In the afterglow of the 2019 American Association for Cancer Research (AACR) Annual Meeting in Atlanta, Georgia, it seems worthwhile to highlight a series of exciting results that affect cancer research and treatment. The meeting focused heavily on immunotherapy advances in several cancers. In addition to the topics discussed in our conference coverage on pages 21 to 29 in this issue, other presentations could inform research efforts moving forward.

The use of chimeric antigen receptor (CAR) T cells may be on the horizon for solid tumors. Results of HEROS 2.0 (NCT00902044), a phase I dose-escalation clinical study by Shoba A. Navai, MD, assistant professor of hematology/oncology at Baylor College of Medicine, showed that lymphodepletion prior to HER2-targeted CAR T cells safely augments T-cell expansion and induces clinical responses in patients with advanced sarcomas. The therapy was tolerated and associated with objective clinical benefit in some patients with advanced HER2- positive sarcoma.

In a presentation on targeting multiple checkpoint receptors, Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milan and head of the Division of Early Drug Development at the European Institute of Oncology, reported on a trial investigating MBG453 and spartalizumab. These agents block the binding of immune checkpoint receptors TIM-3 to phosphatidylserine and PD-1 to PD-L1/2, respectively. Preclinical studies show synergistic antitumor activity of TIM-3 plus PD-1 coblockade. Based on promising early data, the dose-expansion phase II study is ongoing in patients with melanoma or nonsmall cell lung cancer (NSCLC) resistant to anti&ndash;PD-1/PD-L1.

F. Stephen Hodi, MD, director of the Melanoma Center at Dana-Farber Cancer Institute, presented data from 2 randomized phase III trials, CheckMate 066 (NCT01721772) and CheckMate 067 (NCT01844505. Genomic correlates of response to nivolumab versus dacarbazine (CheckMate 066) and nivolumab (Opdivo) plus ipilimumab (Yervoy) combination therapy or nivolumab versus ipilimumab (CheckMate 067) were evaluated for association of tumor mutational burden (TMB) and an inflammatory gene signature with clinical outcomes in patients with melanoma. TMB-high status and a high inflammatory signature score were not correlated and independently associated with clinical outcomes. Higher inflammatory status increased clinical response and longer survival for nivolumab plus ipilimumab and nivolumab monotherapy, suggesting further evaluation of these biomarkers to better characterize the response to immune-oncology regimens in melanoma.

Data from the multicohort study ENCORE-601 (NCT02437136), evaluating entinostat plus pembrolizumab (Keytruda) in patients with advanced melanoma, demonstrated significant clinical activity and acceptable safety in patients with melanoma who have progressed on prior PD-L1 blockade. Ryan J. Sullivan, MD, assistant professor of medicine at Harvard Medical School and of hematology/oncology at Massachusetts General Hospital, reported that preliminary biomarker analysis supported the hypothesis that adding entinostat decreases myeloid-derived suppressor cells and restores inflammation in the tumor microenvironment necessary for successful re-treatment with an antiPD-1/PD-L1.

Articles

Clinical Articles

Robert L. Ferris, MD, PhD, co-physician editor-in-chief, discusses the excitement of immunotherapy at the 2019 AACR Annual Meeting and how this research can inform resarch efforts moving forward.

Translational Immunotherapy Research Informs Ongoing Efforts to Improve Treatment Outcomes

Updated National Comprehensive Cancer Network (NCCN) guidelines in prostate cancer recommend integration of tumor genetic testing into clinical practice for patients with advanced prostate cancer. For patients with regional or metastatic disease, the guidelines recommend testing for homologous recombination gene mutations and for microsatellite instability (MSI) or mismatch repair deficiency (dMMR), according to Emmanuel S. Antonarakis, MBBCh.

In a presentation during the NCCN 2019 Annual Conference in Orlando, Florida, Antonarakis addressed the role of genetic testing.

The genes detected in patients with prostate cancer fall into 2 classes: mismatch repair (MMR) and homologous recombination deficiency (HRD). In an interview with Targeted Therapies in Oncology, Antonarakis, associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland, discussed the prevalence of these different genes.

Two main types of genetic testing, germline or somatic, need to be considered, Antonarakis said.

The updates recommend germline testing for every patient with metastatic prostate cancer and high-risk, localized nonmetastatic disease. Men with very low-risk prostate cancer are excluded from the new guidelines, Antonarakis said. What about somatic testing? &ldquo;The guidelines say that anyone who has lymph node metastases should also undergo tumor somatic testing,&rdquo; he said.

This leads to questions regarding the genes&rsquo; prevalence in prostate cancer and what can be done with this information. The most informative type of gene mutations to the oncologist involve 2 classes of genes, MMR and HRD.

MMR genes are responsible for Lynch syndrome. These genesMSH2, MSH6, MLH1, and PMS2&mdash;are responsible for hypermutated tumors.

The MMR mutation is seen in only about 3% to 5% of all advanced prostate cancers, but the guidelines recommend pembrolizumab (Keytruda) in patients with this mutation.

The second class of mutations, HRD genes, include BRCA2, BRCA1, ATM, and a number of others. &ldquo;Collectively, these gene mutations make up between 20% and 25% of all advanced prostate cancers. Even though testing for these HRD genes is recommended, we do not currently have any FDA-approved therapies specifically targeting those patients,&rdquo; Antonarakis said. &ldquo;There is a lot of interest in using PARP inhibitors like olaparib (Lynparza) or rucaparib (Rubraca) for those patients.&rdquo;

Clinical trials are exploring the use of these agents in patients with an HRD gene. For referral to a PARP inhibitor trial, a patient must first be found to have an HRD mutation, such as BRCA2. &ldquo;The guidelines do not endorse the off-label use of a PARP inhibitor for a patient with an HRD-positive prostate cancer,&rdquo; Antonarakis said.

Studies involving pembrolizumab in patients with dMMR include a phase II study evaluating the clinical activity of pembrolizumab in 41 patients with progressive metastatic carcinoma, with or without dMMR. An objective response rate (ORR) and immune-related progression-free survival rate of 40% (4 of 10 patients) and 78% (7 of 9 patients) were observed, respectively.

Similarly, a phase II study of 86 patients evaluated the efficacy of PD-1 blockade in patients with advanced dMMR cancers across 12 tumor types.

