoms of disease progression or a clinical trial. For symptomatic patients who are low risk, the guidelines suggest interferons, a clinical trial, or ruxolitinib (Jakafi), the only FDA-approved targeted agent for patients with myelofibrosis. Ruxolitinib, a JAK1/2 inhibitor, is also recommended for patients with intermediate-1 and -2 disease, especially for those with intermediate-2 disease who are not candidates for transplant and have a high platelet count.

&ldquo;Ruxolitinib is the only FDA-approved therapy, so obviously it leaves you somewhat challenged when you fail that therapy,&rdquo; Mesa said. &ldquo;That&rsquo;s the greatest unmet need, and certainly many of the current clinical trials are aimed at trying to assist patients that have &lsquo;failed ruxolitinib.&rsquo;&rdquo;

Although the guidelines do consider some options for when a patient is ruxolitinib intolerant or resistant, including agents such as udarabine and busulfan, they strongly encourage clinical trials. However, he noted that the expected updates to the MPN guidelines will delve further into more options for patients following progression on ruxolitinib.

In his presentation, Mesa also addressed several promising second-line agents currently in development, including pacritinib, momelotinib, imetelstat, and PRM-151. &ldquo;We&rsquo;ve seen data recently that certainly was encouraging. Although neither agent is approved yet, both pacritinib and momelotinib had beneficial data in that second-line setting. Data from 2 clinical trials are eagerly anticipated for PRM-151, the antifibrosing agent, as well as imetelstat. Those are 2 second-lines studies that are of great interest. We desperately need other agents approved because we only have 1 approved drug, [and that is] ruxolitinib. If a second drug becomes approved, we will undoubtedly work to revise the guidelines in a very rapid fashion to provide clarity and situational use,&rdquo; Mesa continued.

He remarked that the guidelines are a starting point for oncologists who are less familiar with diagnosing and treating patients with these diseases. However, the experience of oncologists more familiar with MPNs could outweigh the recommendations in the guidelines. &ldquo;We&rsquo;re hopeful that [the guidelines] will be a good resource for community oncologists in clarifying a range of issues with these diseases,&rdquo; Mesa concluded. &ldquo;How one walks that path, there&rsquo;s a lot of individual factors and clinical experience that are highly relevant.&rdquo;

NCCN. NCCN clinical practice guidelines in oncology (NCCN guidelines): myeloproliferative neo- plasms. Version 2.2017. National Comprehensive Cancer Network website. https://www.nccn.org/ professionals/physician_gls/pdf/mpn.pdf. Published October 19, 2016. Accessed March 25, 2017.

The NCCN published its first set of guidelines for myeloproliferative neoplasms in October 2016 and is already looking to update and expand these guidelines to match the need for direction in diagnosing and treating patients with MPNs.

Expected Changes to New Guidelines on MPNs Shared

The genetic profile of treatment-resistant non-small cell lung cancer (NSCLC) may be more complex than initially thought, according to a presentation by Zofia Piotrowska, MD, during the American Society for Radiation Oncology&rsquo;s 2017 Multidisciplinary Thoracic Cancers Symposium. The study results showed that resistance mutations frequently varied between biopsies in patients with NSCLC who acquired resistance from treatment with an EGFR-targeted therapy.

Part of the problem with assessing patients with NSCLC for targeted therapies is that they may become resistant to certain therapies over time or their disease may progress in a way that could entirely change the course of treatment. Many patients with NSCLC have a mutation on the

gene, which accounts for 15% of all lung adenocarcinomas, and will undergo therapy using tyrosine kinase inhibitors (TKIs) to combat this.

mutations are the most common of targetable gene alterations seen in NSCLC, and for patients with

-mutant cancer, EGFR TKIs are standard first-line therapy. Although these drugs initially yield high responses, resistance typically develops after about 9 to 13 months of treatment,&rdquo; explained Piotrowska, a thoracic oncologist at Massachusetts General Hospital Cancer Center.

Piotrowska led a retrospective analysis of 221 patients with advanced

-mutant NSCLC seen at Massachusetts General Hospital between 2008 and 2016. For each patient, the investigators collected data for all biopsies obtained after resistance, including results of clinical molecular testing, treatment history, and biopsy complications. Overall, 61% of patients were T790M-positive, which is the most common resistance mutation noted, having been found in 50% to 60% of all patients who progress on their initial EGFR TKI. The second most common resistance mechanism was

amplification, which was found in 5% of the patients. Eighteen percent were

-mutation positive. However, 19% of patients harbored more than 1 resistance mechanism.

