at Cedars-Sinai in Los Ange&shy;les, California,

, moved to Truckee, California, to &ldquo;recharge his batteries,&rdquo; in his words. Relocating to a quieter area meant working at a medical facility without an oncology program.

&ldquo;I went from a hospital with a thousand beds, with [major cancer centers] right down the street, to a town that had no [oncology] services whatsoever and 100% out-migration of all of our patients with cancer,&rdquo; Heifetz said in an interview at the Association of Community Cancer Centers (ACCC) 36th National Oncology Conference. &ldquo;Tahoe Forest Hospi&shy;tal requested that we develop a cancer program, and&hellip;we decided [to] address issues that were relevant to patients in a rural area. There were 50,000 people up in the mountains who didn&rsquo;t have cancer services.&rdquo;

Heifetz is the founder of the Gene Upshaw Memorial Tahoe Forest Cancer Center, where telehealth is a key resource. During the conference, he described the advantages of remote cancer centers working with larger academic facilities, which can benefit both parties, and how telehealth has made a significant impact.

In 2006, Tahoe Forest Hospital started a rudimentary cancer program. The positive response prompted vol&shy;unteers from the Truckee community to form a cancer advisory council, and a freestanding cancer center officially opened in 2012. Since then, it has provided treatment for the rural community and become a model for telehealth. The center offers ease of access and the opportunity to participate in clinical trials to patients in a rural area.

To bring quality cancer services to patients in Truck&shy;ee and the surrounding area, the Tahoe Forest Cancer Center affiliated with the University of California (UC), Davis, Cancer Care Network in 2008. The smaller center became a part of the larger one&rsquo;s virtual tumor board.

&ldquo;That relationship allowed us to demonstrate that the patients would be safe and that they would be getting state-of-the-art [care],&rdquo; Heifetz said. &ldquo;After about 10 years, starting from zero, we had not only most of the local patients coming in but [also] 62% of our patients coming from outside of our catchment area.&rdquo;

, an assistant in medicine at Vanderbilt University Medical Center in Nashville, Tennessee, who presented with Heifetz at the ACCC meeting on telehealth models, also discussed this during an interview.

&ldquo;In rural areas, telemedicine increases that access to care,&rdquo; Murawski said. &ldquo;A lot of patients have to drive hours and hours to get to visits. [With telemedicine], instead of having to come to the institution every sin&shy;gle day for checkups, patients can get labs at outside facilities, and providers can check in with them at local clinics. They can still be seen by a provider, but maybe not a subspecialist, so [telemedicine is] improving access to those subspecialties where patients might have to drive 3 or 4 hours each way to get to a provider.

To address this issue, 4 other telemedicine clinics were created in connection with the Tahoe Forest Cancer Center, giving patients access to cancer care in their own communities. These clinics, which make up the Rural Oncology Network, are in Quincy, Portola, Loyalton, and South Lake Tahoe. These clinics include smaller hospitals, some of which were struggling finan&shy;cially, according to Heifetz (

&ldquo;We can demonstrate a pipeline of knowledge coming from a mother shipthe font of knowledge, which is an academic cancer center&mdash;to a remote facility like ours in Lake Tahoe and then going to 4 other, more remote facilities&hellip;through our [use] of technology,&rdquo; he said. &ldquo;We believe that this is the right way to address dispar&shy;ities in cancer care.&rdquo;

Even though a patient&rsquo;s initial visit may be at the Tahoe Forest Cancer Center, subsequent visits can be closer to home. In Heifetz&rsquo;s opinion, patients prefer seeing a nurse practitioner or physician assistant at their local health&shy;care facility, and having an appointment with an oncolo&shy;gist, whom they already know, through the computer.

&ldquo;That respects their time, and their buy-in has improved,&rdquo; he said. &ldquo;As the patients are feeling more comfortable with being on the [receiving] end of tele&shy;health, the doctors can see the benefit of doing that.&rdquo;

A cycle of benefits evolved: Because of their affilia&shy;tion with UC Davis Cancer Center, Tahoe Forest Cancer Center gained more people&rsquo;s trust and brought in more patients. That allowed the smaller center to develop a clinical trials program, which gives UC Davis Cancer Center a percentage of their accrualsthe preferential, advanced cases. The higher accrual rates show the National Cancer Institute that UC Davis Cancer Center has &ldquo;effective outreach to community oncologists,&rdquo; Heifetz explained.

Furthermore, Heifetz believes that patients feel more comfortable going to the Tahoe Forest Cancer Center because the physicians are involved in the clinical trials and thus have a better idea of the appropriate treatments. &ldquo;Clinical trials differentiate if you are practicing at the state-of-the-art [level] or not,&rdquo; Heifetz said.

Currently, the Tahoe Forest Cancer Center is recruiting for about 30 clinical trials, includ&shy;ing a study combining ipatasertib with atezoli&shy;zumab (Tecentriq) and paclitaxel to treat patients with locally advanced or metastatic triple-negative breast cancer (NCT04177108).