Investigators reported objective radiographic responses in 53% of patients, with 21% achieving complete radiographic response.

&ldquo;Those studies showed that for the first time, irrespective of what type of cancer you have whether it&rsquo;s colorectal cancer, prostate cancer, or breast cancer&mdash;if you have an MMR mutation, you have an extremely high chance of responding to pembrolizumab,&rdquo; he said.

In prostate cancer, KEYNOTE-1993 investigated pembrolizumab in 258 patients with metastatic castration-resistant prostate cancer. In that study, the ORR for single-agent pembrolizumab was around 4% to 5%, Antonarakis said.

One of the most exciting things in the management of prostate cancer is the investigational use of PARP inhibitors. These agents have been approved by the FDA for a few cancer types, but not for prostate cancer. Olaparib and rucaparib are being studied in the phase III setting.

&ldquo;We are beginning to learn that it does not seem to be enough to have a mutation in 1 of the HRD genes. In fact, the actual gene that is mutated seems to matter,&rdquo; Antonarakis said. &ldquo;There are some mutated genes, such as BRCA2, in which the chance of responding to olaparib or rucaparib is quite highin the 50% to 70% range.

Another relatively common gene is called CHEK2. It was hypothesized that patients with CHEK2 mutations might respond to PARP inhibitors in the context of prostate cancer, but response rates actually were quite low. &ldquo;The emerging data are pointing to the fact that a patient with BRCA1/ BRCA2-mutated prostate cancer will probably have a very good chance of response to a PARP inhibitormaybe 50% to 70% chance&mdash;but perhaps some of the other genes, like ATM, CHEK2, and other more rare ones, may not respond as well.&rdquo;

How well a patient with a germline mutation versus a somatic mutation responds to a particular treatment is still unclear, Antonarakis said.

&ldquo;What we don&rsquo;t yet know is whether, for example, a germline BRCA2 mutation will have a higher response to a PARP inhibitor in prostate cancer compared with a somatic-only mutation. Not only does the gene itself matter but also whether the germline tumor DNA may be an additional factor that might predict sensitivity or perhaps resistance to PARP inhibitors,&rdquo; he said.

Antonarakis emphasized that genetic tests are commercially available, approved by the FDA, and reimbursed by insurance companies, so physicians should not be hesitant to order them. If one of these genes is found to be mutated in the tumor, a saliva or blood sample should be obtained to determine whether this mutation was inherited or not; this can have profound implications for the patient&rsquo;s first-degree relatives.

&ldquo;If you begin by doing tumor sequencing and find a BRCA2 mutation, it is paramount to determine if that BRCA2 mutation was inherited or not. If it was inherited, that patient&rsquo;s family should be counseled about their risk of developing other cancers,&rdquo; Antonarakis concluded.

Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency.

. 2015;372(26):2509-2520. doi: 10.1056/NEJMoa1500596.

Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.

DeBono JS, Goh JCH, Ojamaa K, et al. KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).

. 2018;36(suppl 15):5007. doi: 10.1200/JCO.2018.36.15_suppl.5007.

Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade.

. 2019;5(4):471-478. doi: 10.1001/jamaoncol.2018.5801.

Updated NCCN guidelines in prostate cancer recommend integration of tumor genetic testing into clinical practice for patients with advanced prostate cancer. For patients with regional or metastatic disease, the guidelines recommend testing for homologous recombination gene mutations and for microsatellite instability or mismatch repair deficiency, according to Emmanuel S. Antonarakis, MBBCh.

Integrating Genetic Testing Into Prostate Cancer Guidelines Leads to Improved Treatment Decisions

Approximately one-third to one-half of patients with advanced melanoma respond to PD-1 inhibitor therapy, which is superior to response rates observed with systemic chemotherapy or even single-agent ipilimumab (Yervoy)a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blocker and the first checkpoint inhibitor approved for melanoma.

Nevertheless, a significant proportion of patients have primary, or innate, resistance to PD-1 inhibition and derive no benefit from these therapies that have become the standard of care for advanced melanoma.

In addition, several years have passed since the first patients received PD-1 inhibitors in clinical trials, and it has become clear that although most responses are durable and last several years, one-fourth to one-third of patients relapse despite ongoing treatment.

These patients are categorized as having secondary, or acquired, resistance.

The lack of adequate therapies for advanced melanoma that is resistant to immune checkpoint inhibitors (ICIs) remains an important unmet need in this tumor type. To address this problem, investigators across the globe have expended considerable effort attempting to identify mechanisms of response and resistance to ICIs. The general conclusion is that each patient&rsquo;s response to immunotherapy is likely complex and highly individualized.

Numerous pathways and patient characteristics have been implicated in poor response to PD-1 inhibition, with more discovered every year.

They are broadly divided between tumor-extrinsic, or host, and tumor-intrinsic factors.

Potential host factors include the gut microbiome, diet, the patient&rsquo;s health and immune status, and other medications or treatments.

Tumor-intrinsic mechanisms include histology, genetic and epigenetic changes in the tumor or its microenvironment (TME), and tumor mutational burden.

The wealth of information about resistance mechanisms has inspired the development of many different treatment strategies for preventing or overcoming PD-1 inhibitor resistance, which are being evaluated in ongoing clinical trials.

Jennifer A. Wargo, MD, MMSc, associate professor in the department of Surgical Oncology and Genomic Medicine at The University of Texas MD Anderson Cancer Center in Houston, runs a research laboratory, and is coleader of MD Anderson&rsquo;s Melanoma Moon Shot Program. She said the goal of the almost 7-year-old program is to &ldquo;help end pain and suffering for patients with cancer over the next decade,&rdquo; and it has supported her extensive research into mechanisms of resistance to ICIs and new treatment approaches. &ldquo;We&rsquo;ve made some major discoveries and have been able to run some novel clinical trials that have profoundly improved outcomes for patients with cancer,&rdquo; she said in an interview with Targeted Therapies in Oncology.

Wargo is particularly excited about her group&rsquo;s efforts to untangle the relationship between the gut microbiome and responses to ICIs. She explained that the human body contains more than 100 trillion microbes, which is almost 10 times the number of human cells.