Among the 83 patients with 2 postresistance biopsies, 49% had variations in the resistance mechanisms identified between their first and second biopsies, including 20% of patients who &ldquo;lost&rdquo; the T790M mechanism and 11% who &ldquo;gained&rdquo; it. Of the 17 patients who lost the T790M resistance mutation, 3 had a new resistance mechanism noted upon their second postresistance biopsy, including 1 acquired

&ldquo;The dominant drivers of resistance can fluctuate over time,&rdquo; Piotrowska commented. This presents a challenge for oncologists, because often in practice, patients rarely undergo further biopsies during their treatment and are commonly categorized as positive or negative for a particular resistance mechanism based on a single biopsy and timepoint. The investigators concluded that a binary positive/negative classification may underestimate the heterogeneity of resistant cancers and may prevent patients from accessing potentially effective treatment strategies.

&ldquo;As much as half the time, the dominant resistance mechanisms observed on 1 biopsy may no longer be relevant on a second biopsy, which may uncover a new, potentially targetable, resistance mechanism,&rdquo; Piotrowska said. &ldquo;We hope that these ndings will prompt clinicians to consider repeat biopsies when selecting a new therapy for

Patients who gain a T790M resistance mutation, for example, they can go on to second-line therapy with osimertinib (Tagrisso), which has been approved to treat patients with

T790M-positive NSCLC following progression on a prior EGFR TKI. Piotrowska noted that liquid biopsies can be used for repeat postresistance biopsies, but that there was still an important role for tumor tissue biopsies. &ldquo;Noninvasive testing methods, such as liquid biopsies, may provide another method to more easily characterize resistance over time.&rdquo;

Ravi Salgia, MD, PhD, the moderator of the session, pointed out that the location of each of the biopsies can affect the results due to the heterogeneity of the disease, and Piotrowska confirmed that many of the second postresistance biopsies were taken in a different location.

&ldquo;Heterogeneity of resistance to cancer likely has many different components, and I think our ndings are a re ection, in part, of spatial heterogeneity. In some cases, the patients who had serial biopsies, the lesions that were biopsied, were not the same throughout different timepoints, and so, I think some of what we&rsquo;re seeing is likely related to spatial heterogeneity in these cancers,&rdquo; she said. &ldquo;Clearly this idea that things are static, that just 1 dominant resistance mechanism is at play, is probably oversimplifying the reality, and we need to learn much more.&rdquo;

Piotrowska Z, Stirling K, Heist R, et al. Heterogeneity and variation in resistance mechanisms among 223 EGFR-mutant NSCLC patients with &ge; 1 post-resistance biopsy. Presented at: 2017 Multidisci- plinary Thoracic Cancers Symposium; March 16-18, 2017; San Francisco, CA.

The genetic profile of treatment-resistant non-small cell lung cancer may be more complex than initially thought, according to a presentation by Zofia Piotrowska, MD.

Heterogeneity Found in Resistance Mechanisms in NSCLC

Our understanding of the genomic landscape of metastatic castration-resistant prostate cancer (CRPC) has been rapidly progressing, with new clinical data emerging to clarify and, in many cases, support the use of poly (ADP-ribose) polymerase (PARP) inhibitors in the treatment of these patients.

&ldquo;PARP is an important mediator of DNA repair as the DNA strand breaks,&rdquo; explained Celestia S. Higano, MD, during a presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress&reg; and other Genitourinary Malignancies. &ldquo;And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.&rdquo;

in 2015 showed that genomic testing of bone or soft tissue biopsies from patients with metastatic CRPC proved that 23% of metastatic CRPC tumors harbor DNA repair alterations. Aberrations of the androgen receptor (AR), ETS fusions,

mutations were frequently observed (40%-60% of cases), with TP53 and AR alterations enriched in metastatic CRPC compared with primary prostate cancer.

Additionally, aberrations of BRCA1/2 and ATM genes were observed at substantially higher frequencies (19.3% overall) compared with those in primary prostate cancers. The study found that 89% of affected individuals harbored a clinically actionable DNA aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with pathogenic germline alterations that are actionable. The study also determined that the frequency of DNA repair alterations increases with disease progression.