Running clinical trials takes money, so the facility must justify the expense, according to Heifetz. &ldquo;The justification of that expense is 1 thing only: more patients coming in the door,&rdquo; he said. &ldquo;If you see that your combina&shy;tion of clinical trials, your virtual tumor board, and your academic status results in a growth of your program, you know you&rsquo;re accom&shy;plishing something. In a free market where patients can choose to go to center A versus center B, those are the differentiators that give the patients a sense of security.&rdquo;

An important part of the collaboration between UC Davis and the remote centers involves the virtual tumors boards. Four days a week, specialists from the UC Davis Cancer Care Network discuss the 4 cancers that affect 80% of their patients. On Mondays the tumor board focuses on gastrointestinal cancers; Tuesdays, genitourinary cancers; Wednesdays, lung cancers; and Thursdays, breast cancers. Network affiliates are Rideout Cancer Center, Mercy UC Davis Cancer Center, the AIS Can&shy;cer Center, Tahoe Forest Cancer Center, and UC Davis Comprehensive Cancer Center.

To become good at [handling] those diseases by participating in virtual tumor boards [means] you&rsquo;re going to have more patients coming in the door,&rdquo; Heifetz said.

The virtual tumor boards allow the participating centers to enroll patients in clinical trials faster and more efficiently, and the remote clinics receive more buy-in from their primary care physicians.

Despite the numerous benefits seen with tele&shy;health, legal and financial obstacles exist, and some challenges have no answers just yet.

Heifetz offered the example of sending a patient to a physician outside the state of Cali&shy;fornia: Would that physician seeing the patient remotely need a California license to practice, or would the patient be considered as being seen in the other state?

Providers of telemedicine might need dual licensure to stay within state regulations, Murawski said.

Heifetz posed another question: If the remote appointment takes place inside a hos&shy;pital&rsquo;s telemedicine office, must the remote physician be a member of that medical staff?

Heifetz and Murawski both touched on finan&shy;cial concerns, with Heifetz citing the issues of billing for a physical examination when the physician can&rsquo;t touch the patient and how that examination would be carried out.

Technology such as blood pressure cuffs, oxygen monitors, and heart rate monitors aid examinations from afar, inputting data directly into an electronic health record, according to Murawski. She said that the biggest obstacle for many facilities involves reimbursement for the examination and use of these tools. If pro&shy;viders can be reimbursed through private and public insurers, she said, telehealth will be more feasible: Smaller practices can&rsquo;t always take on those costs, and patients can&rsquo;t always pay out of pocket.

&ldquo;I believe those roadblocks are being managed rapidly, and as those roadblocks go away, we&rsquo;re going to have a much more universal capacity to provide telehealth services,&rdquo; Heifetz said.

Both Heifetz and Murawski believe tele&shy;health also can play an important role in other areas of oncology. Heifetz sees an opportunity for genetic counseling, which usually doesn&rsquo;t require a physical exam. He noted the limited number of genetic counselors, whose services are important in the oncology community.

&ldquo;Down the road, I think social work [could benefit],&rdquo; Murawski said. &ldquo;It would be an easy way for [social workers] to do a checkup to make sure patients are getting all the support&shy;ive care that they need. Psycho-oncology is an opportunity to do a virtual support group, so patients don&rsquo;t have to travel long distances. I think it&rsquo;s endless, what telemedicine could do for our patients with cancer.&rdquo;

The present and future benefits of telehealth in oncology can be observed through Tahoe For&shy;est Cancer Center and its affiliation with the UC Davis Cancer Center, use of other remote clinics, and participation in virtual tumor boards. Even though there are roadblocks to telehealth reaching more locations and more patients, the potential benefit warrants the time needed to get over those hurdles.

&ldquo;I think telehealth is the key to success in a small community practice...the more you can make it easy on your patient to stay close to home, the better your practice is going to sur&shy;vive,&rdquo; Heifetz concluded.

Turgon J, Heifetz L, Murawski S. Telehealth models. Presented at: Associ&shy;ation of Community Cancer Centers 36th National Oncology Conference; October 30-November 1; Orlando, FL

Articles

Clinical Articles

Telehealth Delivers Access to Care and Cutting-Edge Clinical Research to Rural Areas

All patients with advanced renal cell car&shy;cinoma (RCC) assigned to nivolumab (Opdivo) plus ipilimumab (Yervoy) in the phase III CheckMate 214 trial had a longer treatment-free survival (TFS) than patients treated with sunitinib (Sutent). Furthermore, those patients assigned to the combination spent less time experiencing treatment-related adverse events (TRAEs).

Meredith M. Regan, ScD, an associate profes&shy;sor of medicine at Harvard Medical School and an investigator in the Department of Data Sciences at Dana-Farber Cancer Institute, Boston, Massachu&shy;setts, presented results from an analysis of data collected in CheckMate 214 during the 18th Interna&shy;tional Kidney Cancer Symposium.

Immuno-oncology agents have been shown to successfully extend sur&shy;vival in many cancers, so physicians are now able to focus on improving patients&rsquo; quality of life, she said.

&ldquo;When we look at the nivolumab/ipilimumab group versus sunitinib, the treatment-free time is about twice as long,&rdquo; she said. &ldquo;If we think about grade 3 toxicities, there is little time treatment-free with grade 3 or higher treatment-related adverse events.&rdquo;

TFS is defined as the period between the end of first-line treatment and the start of subsequent therapy.

Patients in the nivolumab/ipilimumab arm received the combination every 3 weeks for up to 4 doses, followed by nivolumab alone every 2 weeks. Patients in the sunitinib arm received the agent once daily for 4 weeks of each 6-week cycle.

Treatment continued until disease progression, unac&shy;ceptable toxicity, or patient decision.