&ldquo;A large proportion of those microbes reside in the gut, which has a huge surface area. On one side, you have all these microbes, and on the other side, you have a dense network of immune cells,&rdquo; she said. Microbial metabolites facilitate cross talk between microbes and immune cells in the gastrointestinal tract; they also influence immune system functions locally and then systemically as immune cells migrate from the intestines throughout the body via the lymphatic and circulatory systems.

Wargo said the sheer quantities of microbes and immune cells in the gut and their constant interactions convinced her there is a &ldquo;tight link between the gut microbiome and response to cancer immunotherapy.&rdquo; Bolstered by findings from murine and other preclinical studies,

Wargo and colleagues decided to test the theory in humans with metastatic melanoma. They prospectively collected and analyzed samples of the gut microbiome from 112 patients about to start PD-1 inhibitor therapy.

Later, they assessed whether bacterial diversity at baseline corresponded with treatment outcomes. According to Wargo, &ldquo;Patients who had low diversity of bacteria within the microbiome and a higher abundance of Bacteroidales were far less likely to respond than patients who had what we would characterize as a favorable microbiome, with high diversity and a higher abundance of specific taxa such as Ruminococcaceae or Clostridiales.&rdquo; Also, immune profiling of the TME revealed that enrichment of these favorable taxa in the microbiome of responders was associated with an increase in the CD8-positive T-cell infiltrate in the tumor.

Next, they transplanted stool from the treated patients into germ-free mice, which were subsequently injected with melanoma cells and dosed with an antiPD-1 ligand 1 (PD-L1) inhibitor. Mice transplanted with fecal microbiota from the PD-1 responders had significantly greater tumor shrinkage, better responses to the anti&ndash;PD-L1 regimen, and a more favorable microbiome than mice that received stool from the nonresponders.

&ldquo;We have now gone on to ask, &lsquo;Can we modulate the microbiome and make patients respond better?&rsquo;&rdquo; Wargo said. Investigators from MD Anderson and The Angeles Clinic, in collaboration with Seres Therapeutics and the Parker Institute for Cancer Immunotherapy, are currently recruiting patients with advanced melanoma for an ongoing phase Ib clinical trial of therapies designed to alter the microbiome before PD-1 inhibitor therapy (NCT03817125). One group of patients will receive SER-401, an oral capsule that contains fecal bacterial spores consistent with the microbiome signature of responders to anti PD-1 therapy. Both groups will be treated with nivolumab (Opdivo), a PD-1 inhibitor approved for advanced melanoma.

Wargo said she was encouraged by preliminary data presented at the 2019 American Association for Cancer Research (AACR) Annual Meeting from 2 clinical trials of fecal transplant in patients with melanoma.

She described one study that &ldquo;used a fecal transplant from a complete responder donor, gave that back to patients who had progressed on antiPD-1, and reintroduced checkpoint blockade.&rdquo; Wargo said the patients responded to retreatment and that &ldquo;the fecal transplant was associated with an increased infiltrate of favorable immune cells within the tumor microenvironment.&rdquo;

Another study led by Wargo examined whether certain lifestyle factors influence the microbiome in patients with melanoma. Data were presented at the 2019 AACR Annual Meeting that showed &ldquo;patients who had a high-fiber diet were about 5 times more likely to respond to treatment with antiPD-1 therapy.&rdquo;

Wargo&rsquo;s group also examined the relationship among baseline use of over-the-counter probiotics, the microbiome signature, and treatment response.

&ldquo;About 42% of our patients reported taking a probiotic, and strikingly, patients who took a probiotic had lower diversity of their microbiome and were less likely to respond,&rdquo; Wargo said. The findings suggest that clinicians may want to discuss probiotic use with patients starting immunotherapy.

Overcoming Tumor-Intrinsic Resistance to PD-1 Inhibition

In cancer, chronic antigen exposure leads to exhaustion of CD8-positive tumor-infiltrating lymphocytes (TILs) and upregulation of multiple coinhibitory factors, including PD-1 and PD-L1.13 The success of checkpoint blockade with PD-1/ PD-L1 inhibitors largely depends on their ability to mobilize, reactivate, and expand antigen-specific cytotoxic CD8-positive T lymphocytes.5 Achieving long-term disease control depends on generating a persistent population of effector memory T cells. Defects that lead to loss of T-cell function, limit the expression or recognition of tumor neoantigens, promote an immunosuppressive TME, or facilitate immune escape contribute to treatment failure.5,7 Various strategies to overcome PD-1 resistance or optimize antitumor responses are being evaluated in clinical trials for melanoma and other solid tumors. Several strategies take a combinatorial approach, using a PD-1/ PD-L1 inhibitor as a backbone and adding a novel or existing therapeutic approach (TABLE).

The FDA has already approved dual checkpoint blockade combining a PD-1 inhibitor (nivolumab) with a CTLA-4 inhibitor (ipilimumab) as a first-line strategy for unresectable or metastatic melanoma based on the pivotal CheckMate 067 trial.

Data from the trial showed that the combination produced a significantly better objective response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) than ipilimumab monotherapy.

After preclinical data suggested that ICI therapy might be more effective in the neoadjuvant setting versus the adjuvant setting, Wargo and colleagues initiated a phase II trial to evaluate neoadjuvant use of the ipilimumab/nivolumab combination in patients with high-risk melanoma. The combined approach produced a higher RECIST overall response rate than nivolumab monotherapy (73% vs 25%, respectively) and a higher rate of pathologic complete response (45% vs 25%, respectively). However, the study ended prematurely because of the 73% rate of grade 3 toxicity in the combination arm.

Wargo said despite the disappointing outcome, they succeeded in identifying a possible biomarker of response. &ldquo;Everyone is looking for the holy grail of biomarkers, and a lot of the focus has been on cytotoxic T cells,&rdquo; she said, adding, &ldquo;What we found were major differences in B cells between responders and nonresponders to immune checkpoint blockade.&rdquo;

Responders had higher proportions of class-switched memory B cells and plasma-like cells, whereas nonresponders had a higher proportion of na&iuml;ve B cells.

Switched B cells have been activated to produce a specific class of antibodies, whereas na&iuml;ve B cells have not yet been activated. Wargo said, &ldquo;We found that these B cells were actually forming little lymph nodes within the patient&rsquo;s tumor.&rdquo; She said that although they determined that activated effector B-cell phenotypes contributed to response, other studies have reported that B cells were detrimental to response. Wargo said she hoped more research into biomarkers of ICI response would look beyond T cells to include B cells and other immune cell subtypes.

