With the identification of new oncogenes leading to the development of drugs that target mutations, lung cancer can now be considered a treatable disease. In addition to advances in therapy, improved tumor testing can help the oncologist develop a personalized approach to treating patients.

“Although lung cancer is genomically and immunologically complex, we want to offer our patients our best therapeutic options,” said David R. Gandara, MD, director of the Thoracic Oncology Program at the University of California (UC) Davis Comprehensive Cancer Center in Sacramento, in an interview with 

An essential aspect of staying up to date regarding the best available therapeutic options is to hear from experts about the latest clinical data and understand how they canbe translated into daily practice during major medical conferences. To deliver those messages representsa unique opportunity forcontinuing medical education (CME) programs that blend in-person networking with 21st century technologies.

Combining the benefits of face-to-face interactions with the broad reach of a virtual meeting space, the 21st Annual International Lung Cancer Congress® (ILCC), cochaired by Gandara and hosted by Physicians’ Education Resource®, LLC (PER®), will be held July 23 through 25, 2020, in Huntington Beach, California. One of the benefits of having a virtual component of the meeting is the ability to broadent the conference’s reach. “Attendees and faculty who cannot attend because of travel restrictions will still be able to participate,” Gandara said. Enduring materials will be especially valuable because all sessions will be recorded in audio and video format, so that attendees and sponsors will be able to have this information available when the conference concludes.

The educational opportunities delivered during the meeting will encompass classic lecture formats, panel discussions with leading multidisciplinary experts, interactive question-and-answer sessions, new and recent drug approvals discussions, guidelines, and a special focus on the use of liquid biopsy.

G12C mutations will be a particularly important topic addressed during the conference,” Gandara said. “Historically, this mutation has been an undruggable target because of the difficulty in developing a drug to inhibit this mutation. But now there are 5 drugs in development, and we’ll be hearing about them at ILCC.”

Benefits Currently, the National Comprehensive Cancer Network (NCCN) guidelines for non–small cell lung cancer (NSCLC) recommend testing for 8 oncogene-driven lung cancers before beginning therapy (TABLE).

“This means that it’s even more important for practicing oncologists to realize that even a patient who is a previous smoker might have one of these 8 or 9 oncogenes, because 

 G12C is associated with smoking. The best treatment for them is a targeted therapy, ratherthan chemotherapy or immunotherapy, or even a combination of the two,” Gandara said.

Testing for all these oncogenes in a timely, efficient manner has its challenges, noted Gandara. Genetic panel testing needs to have high sensitivity and specificity, and a have a relatively quick turnaround time of 1 to 2 weeks. “We want oncologists to be able to treat the patient with a personalized or precision medicine approach, rather than an empiric approach,” Gandara said.

Liquid biopsy can help oncologists afford that, providing faster next-generation sequencing that can be carried out simultaneously. This method avoids testing for one gene after another in sequence, which can take a prolonged time. Traditional tissue testing is also limited by the amount of good, viable samples that can be collected during biopsy, and rebiopsy poses a significant challenge to patients.

Gandara discussedone particular aspect of the meeting that he’s looking forward to hearing about and that is the Molecular Tumor Board workshop. He explained that the theme of personalized medicine has been well recognized and adopted by clinicians.

In advanced NSCLC, the use of checkpoint immunotherapy in combination with platinum-based chemotherapy is effective; however, among oncologists there has been a divergence of opinion about what this means. For some, this understanding makes treating NSCLC simpler because it suggests that every patient with NSCLC can be treatedwith thisregimen, and Gandara disagrees.

“This regimen makes treating NSCLC more complex because even with the efficacy of the combination of checkpoint immunotherapy and platinum-based chemotherapy,we need to make sure that a patient who comes in doesn’t have one of the oncogenes that will respond even better to a targetedtherapy,” Gandara said.

At ILCC, this debate and a refined definition involving personalized medicine will be addressed during the molecular tumorboard workshop. Casepresentations will be discussed and the audience’s opinion about the best way to treat a particular case will be tallied. “Would you empirically treatthe patient? Or would you wait until the next-generation sequencing results come back?” Gandara asked.

Perhaps one of the most practice-changing occurrences in lung cancer recently has been the development of agents that target 

 fusions in the disease, as well as the emergence of targeted therapies that have the potential to provide significantly meaningful improvements over the standard of care. RET inhibitors are among the modern strategies used for the treatment of patients with 

 fusion–positive cancers, such as NSCLC that is driven by 

In the phase I/II LIBRETTO-001 trial (NCT03157128), patients with 

 fusion-positive lung cancers and other solid tumors were given selpercatinib. The study assessed themaximumtolerated dose of selpercatinib, recommended phase 2 dose, and objective response rate (ORR) as primary end points. The trial demonstrated an ORR of 68% with selpercatinib in the patientswith 

Another important development relates to extensive-stage small cell lung cancer, which has had minor advances in the last 20 years. Standard therapy involved platinum chemotherapy, but in the past year 2 new regimens have beenaddedtothecurrentplatinum–etoposide chemotherapy base, atezolizumab (Tecentriq) and durvalumab (Imfinzi), Gandara said.

Incorporating all these advancements into the workflow of the community oncologist is a key objective of CME activities for conferences such as the ILCC and other major conferences.