In the overall population (N = 1082), the combina&shy;tion was associated with a TFS of 6.8 months versus 2.9 months for sunitinib at a median follow-up of 30.0 months (95% CI, 2.4-5.3 months). TFS without TRAEs also favored the combination by 3.6 months for grade &ge;3 TRAEs and 3.2 months for grade &ge;2 TRAEs.

Among intermediate- and poor-risk patients, the combi&shy;nation was associated with an improvement of about 2.6 months for TFS without grade &ge;3 or grade &ge;2 TRAEs.

Among favorable-risk patients, the combination induced a difference in TFS without toxicities of 6.8 months (9.4 vs 2.6 months) for grade &ge;3 TRAEs and of 5.2 months (6.9 vs 1.8 months) for grade &ge;2 TRAEs. The nivolumab/ipilimumab combination is not indicated for this population.

Regan noted that not only did the combination appear to improve TFS, but patients also had fewer toxicities during their time off treatment compared with those treated with sunitinib.

&ldquo;We can see, especially in this time when patients are alive and doing well, how are they spending their survival time,&rdquo; she said. &ldquo;The dream is to treat a patient, get them off treatment, and allow them to go back to their life without having to be treated all the time and without having adverse effects of treatment.&rdquo;

Regan added that TFS could represent a novel end point for clinical trials, which would change clinical trial design and drug development.

The FDA approved the nivolumab/ipilimumab combination in April 2018 based on results from CheckMate 214. Frontline treatment with the com&shy;bination reduced the risk for death by 32% compared with sunitinib for patients with metastatic RCC. The risk reduction was 37% in patients with intermedi&shy;ate- and poor-risk RCC, who constituted about 75% of the intent-to-treat population.

The median overall survival (OS) in the overall population was not reached with the combi&shy;nation versus 32.9 months with sunitinib (HR, 0.68; 99.8% CI, 0.49-0.95;

= .0003). In patients with intermediate- and poor-risk RCC, the median OS was not reached in the nivolumab/ ipilimumab arm and was 26.6 months in the sunitinib arm (HR, 0.63; 99.8% CI, 0.44- 0.89;

<.0001). There was no benefit for the combina&shy;tion versus sunitinib in those with favorable risk.

Previously, in CheckMate 067/069, TFS for patients receiving nivolumab plus ipilimumab was greater compared with nivolumab or ipilimumab alone, and time with persistent grade &ge;3 TRAEs composed a small proportion of the TFS period for all treatments.

Regan MM, Atkins MB, Powles T, et al. Treatment free-survival, with and without toxicity, as a novel outcome applied to immuno-oncology agents in advanced renal cell carcinoma. Presented at: 18th International Kidney Cancer Symposium; November 15-16, 2019; Miami, Florida.

Regan MM, Werner L, Rao S, et al. Treatment-free survival: a novel outcome measure of the effects of immune checkpoint inhibitiona pooled analysis of patients with advanced melanoma [published online September 9, 2019]. J Clin Oncol. doi: 10.1200/JCO.19.00345.

All patients with advanced renal cell car&shy;cinoma assigned to nivolumab plus ipilimumab in the phase III CheckMate 214 trial had a longer treatment-free survival than patients treated with sunitinib. Furthermore, those patients assigned to the combination spent less time experiencing treatment-related adverse events.

Nivolumab/Ipilimumab Combo Extends Treatment-Free Survival in RCC

care for some patients with intermediate-stage hepa&shy;tocellular carcinoma (HCC) may include lenvatinib (Lenvima) if investigators further explore results from a proof-of-concept obser&shy;vational study. The recommended treatment for intermediate-stage HCC, transarterial chemo&shy;embolization (TACE), is unsuitable in patients with high-tumor-burden HCC, leaving a signif&shy;icant unmet need in clinical practice for this patient subgroup.

Historically, lenvatinib has demonstrated sig&shy;nificantly and clinically meaningful anticancer efficacy by reducing tumor size or enhancement on dynamic CT in a large proportion of patients (objective response rate [ORR], 61.3%) with inter&shy;mediate-stage HCC.1,2 Intermediate-stage HCC is defined as Barcelona Clinic Liver Cancer stage B. Masatoshi Kudo and colleagues hypothesized that patients with the B2 substage might have better outcomes if initially treated with lenvatinib com&shy;pared with TACE. The high tumor burden causes these patients to exceed the &ldquo;up-to-7&rdquo; rule, in which 7 is the maximum sum (in cm) of the size of the largest tumor and the number of tumors. The group presented their findings at The Liver Meeting 2019 of the American Association for the Study of Liver Diseases, held November 8 to 12, 2019, in Boston, Massachusetts.

The investigators selected study participants from the 642 patients with intermediate-stage HCC who had received first-line treatment with lenvatinib or TACE from 2006 to 2018. After those who had Child-Pugh B or C liver function or were within the up-to-7 rule were excluded, 30 patients treated with lenvatinib were eligible for the study. Almost half had been enrolled in the phase III REFLECT trial, and the rest were treated with lenvatinib in the real-world setting.

Using 1:2 propensity score matching, the 30 patients in the lenvatinib arm were matched with 60 patients treated with TACE in the front&shy;line setting who were also Child-Pugh class A and whose tumor burden placed them out&shy;side the up-to-7 rule. All patients were eval&shy;uated for liver function deterioration, ORR, progression-free survival (PFS), and overall survival (OS).