Wargo said an important goal of investigators is to improve the safety of regimens that combine ICIs. She noted that the OpACIN-neo trial also evaluated neoadjuvant ipilimumab/nivolumab in melanoma and found that &ldquo;you can reduce the dose of the CTLA-4 inhibitor and increase the dose of the PD-1 inhibitor to lower the toxicity while preserving the response.&rdquo;20 She praised the multinational study as an example of what global cooperation can achieve and stressed the importance of &ldquo;breaking down silos&rdquo; between investigators in melanoma. Recently, Wargo and other melanoma experts around the world formed the International Neoadjuvant Melanoma Consortium to advance neoadjuvant melanoma research. They plan to meet in June at the 2019 American Society of Clinical Oncology Annual Meeting.

Lymphocyte-activation gene 3 (LAG-3) is another coinhibitor expressed on various immune cells in the TME, including on the surface of CD8-positive and CD4-positive T cells. LAG-3 is often coexpressed with PD-1 and exacerbates T-cell exhaustion.

Preclinical and early-phase trial data suggest that inhibitors of LAG-3 and PD-1 work synergistically to reactivate T cells.

A phase I/II study evaluated combinatorial therapy with the LAG-3 inhibitor relatlimab (BMS-986016) and nivolumab in heavily pretreated patients with advanced melanoma. The ORR was 11.5%, with patients with &ge;1% of tumor cells positive for LAG-3 expression significantly more likely to respond.

The regimen was well tolerated and is now being studied in a phase II/III trial as first-line therapy for advanced melanoma (NCT03470922). Several ongoing clinical trials are evaluating regimens that combine PD-1 inhibitors with novel ICIs that target other coinhibitory receptors.

Immune-Stimulating Agents Plus PD-1 Inhibition

Instead of blocking pathways that inhibit immune function, immune-stimulating agents amplify immune responses and may act synergistically with PD-1/PD-L1 inhibitors.

Multiple clinical trials are investigating regimens that combine an ICI with a stimulatory checkpoint agonist. Stimulatory checkpoints are molecules that enhance innate and adaptive antitumor immune responses by improving immunologic memory; promoting T-cell activation, differentiation, and proliferation; and boosting T-cell effector function.

Oncolytic viruses, toll-like receptor (TLR) agonists, and anticancer vaccines are other types of immune-stimulating agents being paired with ICIs in clinical trials.

The monoclonal antibody APX005M is a CD40 agonist being investigated with nivolumab for advanced melanoma that has progressed during antiPD-1 therapy, and data from a phase I/II clinical trial of the doublet were presented at the 2019 AACR Annual Meeting. Only 1 of 5 patients with melanoma in the phase I trial responded, achieving a partial response (PR). In the phase II trial, which included 10 patients, investigators documented 2 PRs and no complete responses (CRs). The regimen was well tolerated, and recruitment for the phase II trial is ongoing.

In a phase Ib/II trial, the TLR9 agonist SD-101 was administered with pembrolizumab (Keytruda) to patients with advanced melanoma who were na&iuml;ve to PD-1 inhibitors. The ORR for the 25 participants who completed at least 15 weeks of therapy was 60% (CR, 12%), and the disease control rate (DCR) was 76%. The combination was well tolerated and did not increase the risk of immune-related adverse events (irAEs).

The oncolytic virus T-VEC (talimogene laherparepvec [Imlygic]), a modified herpes simplex virus type 1 approved for advanced melanoma, expresses granulocyte-macrophage colony-stimulating factor to increase tumor-specific antigen presentation by dendritic cells at the injection site, thus creating antigen-specific CD8-positive T cells for the PD-1 inhibitor to reactivate and proliferate. In the phase Ib portion of the MASTERKEY-265 trial, 21 patients with advanced melanoma received single-agent T-VEC followed by a combination of T-VEC and pembrolizumab.

The ORR was 62%, and the CR rate was 33%. Even some patients with a low density of CD8- positive TILs or no IFN-&gamma; gene signature at baseline achieved responses, suggesting that T-VEC turned cold, or nonT-cell inflamed, tumors into hot tumors.

Biopsies after the T-VEC run-in phase showed increases over baseline in the density of infiltrating CD8-positive T cells and upregulated PD-1 expression. Upregulation of PD-1, combined with PD-L1 expression by tumor cells, likely inhibited the antitumor activity of single-agent T-VEC at distant sites. Concurrent PD-1 blockade overcame PD-L1induced resistance to oncolysis in the TME, however, and freed effector T cells to migrate to distant sites.

The findings provide a logical rationale for combining the 2 treatment modalities, and the combination is being studied further in the phase III KEYNOTE-034 trial (NCT02263508).

PD-1 Inhibition With Epigenetic Modulation

Drugs that inhibit DNA methylation or histone deacetylation (HDAC) sensitize cancer cells to ICIs in part by increasing expression of tumor-specific antigens and costimulatory molecules as well as upregulating TIL expression of PD-1/PD-L1.

The novel HDAC inhibitor entinostat (SNDX-275) also impairs the function of myeloid-derived suppressor cells, which cause immunosuppression in the TME.

At the 2019 AACR Annual Meeting, investigators presented preliminary findings from ENCORE-601, a clinical trial that paired entinostat with pembrolizumab.

The study included 53 patients with advanced melanoma who progressed during or after treatment with a PD-1 inhibitor; 70% had also used ipilimumab. The ORR with entinostat plus pembrolizumab was 19%, the median duration of response at data cutoff was 12.5 months, and the median PFS was 4.2 months. The most common grade 3/4 AEs were neutropenia, fatigue, and hyponatremia; only 5 patients experienced grade 3/4 irAEs.

Multiple clinical trials are evaluating the efficacy and safety of combining adoptive cell therapy (ACT) using TILs with a PD-1 inhibitor for patients with advanced melanoma.

One of the main focuses for TILs is in patients with melanoma who did not benefit from antiPD-1 therapy. Data were presented in November 2018 from a phase II trial of lifileucel (LN-144), an investigational cryopreserved autologous TIL therapy, in patients with metastatic melanoma that progressed despite PD-1 inhibitor therapy.