Gandara also shared his experience at the UC Davis Comprehensive Cancer Center delivering care in the face of the coronavirus disease 2019 (COVID-19) pandemic. He said routine follow-up visits have been converted to virtual clinic visits involving telemedicine and videoconferencing. This change also applies to National Cancer Institute (NCI) clinical trials.

“I can see the patient, and they can see me. I can see theirscans and their laboratory results and talk and interact with them,” Gandara said.Importantly, thesetypes of “virtualoffice visits” have been recognized by insurers as reimbursable. Although a physical examination isn’t possible, this methodology provides a way for interval or interim visits to occur without exposing patients to the risk of an office visit and potential exposure to COVID-19.

For those who do need to see a physician, every patient upon entering the UC Davis cancercenterhastheirtemperaturetakenandfills out a questionnaire about symptoms and potential exposure to COVID-19. Patients with a high temperatureor who indicate theyareexperiencingsymptoms associated with this virus are not allowed into the cancer center, but instead are referred to theCOVID-19 referralcenter, where their needs are assessed.

“This is a huge change in practice,” Gandara said.He noted that although many cancer drugs are now orally administered, there remain a select few patients who require infusions." In that case, patients come into the cancer center after they’vebeen checked,and they get their cancer treatment through the infusion center in a safe manner,” Gandara said.

Patients with lung cancer are already a vulnerable population in the age of COVID-19, noted Gandara, as he relayed an interesting anecdote involving social media.He polled practicing oncologists to find out whether they would arbitrarily delay either chemotherapy, immunotherapy,both, or neither in a patient with lung cancer. Of the 357 people who responded, almost 70% said they would treat the patient on schedule, assuming that the patient did not have an active COVID-19 infection.

“A small percentage, about 10%, said they would hold chemotherapy,5% would hold immunotherapy, and about 5% said they would hold both treatment options,”Gandarasaid. “This is open for debate, but my view is that we should treat patients if we can do it safely.” A small number of patients also responded and said that they would like to be treated for their cancer.

Based on the many medical conferences that have been canceled or rescheduled, COVID-19 has an impact on the dissemination of education materials and clinical research results. With the ability to be reimbursed for a virtual office visit, Gandara sees this hurdle being overcome. Further, now that medical meetings can be run on virtual platforms like WebEx or Zoom, Gandara anticipates that CME efforts will change to incorporate more virtual meeting opportunities, but still include the face-to-face component.

“It seems that medicine was heading toward this direction in the first place, but COVID-19 accelerated the pace toward virtual medicine,” Gandara said. “We have used regularly-scheduled WebEx CME programs, grand rounds, and a variety of other platforms and there is good uptake by attendees,” he said.

Among Gandara’s many achievements is his continuing role as an educator. He has played an integral part in the ILCC, which is now in its 21st year.

“The ILCC has always been one of the highest- rated cancer conferences, in terms of attendee ratings, and that is quite an accomplishment,” Gandara said.

Additionally, he has served as president of theInternational Association forthe Study of Lung Cancer, or IASLC, leading its conference in San Francisco.

Other achievements include his work in drug development, for which he has received grants from the NCI for nearly 25 years for his research in early-stage treatments. He is a founding cochair of the NCI Investigational Drug Steering Committee, of which he is still a member.

In the clinical trials arena, he has been a stalwart leader for the SWOG Lung Committee for 15 years. During this period, his research with SWOG has resulted in more than 100 clinical trials.

Finally, Gandara values the importance ofmentorship.“When I had a mentor early in my career,it was incredibly important to me. I have tried to be a good mentor as well,” Gandara said. “At this point, I have mentored over 50 young oncologists, PhD students, and medical students. Today, I’m a mentor to 5 different people who are submitting their grant applications.”

1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer (version 3.2020). Accessed April 23, 2020. 

2. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. 

. 2019;14(suppl 10):S6-S7. doi:10.1016/j.jtho.2019.08.059

3. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. Updated March 18, 2019. Accessed April 23, 2020. 

4. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. Updated March 30, 2020. Accessed April 23, 2020. 

Articles

Clinical Articles

Oncogene Identification and Treatment Advances Guide Lung Cancer Meeting

Chimeric antigen receptor (CAR) T-cell therapies quickly burst into the spotlight of hematology-oncology disease management because of their potential to illicit deep and durable responses from patients whose disease is relapsed or refractory to multiple previous lines of therapy. Relevant professional meetings and oncology publications exploded with research and news about CAR T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

“CAR T cells are a scientific revolution,” Tania Jain, MBBS, assistant professor of oncology at Johns Hopkins University in Baltimore, Maryland, said in an interview with 

 (TTO). “They have brought about a paradigm shift in terms of how we’re treating patients.”

The 2 currently FDA-approved CAR T-cell therapies, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah), are both indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma; additionally, tisagenlecleucel is approved for patients up to 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

With a second wave of approvals likely on the horizon for therapies such as lisocabtagene maraleucel (liso-cel) and idecabtagene vicleucel (bb2121), CAR T is gaining traction and will likely play an increasingly prominent role in the future treatment paradigm in oncology.

CAR T-cell therapy administration is largely limited to the inpatient setting at both academic institutions and large accredited cancer centers, making such treatments unavailable to most patients. Other challenges with this type of therapy include its potential to cause serious toxicities resulting in organ damage and death.