Kudo reported that the ORR was 73.3% in the lenvatinib arm and 33.3% in the TACE arm, with an OR of 5.39 (95% CI, 1.90-16.67;

<.001). The clinical benefit rate, comprising complete responses (CRs), partial responses, and stable disease at &ge;24 weeks, was 96.7% and 36.7% for the lenvatinib and TACE arms, respectively (OR, 48.1; 95% CI, 7.01-2073.85;

<.001). The disease control rate was reported as 100% and 55%, respectively.

The median PFS was 16.0 months (95% CI, 10.9-16.6) in the lenvatinib arm and 3.0 months (95% CI, 2.1-4.3) in the TACE arm, with an HR of 0.19 (95% CI, 0.10-0.35;

<.001). The median OS was 37.9 months (95% CI, 23.1-not reached) in the lenvatinib arm and 21.3 months (95% CI, 15.7-28.4) in the TACE arm, with an HR of 0.48 (95% CI, 0.16-0.79;

To assess liver function deterioration, albu&shy;min-bilirubin (ALBI) scores were compared between baseline and end of treatment, with a higher score indicating worse liver function. For patients treated with lenvatinib, the score rose slightly during the treatment period but returned to the baseline level by the end of treatment. In contrast, the ALBI score in the TACE arm increased significantly over the course of treatment (

<.01), becoming signifi&shy;cantly higher compared with the lenvatinib arm (

<.01 at end of treat&shy;ment). Most importantly, the TACE arm&rsquo;s ALBI score at the end of treatment not only failed to recover to the baseline value but also exhibit&shy;ed the highest tested value. The investigators suggested a reason: The liver injury caused by TACE was irreversible (

Kudo et al reported that the median duration of lenvatinib treatment was 13.1 months compared with 5.7 months in REFLECT.3 Additionally, the median time to first dose reduction was 13.1 weeks compared with 9.9 weeks in REFLECT.5,6

At the liver meeting, Kudo highlighted the case of a 70-year-old man who was negative for markers of both hepatitis virus B and C infection. The patient was also Child-Pugh class A and ALBI grade 1, indicating good liver function and a positive prognosis. However, he had 10-cm multinodular confluent-type HCC, which is associated with a poor prognosis and resistance to TACE. The patient had received 4 mg of lenvatinib daily from September 2014 through September 2018, at which time recur&shy;rence was observed and TACE with cisplatin and lipiodol was performed. He achieved a CR and has been drug free for more than 14 months, Kudo reported.

Based on the demonstrated superiority of len&shy;vatinib in terms of ALBI score, ORR, PFS, and OS, Kudo and colleagues concluded that this agent was more effective than TACE in the first-line setting. Further, they attributed lenvatinib&rsquo;s favorable efficacy to its ability to cause tumor necrosis, tumor vessel normalization, and sup&shy;pression of VEGF increase after TACE.

The investigators concluded that it would be worthwhile to conduct a randomized controlled trial to confirm the results of this proof-of-concept study and establish a new treatment standard for the subpopulation of patients with high-tumor-burden, intermediate-stage HCC.

Kudo M. A new era of systemic therapy for hepatocellular carcinoma with regorafenib and lenvatinib.

. 2017;6(3):177-184. doi: 10.1159/000462153.

Kudo M. Lenvatinib may drastically change the treatment landscape of hepatocellular carcinoma.

. 2018;7(1):1-19. doi: 10.1159/000487148.

Kudo M, Ueshima K, Chan S, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: a multicenter propensity-score matched study. Presented at: The Liver Meeting of the American Association for the Study of Liver Diseases; November 8-12, 2019; Boston, MA.

Mazzaferro V, Llovet JM, Miceli R, et al; Metroticket Investigator Study Group. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.

. 2009;10(1):35-43. doi: 10.1016/S1470-2045(08)70284-5.

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.

Yamashita T, Kudo M, Ikeda K, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset [published online November 12, 2019].

The standard of care for some patients with intermediate-stage hepa&shy;tocellular carcinoma may include lenvatinib if investigators further explore results from a proof-of-concept obser&shy;vational study. The recommended treatment for intermediate-stage hepatocellular carcinoma, transarterial chemo&shy;embolization, is unsuitable in patients with high-tumor-burden hepatocellular carcinoma, leaving a signif&shy;icant unmet need in clinical practice for this patient subgroup.

Encouraging Results in First-Line Setting for HCC Usher Lenvatinib Toward Randomized Controlled Trials

gene that are present at low rates in certain solid tumors have emerged as potentially actionable oncogenic drivers, with targeted therapies making their way to early clinical studies and into some basket trials.

When a patient with no smoking history presents with nonsmall cell lung cancer (NSCLC) and adeno&shy;carcinoma histology, oncologists typically suspect a tumor that is positive for an oncogenic driver. Classic driver mutationsin genes such as

are now regularly tested for in most patients with advanced lung disease based on guideline recommendations and the current standard-of-care treatment options. And, although

alterations are rare, the potential actionability of that type of change in a patient population could change the course of their treatment and serve as reasonable motivation to con&shy;sider this driver going forward.

fusions are present in 0.3% of NSCLC cases and in approximately 0.2% of solid tumors overall, according to work published in

. This gene has multiple potential fusion partners, and the specific genes found fused to

have been shown to vary widely within and across tumor types. Among solid tumor types, NSCLC has one of the highest rates of

fusions; they are also found in renal cell, breast, ovarian, pancreatic, bladder, gallbladder, and colorectal cancers, as well as neuroendocrine tumors and sarcomas.

gene fusion was first described in 2014 by Lynnette Fernandez-Cuesta, PhD, and col&shy;leagues in a study of lung adenocarcinoma; awareness of this genomic alteration has since increased.