The multinational trial enrolled 47 patients, who were infused with manufactured TILs derived from a sample of their tumor. Before infusion, patients underwent nonmyeloablative lymphodepletion; after infusion, they received up to 6 doses of interleukin-2.

The ORR was 38% and included 1 CR; 38% of patients also achieved stable disease, which resulted in a DCR of 77%.

The median duration of response was 6.4 months (range, 1.3-14 months). Almost all the responders (16/17) had not responded to prior treatment with a PD-1 inhibitor. Hematologic toxicities grade &ge;3 were common, with high rates of thrombocytopenia (81%), neutropenia (53%), febrile neutropenia (53%), and anemia (47%). The study is ongoing and has already started recruiting patients for an expanded cohort that will include 80 to 100 participants.

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Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-1119.e1110. doi: 10.1016/j.cell.2017.08.027.

Kluger H, Weiss S, Olszanski A. Phase Ib/II of CD40 agonistic antibody APX005M in combination with nivolumab (nivo) in subjects with metastatic melanoma (M) or non-small cell lung cancer (NSCLC). 2019 American Association for Cancer Research Annual Meeting; March 29-April 3, 2019; Atlanta, Georgia. Abstract CT089. https://bit.ly/2ZTrdsy

Ribas A, Milhem MM, Hoimes CJ, et al. Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are na&iuml;ve to anti-PD-1 therapy. J Clin Oncol. 2018;36(suppl 15; abstr 9513). doi: 10.1200/JCO.2018.36.15_suppl.9513.

Dunn J, Rao S. Epigenetics and immunotherapy: the current state of play. Mol Immunol. 2017;87:227-239. doi: 10.1016/j.molimm.2017.04.012.

Sullivan R, Moschos S, Johnson M. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy. 2019 American Association for Cancer Research Annual Meeting; March 29-April 3, 2019; Atlanta, Georgia. Abstract CT072. https://bit.ly/2I0iPSd.

Sarnaik A, Thomas S, Davar D. Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients following progression on checkpoint inhibitor. 2018 Society for Immunotherapy of Cancer Annual Meeting; November 7-11, 2018; Washington, DC. https://bit.ly/2ZNZV6B.

Investigators across the globe have expended considerable effort attempting to identify mechanisms of response and resistance to ICIs. The general conclusion is that each patient&rsquo;s response to immunotherapy is likely complex and highly individualized.

Melanoma Investigators Strive to Overcome PD-1 Inhibitor Resistance

Oncology practices that adopt the Oncology Care Model (OCM) developed by the Centers for Medicare & Medicaid Services (CMS) face a tough road. The transformation requires changes in infrastructure encompassing administrative and care management service lines, as well as a change in philosophical outlook for clinicians and physician leadership; translational services for clinical interpretation; and internal reporting that is both costly and complex. But those practices that take on this change, although experiencing initial growing pains, are finding benefit as efficient care management strategies are implemented, emergency department and inpatient utilization resources are reduced, and successful reporting for staging and quality is rewarded, Lucio N. Gordan, MD, said during the Association of Community Cancer Centers&rsquo; 45th Annual Meeting & Cancer Center Business Summit in Washington, DC.

He recounted this experience as Florida Cancer Specialists (FCS) made the change.

&ldquo;The transition from a fee-for-service model to a value-based model required a complete practice transformation. The physician buy-in and cultural shift was a challenge,&rdquo; said Gordan, managing physician and president of FCS. No sugar coating was necessary. &ldquo;As far as educating our physicians, that was painful.&rdquo;

Gordan could understand the physicians&rsquo; frustration. &ldquo;Who wants to be clicking your life away on an electronic medical record?&rdquo;

FCS adopted the OCM in the fourth quarter of 2016. The group practice comprises 98 clinical sites, more than 450 providers, and over 3500 team members, and treats 1.5 million returning patients. There were no value-based care contracts in 2015, but currently, 62% of the practice&rsquo;s contracts are value based. What early benefits has the practice seen as a result?

&ldquo;We are in the black,&rdquo; Gordan said, when looking back over performance period 3 (from October 2016  September 2017). &ldquo;Our metrics indicate our hospital admissions rates were 8.5% lower than our peers, [and] we had 29% less emergency department visits compared with OCM peers and 41% less than non-OCM peers.&rdquo; In addition, inpatient admission to short-term acute care was reduced by 19% and unplanned hospital admissions were down 17% (see FIGURES 11, 21, and 31). Not only were utilization metrics down, he said, but the practice also had an overall patient rating of 9.02 out of 10, with an aggregate quality score of 84% on claim, survey, and patient self-reported measures such as pain, depression, and patient satisfaction.

Gordan emphasized the effort that the practice has made to launch and integrate their care management service line. The service is delivered by 100 staff membersincluding oncology nurse care managers, nurse triage experts to address potential emergency issues&mdash;and boasts a patient satisfaction score of 96%. Not only do case managers interact and share information with all participants in the healthcare process, but patients also gain a nursing advocate who can provide emotional support. Physicians and hospitals have complex cases coordinated and facilitated, and payors see a reduction in costs.

Looking ahead, Gordan would like to see some changes in the OCM, including better pricing models for high-risk patients, exclusion of patients with very expensive underlying diseases (eg, sickle cell or hemophilia) or patients who undergo transplantation, real-time notifications to the healthcare team if the patient experiences acute emergencies to enhance closer monitoring, faster access to claims data, and novel therapy adjustments.

The OCM was developed by CMS as an episode payment model to encourage providers in group practices to provide higher-quality, better-coordinated oncology care at a lower cost. It requires group practices to provide a set of enhanced services during 6-month episodes of care. Further, OCM includes a per-beneficiaryper-month payment of $160 for the provision of enhanced services, called a monthly enhanced oncology services payment. There are also opportunities for the group to receive performance-based payments on the basis of reductions in actual expenditures for the practice&rsquo;s beneficiaries compared against risk-adjusted episode target prices and the practice&rsquo;s performance on quality measures.

Charles Saunders, MD, CEO of Integra Connect, a company that provides technology and services in support of oncology practices who have adopted the OCM and copresenter during the session, shared the results of a survey of oncologists and their views on the OCM.