Due to the promising efficacy of these agents, investigators have been working toward viable solutions to bring CAR T-cell therapies to more patients by alleviating difficulties associated with therapy delivery and patient care.

Barriers to Manufacturing CAR T Cells Are Addressed

CAR T-cell therapies, both those currently approved and the many being explored in late-phase clinical trials, are produced from autologous T cells obtained from the patient receiving therapy. This personalization has led to tremendous success, yet it is a large part of why CAR T-cell therapy use remains limited to a select group of patients.

Time is an important consideration for patients who have experienced multiple relapses and may be too weakened by numerous lines of prior therapy to wait several weeks for the CAR T-cell manufacturing process. The effects of previous treatments or the disease itself can also present challenges, as manypatients are rendered lymphopenic and may be unable to produce enough T cells for harvesting. Roadblocks may remain for patients who are not limited by these factors; manufacturing success and effectiveness of the CAR T-cell product can be negatively influenced by disease-related dysfunctions of patients’ T cells.

A new option, off-the-shelf CAR T-cell products, may help solve these problems. These premade products are manufactured using allogeneic donor cells (instead of autologous cells from the patient), and they present immediate advantages to clinicians, such as immediate availability, opportunity for product standardization, and decreased cost.

“The advantages [include] being able to access the cellular therapy in real time, as opposed to autologous products that havetobe manufactured,”Craig S. Sauter, MD, clinical director of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center in New York, New York, explained in an interview withTTO. This is particularly important for patients who are not responding to therapy, which is a current requirement for treatment with CAR T cells, he added.

Findings from a phase I trial (NCT01430390) in patients with relapsed or refractory B-cell malignancies showed that patients with non-Hodgkin lymphoma (NHL) experienced durable responses with an Epstein-Barr virus–specific cytotoxic lymphocyte CAR product derived from cells harvested from third-party donors (rather than from their more precisely matched stem cell donors). All 4 patients with NHL and a single patient with chronic lymphocytic leukemia, who were treated with third-party cells, remained disease free and alive at the time of analysis, with a median follow-up of over 2 years.

“The advantages [of this type of therapy are] that it eliminates the need for apheresis [and] shipping cellular products back and forth. [Instead, clinicians] have a pharmaceutical product on the shelf for access,” Sauter, who was an author on the trial, said. Another notable product being investigated in clinical trials is UCART19, an allogeneic engineered anti CD19CAR T-cell product, which is being evaluated in the phase I CALM trial in adult patients with relapsed or refractory B-cell ALL (NCT02746952) and in the phase I PALL trial of pediatric patients with relapsed or refractory CD19-positive B-cell ALL (NCT02808442). Other off-the-shelf agents are described in theTABLE.

Optimizing Adverse Event Management for the Outpatient Setting

Issues with inpatient CAR T-cell therapy administrationinclude high demands on health care resources and strain on patients and their families. Moving treatment to the outpatient setting has the potential to reduce this strain; however,clinicians taking over care of patients receiving CAR T-cell therapy must be prepared with the proper resources to identify and manage adverse events associated with therapy.

One of the most notable risks to patients receiving CAR T-cell therapy is cytokine release syndrome (CRS), a systemic inflammatory response that is characterized by increased serum levels of inflammatory cytokines, fever, hypotension, hypoxia, and organ dysfunction.

 “[CAR T] can also lead to neurological events and can cause confusion and, in some patients, seizures,”Carlos R. Bachier, MD, Director of Cellular Research at Sarah Cannon Cancer Center in Nashville, Tennessee, explained in an interview with TTO.

Regardless of the infusion setting, patients require close monitoring in the hours and days following therapy administration. A review byLucrecia Yáñez, PhD, MS, and colleagues stated that key criteria for treating patients in the outpatient setting include an educated caregiver and necessary infrastructure allowing for outpatient visits plus adequate emergency and intensive care unit (ICU) access. Patients followed as outpatients must be given twice-daily temperature checks for a minimum of 14 days following treatment and preferably extending up to 3 to 4 weeks following infusion. Anysigns of back pain, skin rash, dizziness, chills, shortness of breath, chest pain, tachycardia, or neurological events that may indicate neurotoxicity or signs of CRS must be reported immediately so treatment can begin as quickly as possible.

Because of the risk of CRS and neurotoxicity, both FDA-approved agents are restricted under the Risk Evaluation and Mitigation Strategy, an FDA-mandated program that builds in caution for use of agents with serious safety concerns.

 Therefore, 2 doses of tocilizumab (Actemra), an interleukin (IL)-6 receptor antagonistthat was approved in 2017 for management of CRS associated with CAR T-cell therapy,

should be on hand for each patient before the infusion of CAR T cells. Steroids have also demonstrated efficacy against CRS, but concernssurrounding CAR T-cell suppression with these agents have established them as a second-line choice after tociluzumab.

Immune effector cell–associated neurotoxicity syndrome (ICANS) is a group of neurologic symptoms associated with treatments such as CAR T-cell therapy. Predisposing factors include younger age, higher tumor burden, high levels of pretreatment inflammation, and history of early or high-grade CRS. Treatments for complications of ICANS vary. Some centers may prescribe prophylactic antiepileptic medications, such as levetiracetam, to prevent seizures in patients with grade 2 or higher neurologic events. Anti–IL-6 therapy can be considered in patients with concurrent CRS, but corticosteroids are the preferred regimen in those with neurotoxicity alone.