, of the Developmen&shy;tal Therapeutics Program at Lombardi Comprehensive Cancer Center and MedStar Georgetown University Health in Washington, DC, are using experimental and currently approved agents in patients with

fusions to determine whether these agents should be more widely applied in clinical practice.

Liu said that in his experience, patients with

fusions do not respond well to standard immunother&shy;apy or immunochemotherapy. This driver represents a viable therapeutic target, and identifying it prompts a corresponding change in treatment plan.

fusions belong to a class of oncogenes termed gene fusions, with large-scale chromosomal rearrange&shy;ments bringing all or part of 2 different genes together to create 1 hybrid gene. &ldquo;This is a different biological mechanism than other gene fusions that we commonly talk about, [such as those involving]

, associate pro&shy;fessor of medicine and director of the Thoracic Oncol&shy;ogy Research Initiative at the University of Colorado Cancer Center in Aurora.

Gene fusions involving receptor tyrosine kinases (RTKs) eliminate the RTK regulatory domain and make the kinase domain constitutively activated.

are constitutively active as fusion proteins, for example, but

fusions are different, said Doe&shy;bele. The genetic rearrangement is structurally similar, but the biochemical mechanism leading to cancer cell growth is slightly different. The

gene encodes neuregulin 1, a ligand for the RTK human epidermal growth factor receptor 3 (HER3); binding results in indirect activation of downstream tumorigenic signal&shy;ing pathways.

The gene fusion overexpresses part of the NRG1 protein at the cell surface, which then binds to HER3,

said Doebele. HER3 then dimerizes with HER2, with subsequent effects similar to those of most other oncogenes: the activation of growth, prolifera&shy;tion, and prosurvival signaling pathways in the cell.1 For many oncogenes, &ldquo;the mutation causes direct acti&shy;vation of the gene itself,&rdquo; he said. Instead, the

fusion overexpresses a ligand for other receptors, which is important to know for targeting.

Traditional DNA-based sequencing methods like Foun&shy;dation Medicine&rsquo;s FoundationOne assays will not find most

fusions, said Doebele. A small number of fusions, including

, can be identified because the panel covers the

gene. &ldquo;As far as we know, these occur only or primarily in lung cancer,&rdquo; he said.1 However,

, and not all can be detected with current DNA sequencing-based assays. Even more specialized molecular tests do not cover all mutations, Doebele said, so it is important to be aware of a test&rsquo;s limitations.

Investigators like Liu and Doebele recommend anchored multiplex polymerase chain reaction assays that are agnostic to the partner to find rarer mutations.

fusions are a key example of an instance in which RNA sequencing is a detection method superior to DNA sequencing, Liu said. When treating a patient for whom no mutations have been identified using a standard-of-care assay for NSCLC, Liu tries to acquire tissue for RNA sequencing to test for all possible drivers. Ideally, he does upfront dual extraction of RNA and DNA for patients with NSCLC.

&ldquo;While these [fusions] are uncommon events, if we detect [just] one, it changes everything,&rdquo; he said, including the understanding of disease biology, how to approach the patient&rsquo;s cancer, and which therapies will be ineffective. Identification of a fusion is critical because it guides therapy from the beginning. He tells patients that finding a driver mutation is unlikely, but if one is found, it makes a big difference in management.

fusions are challenging not only to detect but also to target. No therapies inhibit

specifically, so investigators have tested agents with pan-HER inhibitory activity, such as afatinib (Gilotrif).

&ldquo;The real heart of the initiation point of the sig&shy;naling node is the HER2/HER3 heterodimer,&rdquo; said Doebele. Targeting HER2, HER3, or both is the strategy behind antibodydrug conjugates such as ado-trastuzumab emtansine (T-DM1; Kadcyla) and trastuzumab deruxtecan (DS-8201) for HER2, for example, and U3-1402 for HER3, he said.

In his pulmonary oncology practice, Liu has anecdotally observed that patients with NSCLC and

fusions, who are primarily nonsmok&shy;ers with adenocarcinoma, do not respond well to chemoimmunotherapy or immunotherapy, regardless of PD-L1 status. This is consistent with the literature on similar

driver events, he said. The HER2 pathway is the most promising target, he said, and some patients have had success with afatinib. &ldquo;We&rsquo;ve seen dramatic responses and durable responses with afatinib,&rdquo; he said, some lasting more than 2 years. At this point, Liu said it is important for investigators to determine why afatinib works so well for some patients, but not others.

To date, there are only a few published reports of patients receiving afatinib as targeted therapy for

fusions; afatinib has been used almost exclusively to treat

-mutated adenocarci&shy;noma of the lung. &ldquo;There have been [isolated] case reports in the literature where patients with

fusions responded to afatinib, but there&rsquo;s never been a clinical trial of afatinib to know the response rate,&rdquo; Doebele said, adding that he and Liu collaborated on 7 new case stud&shy;ies of patients with

fusion-positive lung adenocarcinoma given afatinib after multiple previous lines of therapy, the results of which were presented at the European Society for Medical Oncology 2019 Congress.

The TAPUR (Targeted Agent and Profiling Utilization Registry) study is one of several umbrella trials matching patients with various driver mutations to appropriate targeted thera&shy;pies or immunotherapies. One treatment group in this prospective multiarm basket study comprises patients with

fusions, who will receive afatinib (NCT02693535).