&ldquo;Overall, community oncologists are optimistic about value-based care,&rdquo; Saunders said. As a result of OCM adoption, oncologists are changing treatment decisions, especially when it comes to drug choices, added Saunders. &ldquo;About 38% of oncologists surveyed are opting for lower cost therapies; still others are seeking a deeper understanding of drug value.&rdquo;

Saunders said that regimen selection is based on National Comprehensive Cancer Network guidelines, &ldquo;but there has not been an abundance of actual real data that look at the totality of medical claims. The OCM provides that now.&rdquo; With this capability, to link claims history with outcomes, oncologists can understand the differences between regimens and choose better regimens over others.

Saunders said that there has been a lot of criticism of the OCM programthe attribution logic and the high cost of collecting and reporting data are challenges. Despite these difficulties, &ldquo;I suspect, though, that value-based care in oncology is here to stay,&rdquo; Saunders said.

Saunders C, Gordan LN. Case study: realizing the promise of value- based care: what OCM performance data can tell us about the road ahead. Presented at: Association of Community Ccancer Centers 45th Annual Meeting & Cancer Center Business Summit; March 20-22, 2019; Washington, DC.

Kline RM, Bazell C, Smith E, Schumacher H, Rajkumar R, Conway PH. Centers for Medicare & Medicaid Services: using an episode-based payment model to improve oncology care. J Oncol Pract. 2015;11(2):114- 116. doi: 10.1200/JOP.2014.002337.

Oncology practices that adopt the OCM developed by the CMS face a tough road. The transformation requires changes in infrastructure encompassing administrative and care management service lines, as well as a change in philosophical outlook for clinicians and physician leadership; translational services for clinical interpretation; and internal reporting that is both costly and complex.

Despite Initial Challenges, Oncology Practices See Benefit Moving to Oncology Care Model

Findings from ongoing immunotherapy studies are expected to change the treatment paradigm in breast cancer as these agents become available to larger subsets of patients, according to Hope S. Rugo, MD, and Elizabeth A. Mittendorf, MD, PhD, who presented data at the 36th Annual Miami Breast Cancer Conference&reg; hosted by Physicians&rsquo; Education Resource&reg; (PER&reg;), LLC.

The prospects for administering these therapies moved from the realm of pending trials into clinical practice with the FDA&rsquo;s approval on March 8 of atezolizumab (Tecentriq) for patients with metastatic TNBC. The PD-L1 inhibitor is approved in combination with nab-paclitaxel (Abraxane) for patients with unresectable locally advanced or metastatic PD-L1positive TNBC.

&ldquo;The approval of atezolizumab for breast cancer is really important because we have our first approved checkpoint inhibitoror, really, immune agonist&mdash;for the treatment of breast cancer,&rdquo; Rugo, an MBCC cochair who was among the principal investigators in the study, said in an interview with

At the same time, she noted that the initial approval makes the atezolizumab regimen an option for approximately 40% of patients with TNBC, who in turn represent about 15% of those with breast cancer. &ldquo;Now our big challenge is to try and figure out how to expand the use of this class of drugs to other patients and with other chemotherapy combinations,&rdquo; said Rugo, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, Helen Diller Family Comprehensive Cancer Center.

Mittendorf, who leads the Breast Immuno-Oncology Program at Dana-Farber Cancer Institute in Boston, Massachusetts, echoed those sentiments. &ldquo;It&rsquo;s obviously a tremendously exciting day but also a tremendously exciting time,&rdquo; she said in an interview. &ldquo;It&rsquo;s going to be a very fast-paced time&hellip;. Of course, triple negative is just 1 subtype of breast cancer, and so there&rsquo;s going to be tremendous enthusiasm for continuing to explore opportunities to make our other tumor types susceptible to immunotherapy as well.&rdquo;

She said the next steps in the research include determining which patients are likely to respond beyond the PD-L1positive group, how those without PD-L1&ndash;positive expression on immune cell infiltrates will be treated, and what subsequent therapies should be administered to PD-L1&ndash;positive patients who initially respond and then progress.

The atezolizumab combination was approved based on findings from the phase III IMpassion130 study (NCT02425891), which randomized 902 patients with untreated metastatic TNBC to nab-paclitaxel with either atezolizumab or placebo. Patients must have tested positive for PD-L1 expression. The FDA designated the Ventana PD-L1 (SP142) assay, which was used in the study, as a companion diagnostic for the atezolizumab combination.

In the intention-to-treat population, median progression- free survival (PFS) was 7.2 months with the atezolizumab combination and 5.5 months among those who received nab-paclitaxel plus placebo (HR for progression or death, 0.80; 95% CI, 0.69-0.92;

Median overall survival (OS) was 21.3 months with the atezolizumab regimen and 17.6 months with nab-paclitaxel alone (HR for death, 0.84; 95% CI, 0.69-1.02;

For patients with PD-L1positive tumors, the median PFS was 7.5 months with atezolizumab and 5.0 months with nab-paclitaxel alone (HR, 0.62; 95% CI, 0.49-0.78;

<.001). Median OS was 25 months and 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). Positivity was defined as PD-L1 expression on tumor-infiltrating immune cells as a percentage of tumor area, with <1% categorized as negative and &ge;1% as positive (

Rugo said the OS findings are an interim result based on 60% of the events but that the trend would likely be maintained when the data are updated later this year. Even at this juncture, however, the OS benefit for the combination &ldquo;is the amazing part of [these] data,&rdquo; she said.

&ldquo;A 9.5-month differenceit&rsquo;s unequaled. We have not seen it anywhere else,&rdquo; Rugo noted. &ldquo;It tells us 2 things: One is we can change the survival in patients with metastatic TNBC who have immune cells positive for PD-L1. It also tells us we can change the environment of the cancer to change its responsiveness to treatment so that other treatments have to be working better.&rdquo;

The rationale for using immune checkpoint inhibitors as neoadjuvant therapy is also growing. &ldquo;Over the last few years, we have come to understand that more aggressive forms of breast cancer have some degree of host immunity, and as those tumors progress and become more resistant, the host immunity tends to decrease. As the tumor becomes more resistant, it is also able to reduce the body&rsquo;s immune response to the cancer,&rdquo; Rugo said in an earlier interview.