Moving Liso-Cel to the Outpatient Setting

In February of this year, the investigational CAR T-cell product liso-cel was granted priority review by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma who had undergone at least 2 prior therapies.

Investigators believe that liso-cel therapy may have a place in a broad range of patients and in the outpatient setting.

“It turns out liso-cel has a low incidence of [CRS and ICANS], and they occurred relatively late compared with other products,” said Bachier. “Because of this low incidence, the strategy was to deliver liso-cel in an outpatient setting.”

The feasibility of liso-cel administration on an outpatient basiswas evaluatedby Bachier and colleagues, and the results were presented at the 2020 Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood & Marrow Transplant Research, held February 19 to 23, 2020, in Orlando, Florida.

The authors analyzed data from 3 clinical trials of liso-cel, with a focus on the subset of participants who were treated as outpatients. The included trials were the phase I TRANSCEND-NHL-001 (NCT02631044) and phase II OUTREACH (NCT03744676) trials in patientswhohadundergone at least 2 lines of prior treatment, as well as the PILOT study (NCT03483103), which examined liso-cel as second-line therapy in patients who were ineligible for autologous hematopoietic stem cell transplant because of age, organ function, or ECOG performance score. All 3 studies allowed outpatienttreatment, with some patients receiving their therapy in the nonuniversity setting.

“This clinical trial included sites that were not a part of a university but had experience treating patients for stem cell transplant,” Bachier said. “Some of these sites that participated were notyour traditional university centers that had traditionally been involved in the development of these therapies.”

Much caution was required in order to maximize patient safety and treatment efficacy. “The approach of doing CAR T-cell therapy, in general, in the outpatient setting requires a robust clinical ability of the centers,” said coauthor David G. Maloney, MD, PhD, medical director of Cellular Immunotherapy at the Immunotherapy Integrated Research Center of Fred Hutchinson Cancer Research Center in Seattle, Washington, in an interview. “We were able to get people safely to the hospital, and it was rare that you would have to do escalation of care when people were admitted. Most of the time, patients could bemanaged…and wereout of the ICU, withrare exceptions. But again, you still have to have the wherewithal to get patients to the ICU pot entially for aggressive care if needed.”

Results of the analysis of outpatient data from the 3 trials showed that rates of toxicity and response were similar to those previously reported for the entire patient cohort (both inpatients and outpatients) of the TRANSCEND-NHL-001 trial.

“Based on these results, the indication is that you can deliver [liso-cel] in the outpatient setting and the outcomes are good compared with those treated in the inpatient setting,” said Bachier. “Aside from that, it also showed that liso-cel could be safely administered outside of university programs and in more community-based programs, most of them being aligned [with] or part of stem cell and bone marrow transplant programs.”

Next Steps for Bringing CAR T Into More Clinical Settings

When planning or setting up a CAR T-cell therapy outpatient program, investigators anticipate possible barriers to successfultreatment. The greatest barrier, according to Bachier, is access to physicians and staff who are knowledgeable and trained to manage toxicities related to CAR T-cell therapy. “These therapies still should not, in my opinion, be delivered [by clinicians in] community centers that do not have the expertise to deliver the therapies safely,” he said.

Maloney added that centers should be required to have the ability to triage patients 24/7 and allow for patients to be directly admitted to the hospital if needed. In the case of the analysis of outpatient data from the 3 liso-cel trials however, he said, “We found that around 30% to 40% of patients did not actually ever require hospitalization, whichis quite interesting.” Most of the 60% to 70% of patients who were hospitalized were admitted for fever, he added.

In addition, sites must gain accreditation and approval, Jain pointed out.

“Every center that intends to do CAR T-cell therapy is first approved by each of the companies [that manufacturethese agents],” Jain said. “The centers also have to be approved by FACT [Foundation for the Accreditation of Cellular Therapy], which is the same organization that approves centers for allogeneic stem cell transplant. These are some of the largest things that a center needs to go through, which takes care of things like developing standard practices and other guidelines to make sure that these [therapies] are used safely and appropriately.”

Forward-Looking Aspects of Cellular Therapy

As investigators and oncologists explore the feasibility of moving CAR T-cell therapy into more settings, 2 questions arise: What settings have on this therapy?

What type of training and skills do clinicians need? Like other clinicians, Sauter has concerns about new allogeneic cellular therapies,andhe hopes future research will focus on mitigating these challenges. “The concern would be that these are not autologous products and there is the risk of rejection from the host immune system,” he said. “Strategies to circumnavigate that risk are at the forefront of investigationin off-the-shelf CAR T cells.”

The research is not stopping with CAR T-cell therapy,though. “We’re seeing a lot of new molecules coming in that will be challenging the roles of CAR T cells, [such as] specific antibodies, which may even work in cases of CAR T-cell failure,” Maloney said. “We are still learning how to make those more effective and safer.”

1. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine releasesyndrome.FDAwebsite.PublishedAugust30,2017.AccessedApril14, 2020. bit.ly/2RC4eQ8

2. FDA approves axicabtagene ciloleucel for large B-cell lymphoma. FDA website. Published October 18, 2017. Accessed April 14, 2020. bit.ly/2yYIQOp

3. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA website. Published May 1, 2018. Accessed April 14, 2020. bit.ly/34zPoi8

4. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17(3):147167. doi: 10.1038/s41571-019-0297-y

5. DepilS,DuchateauP,GruppSA,MuftiG,PoirotL.‘Off-the-shelf’allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19(3):185199. doi: 10.1038/s41573-019-0051-2

6. Curran KJ, Sauter CS, Kernan CS, et al. Durable remission following “off-theshelf” chimeric antigen receptor (CAR) T-cells in patients with relapse/refractory (R/R) B-cell malignancies. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, 2020; Orlando, FL. Abstract 120. bit.ly/2ufDYCu

7. Yáñez L, Sánchez-Escamilla M, Perales MA. CAR T cell toxicity: current managementandfuturedirections. Hemasphere.2019;3(2):e186.doi:10.1097/ HS9.0000000000000186

8. Risk evaluation and mitigation strategies | REMS. FDA website. Updated August 8, 2019. Accessed April 14, 2020. bit.ly/2ykhLVt

9. JainT,BarM,KansagraAJ,etal.UseofchimericantigenreceptorTcell therapy in clinical practice for relapsed/refractory aggressive B cell non-Hodgkin lymphoma: an expert panel opinion from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 2019;25(12):2305-2321. doi: 10.1016/j.bbmt.2019.08.015

10. U.S. Food and Drug Administration (FDA) accepts for Priority Review Bristol-Myers Squibb’s Biologics License Application (BLA) for lisocabtagene maraleucel (liso-cel) for adult patients with relapsed or refractory large B-cell lymphoma. News release. Bristol-Myers Squibb; February 12, 2020. Accessed April 15, 2020. bit.ly/37ruQbs

11. Helwick C. Strong activity shown for lisocabtagene maraleucel CAR T-cell therapy in aggressive large B-cell lymphoma. ASCO Post website. Published February 25, 2020. Accessed April 15, 2020. bit.ly/3eoD0pT

12. Bachier CR, Palomba ML, Abramson JA, et al. Outpatient treatment with lisocabtagene maraleucel (liso-cel) in 3 ongoing clinical studies in relapsed/refractory (R/R) large B cell non-Hodgkin lymphoma (NHL), including second-line transplant noneligible (TNE) patients: TRANSCEND NHL 001, OUTREACH, and PILOT. Presented at: 2020 Transplantation & Cellular Therapy Meetings; February 19-23, Orlando, FL. Abstract 29. bit.ly/37I7DC9

Relevant professional meetings and oncology publications exploded with research and news about chimeric antigen receptor T cells, and this cellular therapy strategy is now being explored across hematologic and solid malignancies.

 Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings

Results of a phase II/III clinical trial in women with low-grade serous ovarian cancer demonstrated greater survival outcomes for those treated with MEK inhibitor therapyversus standard-of-care (SOC) options in the recurrent setting.

David M. Gershenson, MD, discussed the findings for trametinib (Mekinist) monotherapy in aninterview with 

. “This was not only the first study of trametinib in this patient population, but it also turned out to be the first positive randomized clinical trial of any targeted agent in low-grade serous carcinoma,” he said. “It establishes trametinib as a new standard-of-care treatment option for women who have low-grade serous carcinoma.”

In the NRG-GOG 0281 trial (NCT02101788), treatment with trametinib resulted in a 52% reduction in the risk of disease progression or death. The median progression-free survival (PFS) was 13.0 months (95% CI, 9.9-15.0) with trametinib compared with 7.2 months (95% CI, 5.6-9.9) for physician’s choice of SOC therapy (HR, 0.48; 95% CI, 0.36-0.64; 1-sided

 <.0001). Median overall survival (OS) also was longer with trametinib therapy, but the results did not reach statistical significance.

Low-grade serous carcinoma of the ovary or peritoneum is a rare subtype that comprises 5% to 10% of all serous cancers, Gershenson and colleagues said in their conference abstract. Most of these malignancies are diagnosed in advanced stages and more than 70% of those with stage II to IV disease will experience relapse.

Although chemotherapy and hormonal therapy are frequently administered to patients in the primary and recurrent disease settings,

 lowgrade serous carcinoma is also characterized by alterations in the MAP kinase cell-signaling network, which includes MEK proteins.

 Trametinib targets MEK1/2 kinases and is given in combination with the BRAF inhibitor dabrafenib (Tafinlar) in patients with melanoma, non–small cell lung cancer, and anaplastic thyroid cancer metastases with 

In NRG-GOG 0281, patients were randomized to receive either trametinib at 2 mg daily or 1 of 5 SOC options: paclitaxel (80 mg/m2 weekly for 3 of 4 weeks), pegylated liposomal doxorubicin (40-50 mg on day 1 of each 28-day cycle), topotecan (4.0 mg/m

 weekly for 3 of 4 weeks), letrozole (2.5 mg daily), or tamoxifen (20 mg twice daily). Patients who progressed on SOC were allowed to cross over to trametinib. The primary end point was PFS; secondary objectives included OS, objective response rate (ORR), and toxicity.