In a phase II study of olaparib (Lynparza), a PARP inhibitor, treating patients with metastatic CRPC and DNA repair defects, the drug was proven to lead to high response rates in this patient population. The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel (Taxotere), abiraterone acetate (Zytiga), enzalutamide (Xtandi), or cabazitaxel (Jevtana). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33%) had a response to the treatment with olaparib, with 12 receiving the treatment for more than 6 months.

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to olaparib in 14 of 16 patients, including all 7 with loss of BRCA2. &ldquo;They didn&rsquo;t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,&rdquo; commented Higano, professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.

DNA repair alterations are present in approximately 25% to 30% of cases of metastatic CRPC. These include BRCA1/2, ATM, Fanconi&rsquo;s anemia, CHEK2, and other gene alterations. Higano stressed that there are 2 ways a patient can have these alterations: either in tumor DNA, which is observed in about 25% of patients, or in the germline setting, which is observed in approximately 12% of patients.

If these DNA repair alterations are present after treatment with abiraterone, docetaxel, or enzalutamide, there is a higher response rate to olaparib. However, 1 challenge is the lack of data regarding the overall survival (OS) benefit for patients with CRPC, although olaparib has a breakthrough designation from the FDA based on a study published in the New England Journal of Medicine.2 &ldquo;It&rsquo;s not that difficult to get olaparib for your patients,&rdquo; Higano commented.

Numerous other PARP inhibitors are also in development, including veliparib, niraparib (Zejula), rucaparib (Rubraca), and talazoparib. Additionally, there are many combinations studies with PARP inhibitors, and so patients who do not have a DNA repair alteration are not necessarily excluded from the potential benefits of PARP inhibitors.

One such combination study is the phase I KEYNOTE-365 trial, which is investigating the safety and efficacy of combination therapies with pembrolizumab (Keytruda) in patients with metastatic CRPC (NCT02861573). There will be 3 cohorts in this study, each with approximately 70 participants: cohort A will receive pembrolizumab combined with olaparib, cohort B will receive pembrolizumab combined with docetaxel and prednisone, and cohort C will receive pembrolizumab combined with enzalutamide.

A phase II randomized, open-label, multicenter trial is also assessing the efficacy abiraterone and prednisone with or without added olaparib in comparison with olaparib monotherapy (NCT03012321). Patients with metastatic CRPC that have an

mutation will be randomized to 1 of 3 arms.

There are some challenges facing the development of PARP inhibitors. One of the problems is that it takes a long time, often 2 to 6 weeks, for the results of tumor biopsies and germline tests to be processed for eligibility for biomarker-driven trials. Despite these challenges, several studies of PARP inhibitors driven by DNA repair biomarkers are ongoing. In the phase III, randomized TRITON3 study, investigators will be assessing how patients with metastatic CRPC and evidence of a homologous recombination gene deficiency respond to treatment with rucaparib verses treatment with a physician&rsquo;s choice of abiraterone, enzalutamide, or docetaxel (NCT02975934). This study is currently enrolling participants who have a deleterious mutation in the BRCA1/2 or ATM gene.

&ldquo;The thing that makes this trial stand out from all the others is that most of the other trials require patients to have failed docetaxel, whereas this rucaparib trial allows patients to be treated with rucaparib or a choice of abiraterone, enzalutamide, or docetaxel. In terms of patient accrual, patients are allowed to cross over to the rucaparib arm once they fail in the control arm,&rdquo; Higano said.

In the phase II Galahad study of niraparib, investigators are assessing the efficacy, safety, and pharmacokinetics of niraparib in men with metastatic CRPC and DNA repair anomalies (NCT02854436). The trial is looking at overall response rate as its primary endpoint, with OS and time to prostate-specific antigen progression included as secondary endpoints.

&ldquo;I think it&rsquo;s become increasingly apparent that we need a thorough family history of cancer that might point to patients with DNA repair defects,&rdquo; said Higano. As genomic testing for directing targeted therapies becomes more integrated into the standard of care for patients with CRPC and PARP inhibitors show more durable responses in clinical trials, these agents will become increasingly available.

Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [erratum appears in Cell. 2015;162(2):454]. Cell. 2015;161(5):1215-1228. doi: 10.1016/ j.cell.2015.05.001.

Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate can- cer. N Engl J Med. 2015;373(18):1697-1708. doi: 10.1056/NEJMoa1506859.

Our understanding of the genomic landscape of metastatic castration-resistant prostate cancer has been rapidly progressing, with new clinical data emerging to clarify and, in many cases, support the use of PARP inhibitors in the treatment of these patients.