&ldquo;This means the first breast cancers that were studied in trials of immune checkpoint inhibitorstriple negative [hormone and HER2 receptor negative], advanced, heavily pretreated, and very aggressive&mdash;were actually the least likely to respond,&rdquo; Rugo said. &ldquo;If we had gotten unlucky in those early trials, we would not have seen enough response to spur more research, but we got lucky. We saw some response, although it was less than 10%, and went on. Response rates rose to a fairly respectable 23% in trials that used checkpoint inhibitors as first-line therapy for advanced disease, and now there is growing evidence that these agents may work even better in the adjuvant or neoadjuvant setting.&rdquo;

Early-stage trials and preliminary data from larger trials suggest that adding checkpoint inhibitors to neoadjuvant chemotherapy may improve outcomes. The 2018 European Society for Medical Oncology Congress featured interim data from the first 19 patients in a phase II trial of neoadjuvant atezolizumab plus nab-paclitaxel in TNBC (NCT02530489). Eligible patients had chemotherapy-sensitive TNBC based on their response to anthracycline therapy. Participants received neoadjuvant atezolizumab plus nabpaclitaxel followed by atezolizumab for 3 months after surgery.

The phase I KEYNOTE 173 trial (NCT02622074) tested pembrolizumab (Keytruda), a PD-1 inhibitor, in combination with 1 of 6 chemotherapy regimens as neoadjuvant treatment for previously untreated locally advanced TNBC. Some of the chemotherapy regimens performed better than others, but the combination of neoadjuvant immunotherapy and chemotherapy, followed by surgery and more immunotherapy, was effective across the board: Sixty percent of all patients (90% CI, 30%-85%) achieved pathologic complete response (pCR; defined as ypT0/Tis ypN0).

Earlier data from the phase II I-SPY 2 trial showed that the addition of pembrolizumab to standard neoadjuvant chemotherapy increased the estimated pCR response rate nearly 3-fold in patients with locally advanced TNBC (60% vs 20%) and nearly 3-fold in patients with locally advanced hormone receptorpositive/HER2-negative breast cancer (34% vs 13%).

Participants had invasive breast cancer (tumor size, &ge;2.5 cm).

Several larger trials are now testing neoadjuvant immunotherapy in women with aggressive breast cancers. The phase III KEYNOTE-522 trial (NCT03036488) is randomizing 1174 women with operable TNBC to 24 weeks of either chemotherapy and pembrolizumab or chemotherapy and placebo before definitive surgery, and maintenance therapy with either pembrolizumab or placebo.

A phase II study (NCT03546686) is comparing the addition of nivolumab (Opdivo) plus ipilimumab (Yervoy) to cryoablation as preoperative therapy versus standard-of-care definitive surgery in patients with TNBC who have undergone neoadjuvant taxane-based chemotherapy and then surgery. Women in the experimental arm will also receive nivolumab after surgery. The trial, which is seeking to recruit 150 patients, has a primary endpoint of event-free survival after 36 months.

As clinical trial data continue to mature, investigators will get a sharper picture of the toxicities that may occur with checkpoint inhibition in breast cancer. Overall, the AEs most associated with immune checkpoint inhibitor therapy include colitis, pneumonitis, dermatologic AEs, and endocrine dysfunction.

&ldquo;We are getting data from these trials, and from normal clinical practice, that emphasize the need for constant vigilance. They can create a very wide range of immune toxicities that can arise at nearly any time and quickly become life-threatening,&rdquo; Rugo said. &ldquo;I have been using these agents for years now, and I&rsquo;m still seeing reactions that I have never seen before. I have a patient who received 1 dose of pembrolizumab and developed a full-body rash that has required 9 weeks of steroids and suspended treatment.&rdquo;

Although immune checkpoint inhibition has been approved for about 15 tumor types, breast cancer was initially not considered immunogenic enough to respond to such treatments. &ldquo;Unlike many solid tumors, breast cancer has not typically been responsive to modulation of the immune system,&rdquo; Mittendorf and Rugo wrote in a joint MBCC abstract.

The agents work well in tumor types with higher immunogenicity and tumor mutational burden, which may help promote an antitumor immune response to neoantigens that can then be reactivated with monoclonal antibodies aimed at immune checkpoints, they noted. &ldquo;In breast cancer, proliferative subsets, such as TNBC and HER2-positive disease, have a higher tumor mutational burden and could be more amenable to immunotherapy,&rdquo; they wrote.

The use of PD-1 or PD-L1 inhibitors as monotherapy has demonstrated durable responses at low rates ranging from 4.8% to 19.0% in 4 phase I studies in patients with metastatic breast cancer, the abstract said.

Investigators are looking to combination regimens in an effort to enhance the effects of immune checkpoint inhibitors. Ongoing studies are evaluating immunotherapy combinations that include immune agonists, radiation therapy, PARP inhibitors, MEK inhibitors, HDAC inhibitors, HER2-targeted therapy, and CDK4/6 inhibitors, as well as vaccines.

&ldquo;Although rare durable responses have been seen [with monotherapy], it is clear that combination therapy is a critical next step in the study of immunotherapy for breast cancer,&rdquo; Mittendorf and Rugo said.

Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.

2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.

Litton JK, Moulder SL, Hess KR, et al. Neoadjuvant trial of nab-paclitaxel and atezolizumab (Atezo), a PD-L1 inhibitor, in patients (pts) with chemo-insensitive triple negative breast cancer (TNBC).

2018;29(suppl 8; abstr 224P). doi: 10.1093/annonc/mdy270.219.

Schmid P, Park YH, Mu&ntilde;oz-Couselo E, et al. KEYNOTE-173: phase 1b multicohort study of pembrolizumab (Pembro) in combination with chemotherapy as neoadjuvant treatment for triple-negative breast cancer (TNBC). Presented at: 2018 San Antonio Breast Cancer Symposium; San Antonio, TX; December 4-8, 2018. bit.ly/2Vjkcl8.

Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2.

2017;35:(suppl; abstr 506). doi: 10.1200/JCO.2017.35.15_suppl.506.

Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018.

2018;320(16):1702-1703. doi: 10.1001/ jama.2018.13995.

Findings from ongoing immunotherapy studies are expected to change the treatment paradigm in breast cancer as these agents become available to larger subsets of patients, according to Hope S. Rugo, MD, and Elizabeth A. Mittendorf, MD, PhD, who presented data at the 36th Annual Miami Breast Cancer Conference&reg;&nbsp;hosted by Physicians&rsquo; Education Resource&reg;, LLC.