In all, 260 patients with a median age of 56.2 years were enrolled between February 2014 and April 2018. The primary site of malignancy was the ovary for 90.8% of participants and the peritoneum for 9.2%. Overall, 48.1% underwent 3 or more prior lines of therapy. Median follow-up was 31.4 months. 

In addition to a significant improvement in PFS, trametinib therapy also resulted in a higher response rate than SOC. The ORR was 26.2% (95% CI, 19.0%-34.0%) with trametinib versus 6.2% (95% CI, 2.0%-10.0%) with SOC, which translated into an odds ratio favoring trametinib of 5.4 (95% CI, 2.4-12.2; 

Response duration for those who received trametinib was longer compared with participants in the SOC arm; the median duration with trametinib was 13.6 months (95% CI, 8.1-18.8) versus 5.9 months (95% CI, 2.8-12.2) with SOC.

Additionally, median OS was 37.0 months (95% CI, 30.3-not estimable) with trametinib versus 29.2 months (95% CI, 23.5-51.6) with SOC, which represented a 25% reduction in the risk of death but not a statistically significant improvement (HR, 0.75; 95% CI, 0.51-1.11; 1-sided 

 = .054). The OS analysis in the SOC arm included patients who had crossed over to trametinib therapy after progressing on SOC. Among patients who crossed over (n = 88), the median PFS was 10.8 months (95% CI, 7.3-12.0), the ORR was 15% (95% CI, 7.0-22.0), and the duration of response was 15.9 months (95% CI, 4.2-22.

Adverse events (AEs) were more prevalent in patients who received trametinib than in those in the SOC arm. Common all-grade AEs in the trametinib and SOC arms, respectively, were skin rash (92.1% vs 48.5%), fatigue (72.5% vs 57.8%), diarrhea (72.4% vs 33.6%), nausea (60.6% vs 50.8%), and anemia (51.9% vs 43.0%). 

The principal toxicities of grade 3 severity or higher for trametinib versus SOC therapy, respectively, were hematologic (13.4% vs 9.4%), gastrointestinal (27.6% vs 29%), skin (15% vs 3.9%), and vascular (18.9% vs 8.6). AEs of special interest included decreased ejection fraction in 7.9% of patients who received trametinib compared with 0.8% with SOC and pneumonitis in 2.4% and 0% of patients, respectively. Among all participants, 35.4% in the trametinib arm discontinued treatment due to an AE or complication compared with 12.3% in the SOC arm.

Gershenson, who is a professor of gynecologic oncology at The University of Texas MD Anderson Cancer Center in Houston, conducted this study of trametinib after an initial phase II study of patients with low-grade serous ovarian cancer treated with selumetinib, also an MEK1/2 inhibitor, demonstrated an ORR of 15% in this patient population.

 The FDA approved selumetinib as a therapy for pediatric patients 3 years or older with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas.

Although trametinib is not FDA approved for ovarian cancer, the National Comprehensive Cancer Network added trametinib to the guidelines as an option for patients with platinum-sensitive and platinum-resistant recurrent low-grade serous carcinoma after findings from NRG-GOG 0281 were presented at the European Society for Medical Oncology 2019 Congress (

NRG Oncology and the National Cancer Research Network collaborated on the study.

1. Gershenson DM, Miller A, Brady W, et al. A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer. Presented at: 2020 Society of Gynecologic Oncology Annual Meeting; March 28-31, 2020; Toronto, Canada. Abstract 42. bit.ly/2XFKxdP

2. NCCN Clinical Practice Guidelines: ovarian cancer, including fallopian tube cancer and primary peritoneal cancer. Version 1.2020. National Comprehensive Cancer Network website. Updated March 11, 2020. Accessed April 6, 2020. bit.ly/2VcFsIh

3. Mekinist. Package insert. Novartis Pharmaceuticals Corporation; 2019. Accessed April 6, 2020. bit.ly/2Vx2Yil

4. Farley J, Brady WE, Vathipadiekal V, et al. Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study. 

. 2013;14(2):134-140. doi:10.1016/S1470-2045(12)70572-7

5. FDA approves selumetinib for neurofibromatosis type 1 with symptomatic, inoperable plexiform neurofibromas [news release]. Silver Spring, MD: CDER Office of Communications. April 10, 2020.

6. Trametinib improves outcomes for women with low-grade serous carcinoma of the ovary/peritoneum on NRG Oncology trial. NRG Oncology website. Published September 29, 2019. Accessed April 6, 2020. bit.ly/3aQG5wH

Encouraging survival outcomes were seen with trametinib in patients with low-grade serous ovarian cancer treated in a phase II/III clinical trial.

Trametinib Shows Promising Benefit for Low-Grade Serous Ovarian Cancer

The coronavirus disease 2019 pandemic has brought about many firsts and lasts for those of us in oncology. As I prepared to write this month’s editorial, I thought about how quickly medical conferences would need to adapt in the coming months. I reached out to my colleagues at Targeted Therapies in Oncology and learned that the 37th Annual Miami Breast Cancer Conference® was one of the last “fully live” congresses they covered. The American Association for Cancer Research (AACR) Annual Meeting, which typically draws over 20,000 people, this year was run virtually after an initial delay. The American Society of Clinical Oncology (ASCO) Annual Meeting, which I often joke with my colleagues is the “Mount Everest” of cancer research, typically attended by 40,000 to 50,000 people from around the world who are dedicated to advancing cancer treatments, will similarly occur virtually in 2020.