Other targeted therapies being evaluated for the treatment of

fusionpositive cancers include the antibody-dependent cell-mediated cytotoxicity&ndash;enhanced Biclonics agent zenocutu&shy;zumab (MCLA-128),7 which targets the HER3 pathway. MCLA-128 data presented at the Interna&shy;tional Conference on Molecular Targets and Can&shy;cer Therapeutics showed tumor shrinkage in all 3 patients studied, 2 with pancreatic cancer and 1 with NSCLC and brain metastases.

Tarloxotinib is a prodrug of an EGFR inhibitor that is activated under the hypoxic conditions common in tumor tissue.

It was developed by Rain Therapeutics, a company Doebele cofound&shy;ed in 2017. &ldquo;We designed [this agent because the] drugs targeting EGFR are toxic. That&rsquo;s one of the limitations of afatinib,&rdquo; said Doebele. Although afatinib is a good inhibitor of EGFR and HER2, its adverse effects (AEs) can include rash and diarrhea, he said. The incidence of AEs is significantly reduced with tarloxotinib because of its limited activity in healthy tissue.

Obtaining the proper molecular testing is key for all patients, particularly those in whom the presence of a molecular driver is strongly sus&shy;pected. &ldquo;We&rsquo;re on our way to identifying the best way to treat patients with

fusionpositive cancer...the real challenge is identifying the patients [with the mutations]. There&rsquo;s a fairly low frequency,&rdquo; said Liu.

Doebele recommends using a targeted DNA panel for common drivers such as

alterations and an anchored multiplex panel for the majority of gene fusions. With lung tumors, it is relatively easy to justify panel test&shy;ing test&shy;ing for many oncogenes. &ldquo;We think most lung adenocarcinomas have an oncogenic driver,&rdquo; he said. Pancreatic ductal adenocarcinoma (PDAC), however, is known to have almost exclusively activating

&ldquo;One strategy is to say if they have

, then you stop testing. If they don&rsquo;t, test for

,&rdquo; he said. One study showed that patients with

This was a small trial, however, and further investigation is needed, Doebele said.

fusions are sometimes found, do not have many targeted therapies, making it harder to justify an anchored multiplex panel, Doebele said. &ldquo;I believe in broad testing. If you look, you will find them. [Finding an

fusion is] a relatively rare event0.3% is 1 in 300 patients. [But] as we find more and more rare targets and you have a comprehensive panel strategy, your cumulative odds of finding something relevant go up.&rdquo; For instance, 8 targets with an incidence of 0.3% each means more than a 2% chance of finding 1 of them, which clearly increases the justifica&shy;tion for ordering an anchored multiplex panel.

Doebele acknowledges that some push&shy;back exists against testing for rare drivers, with questions about whether it is worth the investment. &ldquo;A lot of drugs we prescribe don&rsquo;t have good response rates. When one works, it&rsquo;s great. But immunotherapy doesn&rsquo;t work in a lot of patients. A single dose of that [type of] drug costs more than one of these tests,&rdquo; he said, noting that there are good therapies for

fusions and trials investigating new treatments.

fusions are a relatively new target, knowledge of them &ldquo;probably hasn&rsquo;t filtered down to the community [setting] at this point,&rdquo; Doebele said, adding that oncologists need to learn what the molecular panels cover.

&ldquo;Oncologists today have been forced to become molecular pathologists, and it&rsquo;s chal&shy;lenging to interpret some of these results,&rdquo; said Liu. He encourages oncologists to call the test&shy;ing companies to walk them through a patient&rsquo;s results and, at the very least, to carefully review the entire report. He said that critical findings are sometimes presented in bold print on page 1 and easy to interpret; however, the results may be &ldquo;buried&rdquo; in a long report in other instances. &ldquo;What a tragedy [it would be] to have an

fusion detected and miss it because you&rsquo;re only looking at the top-line results,&rdquo; he declared.

fusions, clinicians&rsquo; options include referring patients to an appropriate clinical trial or prescribing off label, said Doebele.

fusions are less straightforward than some other drivers, but there may be multiple ways to target them.

Jonna S, Feldman RA, Swensen J, et al. Detection of

. 2019;25(16):4966-4972. doi: 10.1158/1078-0432.CCR-19-0160.

Fernandez-Cuesta L, Plenker D, Osada H, et al.

. 2014;4(4):415-422. doi: 10.1158/2159-8290.CD-13-0633.

Medves S, Demoulin J-B. Tyrsoine kinase gene fusions in cancer: translating mechanisms into targeted therapies. J Cell Mol Med. 2012;16(2):237-248. doi: 10.111/j.1582-4934.2011.01415.x.

Yun S, Koh J, Nam SK, et al. Clinical significance of overexpression of NRG1 and its receptor HER3 and HER4, in gastric cancer patients.

. 2018;21(2):225-236. doi: 10.1007/s.10120-017-0732-7.

Liu SV, Duruisseaux M, Tolba K, et al. Targeting NRG1-fusions in multiple tumour types: afatinib as a novel potential treatment option.

. 2019;30(suppl 5; abstr 1969P). doi: 10.1093/annonc/mdz268.096.

Duruisseaux M, Laskin JJ, Tolba K, et al. Targeting NRG1-fusions in lung adenocarcinoma: afatinib as a novel potential treatment strategy. Presented at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract P1.14-25. doi: 10.1016/j.jto.2019.08.1176.

Clinical Pipeline. Merus website. bit.ly/305JTpv. Accessed January 6, 2020.