Role of PARP Inhibitors Clarified in Prostate Cancer

Surgical resection, including cytoreductive nephrectomy, remains an effective option for many patients with metastatic renal cell carcinoma (RCC), with results of randomized trials showing a survival benefit with the addition of nephrectomy. However, many patients will have a recurrence. Much research has been done to define the role of neoadjuvant and adjuvant therapies in these patients, but the standard of care has not significantly changed.

&ldquo;The [benefit] of giving therapy, like a tyrosine kinase inhibitor for instance, would be to start systemic therapy right away, have the tumor shrink, and the nephrectomy will be easier,&rdquo; said David M. Nanus, MD, during his presentation at the New York GUTM: 10th Annual Interdisciplinary Prostate Cancer Congress and Other Genitourinary Malignancies meeting.

Nanus explained that rapid initiation of systemic therapy prior to surgery could decrease cancer-related mortality and eliminate these risks in patients who would not benefit from nephrectomy. However, commented Nanus, the Mark W. Pasmantier Professor of Hematology and Oncology in Medicine, Weill Cornell Medicine, &ldquo;it may add to the morbidity or mortality of surgery if you give the drug; you may &lsquo;decondition&rsquo; the patient and [then] they can&rsquo;t get systemic therapy. And it hasn&rsquo;t been proven that it improves survival, so why should we do it?&rdquo;

Previously, there were several prospective clinical trials in the neoadjuvant setting prior to cytoreductive nephrectomy, but such investigations have become less frequent due to the recent push to develop immunotherapies. One such study was a phase II trial of pazopanib (Votrient) in patients with localized RCC to optimize the preservation of the renal parenchyma.

Of 13 patients originally unable to undergo a partial nephrectomy, 6 underwent surgery. There was also a significant decrease in the size of the tumors in the patients. "I think that keeping a patient from going on dialysis by shrinking the tumor preoperatively is something that should be done," Nanus commented.

In another phase II study assessing pazopanib therapy prior to nephrectomy in patients with metastatic clear cell RCC (ccRCC), investigators discovered that a nephrectomy could be performed safely after upfront treatment with pazopanib and was associated with good outcomes in patients with intermediate-risk disease.

A significant reduction in the primary tumor was observed, with a median reduction of 14.4% (range, 1.4%-21.1%). &ldquo;Progression-free survival in this study was about 7 months, so it&rsquo;s not very clear that giving preoperative [pazopanib] in the metastatic setting made a big difference,&rdquo; Nanus said. &ldquo;I think giving cytoreductive neoadjuvant therapy should be restricted to select patients.&rdquo;

Nanus explained that patients tend to relapse at high rates, with a tendency toward mortality for those who progress to metastatic disease. Patients in these populations could benefit from an adjuvant treatment if one is proven effective. However, investigations into adjuvant treatments have been a mixed bag, at best, with several trials leading to negative results.

The phase III ARISER trial assessed adjuvant girentuximab (Rencarex), an antibody to the RCC-associated G250 antigen that is especially overexpressed in ccRCC, in patients with nonmetastatic RCC. The investigators determined that girentuximab had no clinical benefit as an adjuvant treatment for patients with high-risk ccRCC based on a median disease-free survival (DFS) of 71.4 months for the girentuximab arm (n = 433); DFS was not reached in the placebo arm (n = 431). Overall survival (OS) was not reached for either arm.

The phase III ASSURE trial, compared adjuvant sorafenib (Nexavar) or sunitinib (Sutent) with placebo for patients with unfavorable RCC. There was no difference observed in 5-year DFS or OS between the 3 arms.4 A preplanned ccRCC subset analysis also revealed that there was no significant difference among the 3 arms.

Recently updated data from the ccRCC subset of this trial on patients whose RCC was removed by surgery show that there was no improvement in DFS and OS.5 In the secondary analysis, the 5-year DFS rates were 47.7%, 49.9%, and 50.0% for sunitinib, sorafenib, and placebo, respectively. Additionally, dose intensity did not affect outcomes.

From the phase III S-TRAC study, which compared the efficacy and safety of sunitinib versus placebo for patients at a high risk for recurrent RCC, early data show that DFS was longer in the sunitinib group than in the placebo group (6.8 vs 5.6 years), although at the cost of a higher rate of adverse events.

However, the results were only just statistically significant (HR, 0.76; 95% CI, 0.59-0.98; P = .03).