These facts take your breath away and lend further perspective to the far-reaching impact that this public health crisis has had on every aspect of our personal and professional lives.

But we can and must adapt, and I firmly believe that in the most trying times, innovation and ingenuity enable us to leap forward. Even before the pandemic, major congresses such as the AACR, ASCO, and the European Society for Medical Oncology could not be even better attended because of a variety of factors including cost, distance, and obstacles and delays in obtaining visitors’ visas for foreign attendees. Although the technology to make these meetings widely accessible virtually in real time was available, putting it in motion was not a priority; after all, nothing beats attending in person. But the situation has changed and conference organizers have had to adapt quickly. It’s almost certain that the virtual format will allow more people to attend. Without the distractions and chaos that accompany large meetings, it is likely more people will be fully engaged and toggle between sessions of interest with ease. What will be missed and cannot be replaced: the personal interactions, networking, and casual conversations over dinner that unite cancer researchers and often are the seeds of very fruitful collaborations and lifelong friendships. I will certainly miss that this year.

I am also confident that when this period of pandemic ends, cancer care and research will somehow be better for it. We will continue to find innovative ways to come together both in person and virtually to more widely disseminate valuable information regarding important advances in cancer research. We will similarly find more efficient ways to deliver expert care that also minimizes the burden on patients who would otherwise have to travel long distances. For that reason, I’m excited about the new meeting format—it’s certainly a first for me.

"We will continue to find innovative ways to come together both in person and virtually to more widely disseminate valuable information regarding important advances in cancer research."

Medical Meeting Planners Pivot to Share Advances With the Oncology 

De-escalating therapy has the potential to dramatically reshape the treatment of patients with HPV-associated oropharyngeal cancers, but only if a number of key trials come back with positive long-term data with 3 cycles of cisplatin at 100 mg/m

 times 3, given every 3 weeks, Sue Yom, MD, PhD, a professor in the Departments of Radiation Oncology and Otolaryngology-Head and Neck Surgery atthe University of California, San Francisco, said in an interview with 

Sure, there were some minor variations over the years, small alterations made on a case-by-case basis. “But long story short, that’s fundamentally what was happening: 70 Gy with 3 cycles of high-dose cisplatin,” Yom said. The story began to change a little over a decade ago, with the introduction of a variable that could potentiallychange the course of therapy for a large percentage of patients with head and neck cancers. Today, the operative word remains potentially.

In 2008, Maura L. Gillison, MD, PhD, of JohnsHopkins University, and colleagues found thatwhether head and neck squamous cell carcinoma tumors were associated with the human papillomavirus (HPV) turned out to be a major prognostic indicator.

“When that finally came to be reported, there was a very, very striking result,” said Barbara Burtness, MD, a professor of medicine (medical oncology), Disease-Aligned Research Team leader of the Head and Neck Cancers Program, and coleader of Developmental Therapeutics at Yale Cancer Center in New Haven, Connecticut Patients with HPV-associated stage III or IV head and neck squamous cell carcinoma of the oropharynx or larynx had a 2-year overall survival (OS) rate of 95% versus 62% for patients with HPV-negative tumors.

Two years later, Gillison collaborated with K. Kian Ang, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston and published the results of a study in oropharyngeal cancer (NCT00047008), which again found that HPV made a difference in terms of survival.

Patients with HPV-positive tumors had better OS and progression-free survival (PFS) than patients who were HPV negative (

<.001 for both comparisons). Ang and colleagues reported thatthe 3-year OS rate was 82.4% (95% CI, 77.2%-87.6%) in patients who were HPV positive compared with 57.1% (95% CI, 48.1%-66.1%) in those who were HPV negative. Similarly, the 3-year PFS rate favored the HPV-positive group, at 73.7% (95% CI, 67.7%-79.8%) versus 43.4% (95% CI, 34.4%-52.4%) for the HPV-negative group (

The 3-year absolute benefit of HPV-positive status for OS was 25% (95% CI, 11%-40%), and the absolute benefit for PFS was 30% (95% CI, 15%-45%).

The results were similar with stratification according to p16 expression status. The 3-year rates of OS were 83.6% (95%CI,78.7%-88.6%) in the subgroup that was positive for p16 expression and 51.3% (95% CI, 41.5%-61.0%) in the subgroup that was negative (

<.001). Three-year PFS rates were 74.4% (95% CI, 68.5%-80.2%) and 38.4% (95% CI, 28.9%-47.9%), respectively (

The study also found that the number of pack-years an individual smoked had a substantialnegative impact on prognosis.

These findings raised serious questions because the current standard of care, unchanged from that described by Yom, can have a profound effect on the life of a patient who survives the cancer. “The after- effects of that dose of radiation are quite real, and they include chronic pain, chronic swallowing difficulties, dry mouth, and dental complications,” Burtness said.

“We are concerned that these patients may be at higher risk for death from the late effects of the treatment.”

Moreover, patients with HPV-associated cancers tended to be younger at diagnosis than those with non-HPV cancers. Patients who develop the cancer in their 50s might have decades of life left—plenty of time for the long-term adverse effects (AEs) of aggressive treatment to show up.

The issue is pressing because HPV-associated cancers represent about 7 in 10 cases of oropharyngeal cancer.