Bispecific antibody MCLA-128 shows clinical activity in patients with solid tumors harboring NRG1 gene fusions [news release]. Boston, MA: American Association for Cancer Research; October 27, 2019. bit.ly/2Zey93h. Accessed December 20, 2019.

Tarloxotinib. Rain Therapeutics, Inc, website. bit.ly/2PLoZZf. Accessed December 20, 2019.

Waters AM, Der CJ. KRAS: the critical driver and therapeutic target for pancreatic cancer.

. 2018;8(9):a031435. doi: 10.1101/cshperspect.a031435.

Jones MR, Williamson LM, Topham JT, et al. NRG1 gene fusions are recurrent, clinically actionable gene rearrangements in KRAS wild-type pancreatic ductal adenocarcinoma.

. 2019;25(15):4674-4681. doi: 10.1158/1078-0432.CCR-19-0191.

Alterations of the NRG1 gene that are present at low rates in certain solid tumors have emerged as potentially actionable oncogenic drivers, with targeted therapies making their way to early clinical studies and into some basket trials.

NRG1 Emerges as a Potentially Actionable Target in Lung Cancer and Solid Tumors

Although groundbreaking research findings are met with much fanfare during large medical conferences, their practical application to the community oncology clinic may not always be immediately clear. Ways of integrating findings into a physician&rsquo;s practice are not covered, even though presentations feature some of the high&shy;est-level clinical trials, retrospective reviews, and labo&shy;ratory research. The

Miami Breast Cancer Conference&reg; is not the only big conference covering breast cancer research, but it fills an important gap that others do not.

Many attendees of the Miami Breast Cancer Confer&shy;ence&reg; find it complementary to the San Antonio Breast Cancer Symposium, according to

, program cochair of the Miami conference.

&ldquo;Our faculty, many of whom have presented their research at the San Antonio conference, come to Miami research at the San Antonio conference, come to Miami to say, &lsquo;Here&rsquo;s how you use this clinically. Here&rsquo;s how we apply the research lessons learned at meetings like San Antonio. Here&rsquo;s what we believe best practice are for applying this to you day-to-day practice,&rdquo; said Borgen, who is chair of the Department of Surgery at Maimon&shy;ides Medical Center and director of the breast cancer program at Maimonides Cancer Center in Brooklyn, New York. &ldquo;And I think that&rsquo;s a unique niche that [the Miami Breast Cancer Conference

Borgen spoke about important breast cancer advances and the overall goal of the meeting, which is hosted by Physicians&rsquo; Education Resource&reg;, LLC, in Florida, from March 5 to 8, 2020, in an interview with

&ldquo;[The conference will offer] clinically applicable information designed for the practicing surgeon, oncol&shy;ogist, radiation oncologist, radiologist, and pathologist who is in the trenches, diagnosing and treating breast cancer every day,&rdquo; Borgen said.

In a fortuitous turn, during last year&rsquo;s Miami Breast Cancer Conference&reg;, the FDA approved atezolizumab (Tecentriq) for adult patients with PD-L1positive, unresectable locally advanced or metastatic triple-negative breast cancer.

This was the first immunother&shy;apy approved for treating patients with breast cancer, and the oncology community has since learned more about this kind of treatment, which Borgen said will be featured at the conference in 2020.

T-DM1 (ado-trastuzumab emtansine; Kadcyla), an antibody-drug conjugate, has also received approval since last year&rsquo;s conference.

It is used as neoadjuvant therapy when treating patients with HER2-positive breast cancer who have residual tumor burden. &ldquo;We continue to refine our understanding and treatment of HER2-positive breast cancers, said Borgen.

We&rsquo;ve also seen at least 3 commercially available cell cycle checkpoint inhibitors in the estrogen receptor positive, HER2-negative space,&rdquo; Borgen continued. &ldquo;These drugs have set a new standard of care, partic&shy;ularly in the metastatic setting&hellip;, [and] the strong implication is that breast cancer is certainly more complicated to treat than at any [other] time in history.&rdquo;

Some 10 to 15 years ago, clinicians treated breast cancer as though it was a single disease instead of a family of diseases, according to Borgen. Now that there is a &ldquo;deeper understanding&rdquo; of breast cancer and its subtypes, he said, targeted treatments have emerged.

In the past, patients would receive surgery first, followed by chemotherapy, then radiation, and lastly hormone treatment. Today that sequence starts with neoadjuvant chemotherapy or a neoadjuvant estro&shy;gen blockade, &ldquo;so something as fundamental as the sequence of the treatments has changed dra&shy;matically over the past decade,&rdquo; said Borgen.

For instance, targeted immunotherapy agents such as trastuzumab (Herceptin), pertuzumab (Perjeta), and T-DM1; the checkpoint inhibitor atezolizumab; and PARP inhibitors such as olaparib (Lynparza) and talazoparib (Talzenna) are effective in patients with metastatic breast cancer who also have a

patho&shy;genic mutation. Borgen said that almost all patients with metastatic breast cancer are now routinely tested for these mutations.

&ldquo;It&rsquo;s a more complicated horizon,&rdquo; Borgen said. &ldquo;But the glass is clearly half full because patients are doing better than they&rsquo;ve ever done before. Survival rates continue to increase, and that increase is accelerating. So, the future is incredibly bright.&rdquo;

Borgen believes the most exciting research coming out for breast cancer is in the neoadjuvant space, like neoadjuvant endocrine and hormonal therapy and chemotherapy. Because of these ther&shy;apies, clinicians can often lessen the magnitude, disfigurement, and disability related to surgery.