There are many challenges in assessing treatments in the neoadjuvant and adjuvant settings for patients with RCC, Nanus pointed out DFS may not reflect OS, the 5-year follow-up period may not be long enough, dose reductions and discontinuations make it tricky to compare trials, and there are varying eligibility factors and treatment durations.

Conversely, there are a lot of opportunities in these settings. There is a clinical need to improve survival in these patients. &ldquo;This is a patient population that we&rsquo;ve really let down; a lot of these patients go through surgery and then they relapse,&rdquo; Nanus said.

With large datasets incoming, there will be an opportunity to develop prognostic and molecular models to determine which patients are at the highest risk for recurrence and who would benefit from certain therapies.

Rini BI, Plimack ER, Takagi T, et al. A phase II study of pazopanib in patients with localized renal cell carcinoma to optimize preservation of renal parenchyma. J Urol. 2015;194(2):297-303. doi: 10.1016/j.juro.2015.03.096.

Powles T, Sarwar N, Stockdale A, et al. Safety and e cacy of pazopanib therapy prior to planned ne- phrectomy in metastatic clear cell renal cancer. JAMA Oncol. 2016;2(10):1303-1309. doi: 10.1001/jama- oncol.2016.1197.

Chamie K, Donin NM, Klöpfer P, et al. Adjuvant weekly girentuximab following nephrectomy for high-risk renal cell carcinoma: the ARISER randomized clinical trial [published online October 27, 2016]. JAMA Oncol. 2016. doi: 10.1001/jamaoncol.2016.4419.

Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial. Lancet. 2016;387(10032):2008-2016. doi: 10.1016/S0140-6736(16)00559-6.

Haas NB, Manola J, Dutcher JP, et al. Adjuvant treatment for high-risk clear cell renal cancer: updated results of a high-risk subset of the ASSURE randomized trial [published online March 9, 2017]. JAMA Oncol. 2017. doi:10.1001/jamaoncol.2017.0076.

Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcino- ma after nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi: 10.1056/NEJMoa1611406.

Much research has been done to define the role of neoadjuvant and adjuvant therapies in metastatic renal cell carcinoma patients who have diseease recurrence after surgical resection, but the standard of care has not significantly changed.

Determining a Role for Neoadjuvant/Adjuvant Therapy in RCC

Updates to the National Comprehensive Cancer Network (NCCN) guidelines for the management of advanced nonsmall cell lung cancer (NSCLC) stress the importance of multiplexed biomarker testing at diagnosis to aid in the selection of appropriate first-line and subsequent lines of therapy, said presenters at the 2017 NCCN Annual Conference.

The latest version of the guidelines recommends that PD-L1, in addition to molecular analysis, be employed as a biomarker to direct initial therapy, with &ge;50% expression established as the threshold for a positive result. The PD-L1 test &ldquo;decides whether a patient has enough of the marker to warrant initial immunotherapy,&rdquo; said presenter Gregory J. Riely, MD, PhD.

PD-L1 testing is currently &ldquo;all over the map,&rdquo; he added. Immunohistochemistry assays using 28-8, 22c3, or E1L3N as antibodies to detect PD-L1 expression were generally concordant in their findings, but the assay using the SP142 antibody was an outlier that detected significantly less PD-L1 expression in tumor cells than the other 3 platforms.

In addition, PD-L1 expression is likely stable, he said, so there is no clear benefit to a repeat biopsy for assessment of PD-L1 unless the prior sample has been exhausted.

Riely, vice chair, Clinical Trial Office, Department of Medicine, Memorial Sloan Kettering Cancer Center, suggested that institutions should customize their molecular analysis approach. Many use a combination of immunohistochemistry, fluorescence in situ hybridization, and DNA sequencing to detect abnormalities in key genes.

Based on the results of PD-L1 testing and molecular analysis, the NCCN developed an algorithm for initial therapy for patients with stage IV NSCLC. Patients with

mutations or rearrangements at diagnosis, which collectively constitute about 25% of NSCLC, should receive targeted therapy as first-line treatment.

Pembrolizumab (Keytruda) is recommended (category 1) as a first-line choice for patients with NSCLC whose tumors are positive for PD-L1, and negative or unknown for mutations or rearrangements in

Updates to the NCCN guidelines for the management of advanced NSCLC stress the importance of multiplexed biomarker testing at diagnosis to aid in the selection of appropriate first-line and subsequent lines of therapy.