Immunotherapy Potential in Breast Cancer Draws Excitement

Radioembolization is an effective treatment option for patients with neuroendocrine neoplasms (NENs) and liver metastases, demonstrating a disease control rate (DCR) of >90% in an international, retrospective study.

&ldquo;In a broad spectrum of NENs and at different moments of the disease, radioembolization is safe, effective, and can relieve symptoms, even in heavily pretreated, progressive patients with high intrahepatic tumor load,&rdquo; the study authors, led by Arthur J. A. T. Braat, MD, wrote in their report. &ldquo;In one-fourth of patients, objective response might improve after the commonly used 3-month evaluation scan.&rdquo;

Previously, radioembolization was seen as promising for patients with NENs and liver metastases, especially as few toxicities are seen from treatment. Yet, data to date on radioembolization in this patient population have been limited.

The study aimed to fill the gaps of currently available literature by looking at a larger group of patients who had received radioembolization and addressing baseline characteristics and their effects on response rates and survival.

A retrospective analysis was conducted of 244 patients with NENs and liver metastases who underwent treatment with radioembolization with Y-90 resin microspheres between July 2004 and May 2016 and had at least a 3-month follow-up scan. Although approximately 10% of the patients received multiple radioembolization treatments, the study focused on first treatment only, as repeated radioembolizations could cause increased toxicity.

The primary endpoint of the study was radiologic response at 3 and 6 months after treatment by both RECIST 1.1 and modified RECIST (mRECIST) criteria. Follow-up imaging at 6 months, however, was only available for 51.6% of patients.

A majority of the patients had an ECOG score of 0 (47.2%) or 1 (43.0%), and 91% had progressive disease before radioembolization. Most patients had World Health Organization/European Neuroendocrine Tumor Society grade 1 (39.3%) or grade 2 (35.7%) disease, 10.2% had grade 3 disease, and the grade was unknown in 14.8%.

The primary tumor, which was most commonly in the small bowel (34.9%) or pancreas (31.2%), was surgically resected in 45.5% of patients. Extrahepatic metastases were also noted in 66% of patients, notably in the lymph nodes (47.1%).

Most patients had diffuse liver metastases, and type III liver involvement was noted in 95.1%; 40.2% had more than 50 intrahepatic lesions and 14.5% had an intrahepatic tumor load of &ge;75%. The majority (95.1%) had received multiple prior treatments.

The objective response rate (ORR) was 15.7% at the first assessment, which was approximately 3 months after treatment, and 28.5% at the second, which was about 6 months after treatment, by RECIST 1.1 criteria, and they were 42.8% and 62.9%, respectively, by mRECIST criteria. The DCRs by RECIST 1.1 criteria were 91.3% and 91.4% at first and second follow-up, respectively, and 91.3% and 91.4%, respectively, by mRECIST criteria (TABLE).

&ldquo;This is the first time a prolonged response for at least 6 months has been objectively demonstrated in patients with available imaging after 6 months, and in approximately one-quarter of those patients, the optimal time to evaluate treatment might be later than 3 months,&rdquo; Braat et al wrote.

Responses did not appear to correlate with NEN grade or primary tumor origin by both mRECIST and RECIST 1.1 criteria.

Median overall survival (OS) after radioembolization was 2.6 years overall (95% CI, 2.2-3.0). This was significantly longer in patients with grade 1 and 2 neuroendocrine tumors (NETs; 3.1 and 2.4 years, respectively) compared with those with grade 3 NETs/neuroendocrine carcinomas (0.9 years; P <.001).

Three months after radioembolization, 32% of patients had no toxicities versus 55% at 6 months. Known radioembolization-related adverse events (AEs), including fatigue, abdominal pain, and nausea, were observed in 56% of patients within the first 3 months, and persisted in 6% at 6 months. Missing data on toxicity were noted in 12% and 39% of patients at 3 and 6 months, respectively.

According to multivariate analysis, DCR by RECIST 1.1 at 3 months was predictive of a better median OS (HR, 0.4; P <.01) and grade 3 disease, whereas unknown NET grade, intrahepatic tumor load &ge;75%, and presence of extrahepatic disease were all predictive of a worse median OS. The results of the study were consistent with a prior meta-analysis looking at radioembolization in NENs.

&ldquo;Prospective randomized controlled studies on radioembolization in NENs are desperately needed, although it should also be recognized that clinical experience, captured in high-quality retrospective study cohorts, is indispensable in this difficult-to-study heterogeneous patient population. Currently, treatment algorithms typically place radioembolization after failure of systemic treatments. However, in [patients with NEN] with disease limited or &lsquo;dominant&rsquo; to the liver, radioembolization might be a more appropriate choice prior to, or in combination with, first-line systemic treatment,&rdquo; the study authors concluded.

Braat AJAT, Kappadath SC, Ahmadzadehfar H, et al. Radioembolization with 90Y resin microspheres of neuroendocrine liver metastases: international multicenter study on efficacy and toxicity. Cardiovasc Intervent Radiol. 2019;42(3):413-425. doi: 10.1007/s00270-018-2148-0.

Devcic Z, Rosenberg J, Braat AJA, et al. The efficacy of hepatic 90Y Resin radioembolization for metastatic neuroendocrine tumors: a meta-analysis. J Nucl Med. 2014;55(9):1404-1410. doi: 10.2967/jnumed.113.135855.

Radioembolization is an&nbsp;effective treatment option for patients with neuroendocrine neoplasms and liver metastases, demonstrating a disease control rate of &gt;90% in an international, retrospective study.

May 2019 | Targeted Therapies in Oncology

Translational Immunotherapy Research Informs Ongoing Efforts to Improve Treatment Outcomes

Integrating Genetic Testing Into Prostate Cancer Guidelines Leads to Improved Treatment Decisions

Melanoma Investigators Strive to Overcome PD-1 Inhibitor Resistance

Despite Initial Challenges, Oncology Practices See Benefit Moving to Oncology Care Model

Immunotherapy Potential in Breast Cancer Draws Excitement

Radioembolization Is Effective in Neuroendocrine Tumors With Liver Metastases