&ldquo;We&rsquo;re doing smaller yet more sophisticated surgeries because patients are receiving medi&shy;cal therapy first,&rdquo; Borgen explained.

Because more emphasis is on the medical therapies being used to treat patients with breast cancer, the way the Miami Breast Cancer Conference&reg; delivers that message has evolved over time. In the 1980s, when the meeting was founded, mastectomy was the most common surgery for patients. Although estrogen block&shy;ade with tamoxifen was available, it was not widely used, so the focus of the meeting was almost completely surgical.

&ldquo;If you fast-forward to today35 years later&mdash; our audience is still about 60% surgeons, but the other 40% is vitally important and rounds out the team because today it&rsquo;s impossible to treat this disease without a true multimodal approach,&rdquo; Borgen said. &ldquo;&hellip;And I think the Miami conference is unique in that it is truly multidisciplinary.&rdquo;

At the conference, Borgen will present twice; the first presentation will be at the ple&shy;nary session on Friday, March 6. His research focuses on patients with breast cancer who had late diagnoses, some with a series of imaging studies, to show a &ldquo;natural history of untreated breast cancer in the modern era with modern diet and modern stresses,&rdquo; he explained. His presentation will look at the growth of breast cancer over the course of years, showing that it is &ldquo;completely impossible&rdquo; to predict its growth rate. In the data set presented, all the patients&rsquo; tumors were ER-positive and HER2-negative.

&ldquo;They should be a homogenous population, but what we show is how breast cancers actual&shy;ly grow in a random, scattershot fashion,&rdquo; Bor&shy;gen stated. &ldquo;This has a lot of implications. For example, in the medical-legal world, [if there is an issue with the diagnosis], the parties in the action will make bold statements about how big  the tumor might have been or how big it was a year or two ago. This falls under the head of what&rsquo;s called tumor doubling time, and what we show in this paper is that it&rsquo;s almost impossible to predict a tumor doubling time.&rdquo;

The second presentation focuses on Borgen&rsquo;s work in eliminating opioids from breast cancer surgery. When Borgen moved from Memorial Sloan Kettering Cancer Center to Maimonides Cancer Center, he learned the surrounding neighborhood had an opioid problem, made apparent in the emergency department daily.

&ldquo;A study showed that four-fifths of those addicts and victims of overdose started with an [physician]-prescribed narcotic, so about 5 years ago, we got heavily involved in trying to reverse this,&rdquo; Borgen said.

Borgen and his colleagues have followed a mul&shy;timodal analgesia plan to treat over 1000 consecutive patients who were getting a lumpectomy or mastectomy without reconstruction. This means that all their patients were discharged without a narcotic prescription, a model he hopes can be adopted on a national level.

In addition to his presentations, one of the sessions Borgen thinks is important centers on how to deliver bad news to patients, which has become more relevant as the diagnosis of breast cancer has evolved. Borgen explained that because the oncology community has a deeper understanding of breast cancerand the options of what the patient&rsquo;s diagnosis could be as well as the more wide-ranging effects on a patient&rsquo;s life&mdash;delivering the news to a patient has become more challenging.

To deal with this issue, last year&rsquo;s conference included a first-time session on the discipline. The audience chose a topic and a faculty mem&shy;ber, and that faculty member broke the bad news to an actress pretending to be the patient.

&ldquo;Then the audience critiqued what worked, what didn&rsquo;t work, what words were powerful, what words you should avoid, and what the style was,&rdquo; said Borgen. &ldquo;And I think the art of breaking bad news is unbelievably important, especially to our fellows and trainees.&rdquo;

This year&rsquo;s presentation, named the &ldquo;Exigent Matters Workshop,&rdquo; will be held on Sunday, March 8.

In short, the primary treatments for patients with breast cancer have changed in the past months and attending the Miami Breast Cancer Conference&reg; will help physicians apply these important therapies in their practices.

Although groundbreaking research findings are met with much fanfare during large medical conferences, their practical application to the community oncology clinic may not always be immediately clear.

Miami Breast Cancer Conference: Applying Research Shared on Friday to Patient Care on Monday

Integrating a geriatric assessment (GA) into the care of older adults who are receiving cancer treatment in communi&shy;ty oncology practices improves patient and caregiver satisfaction and encourages commu&shy;nication about aging-related concerns, accord&shy;ing to results of a clinical trial that enrolled 541 patients with advanced cancer.

Integrating a geriatric assessment into the care of older adults who are receiving cancer treatment in communi&shy;ty oncology practices improves patient and caregiver satisfaction and encourages commu&shy;nication about aging-related concerns, accord&shy;ing to results of a clinical trial that enrolled 541 patients with advanced cancer.

January 2020

Telehealth Delivers Access to Care and Cutting-Edge Clinical Research to Rural Areas

Nivolumab/Ipilimumab Combo Extends Treatment-Free Survival in RCC

Encouraging Results in First-Line Setting for HCC Usher Lenvatinib Toward Randomized Controlled Trials

NRG1 Emerges as a Potentially Actionable Target in Lung Cancer and Solid Tumors

Miami Breast Cancer Conference: Applying Research Shared on Friday to Patient Care on Monday

First Randomized Clinical Trial Evaluating Geriatric Assessment Reveals High Satisfaction With Communication About Aging-Related Concerns