 The most recent statistics from the Centers for Diseases Control & Prevention suggests that 3500 new cases of HPV-associated oropharyngeal cancers are diagnosed in women versus 15,500 diagnosed in men (

Cherie-Ann O. Nathan, MD, chairman of the Department of Otolaryngology–Head and Neck Surgeryat Louisiana State University Health Shreveport, said the new findings underscored the need for more research. “We need to start to look at de-escalating for that low-risk group,” she said.

Deciding that different strategies might be warranted and choosingwhich approaches make the most sense are 2 different considerations, and both come withdifficult questions. Burtness said it can be a challenge just to figure out how to tackle the question.

I think, first of all, it’s challenging to do deintensification trials because they require very large sample sizes, and you want to be sure you’re not deintensifying [treatment in] somebody who would be cured by the full treatment and wouldn’t be cured by the reduced regimen,” Burtness said.

For the most fortunate patients, the OS rate with the current standard of care is in the range of 90% to 95%, setting a high bar for its replacement, Yom said. “It’s a huge ethical and practical situation where you’re actually having to estimate: ‘What would it take to prove that this less intense alternative was as good?’” Yom said.

“Patients do get better with time,” Yom said. “After a year or 2, they can live very normal lives.It’s actually a great treatment in some ways, and 1 question is if we should even be messing with it.”

Another strategy is to reduce the dose or field of radiation. In Yom’s much-anticipated trial, NRG-HN002 (NCT02254278), 306 patients with p16-positive, non–smoking-associated, locoregionally advanced oropharyngeal cancer were stratified by unilateral or bilateral radiation and randomized into 2 groups.

 One group received 60 Gy of intensity-modulated radiation therapy (IMRT) for 6 weeks plus cisplatin (IMRT + C) at 40 mg/m

 weekly. The other group received 60 Gy of modestly accelerated IMRT alone for 5 weeks. The goal was to compare the arms in terms of 2-year PFS rates without unacceptable swallowing difficulty at 1 year. The IMRT + C group met the desired benchmarks; the IMRT alone group did not.

Although the study was just a phase II trial, Yom said the results were encouraging and will lead to further study.

Another strategy is to perform surgery up front, Nathan said. If the margins are negative and there is not a significant number of metastatic lymph nodes or significant extranodal extension, chemotherapy might be avoided. She said transoral surgery has become much more effective and precise in the age of robotics. A common site of lymph node involvement is the retropharyngeal region, shown in 

“When robotic surgery became popular and we were able to get margins on these tumors at the base of [the] tongue and tonsils, people started saying [that] for the HPV-associated [tumors], you don’t need the typical wide margins of 5 mm; you could get away with 3 mm,” she said.“ So, the whole purpose of transoral surgery was that after removing the tumor, you could de-escalate.”

Other research has tested the replacement of cisplatin with cetuximab (Erbitux), though one study found that the latter resulted in inferior OS.

With the exception of the cetuximab strategy, the novel approaches have shown promise. However, Nathan said, clinicians should realize that these are all still hypotheses; there is much that is not yet known.

“Unfortunately, people look at all [these] retrospective data and small institutional trials and make [treatment] decisions, not realizing that it’s still not standard of care,” Nathan said. “It’s fine to de-escalate, but always de-escalate if you can on a clinical trial.”

A number of important ongoing trials have the potential to add significant scientific rigor to the debate. Among them is Eastern Cooperative Oncology Group’s ECOG-E3311 trial (NCT01898494), which is examining transoral surgery followed by low- or standard-dose radiation therapy with or without chemotherapy. Initial findings are expected to be presented at the 2020 American Society of Clinical Oncology Annual Meeting and the trial is expected to be completed in 2023. The PATHOS trial (NCT02215265), which is evaluating transoral resection followed by reduced-intensity radiotherapy with or without cisplatin, is expected to be completed in 2026.

Yom and colleagues are working on NRGHN005 (NCT03952585), a phase II/III study in which patients will undergo deintensified radiation therapy with cisplatin or the PD-1 inhibitor nivolumab (Opdivo) versus standard-of-care chemoradiation. The investigators used an innovative design so that the study will produce scientifically rigorous results for the 70 Gy versus 60 Gy question at the phase III level, even if the nivolumab phase II investigation does not meet its targeted end points, Yom told 

In the meantime, Burtness said, the data are beginning tosuggest, if not conclusively, which types of patients might be a good fit for deintensification. “The omission of chemotherapyin the postoperative setting after transoral resection is probably better for patients with smaller nodes, maybe only 1 or 2 nodes,” she said. “The use of more induction chemotherapy and a lesser dose of radiation is better, obviously,for patients who are going to tolerate chemotherapy well. The omission of systemic chemotherapy and the use of immunotherapy may eventually [lead to the development of] a biomarker signature.”

She cautioned that it is not clear that all HPV-associated cancers should be treated the same way. Certain other factors appear to affect the opportunity for deintensification. “Repeatedly, we’ve seen [that] patients with T4 cancers don’t do well with deintensification,” she said. “Patients who’ve smoked more than 10 pack-years won’t do well.”

Burtness added that there is a good chance the end result of all the research will simply be that certain deintensification strategies are better for certain patient populations. Yom agreed. “One of our goals is to make deintensification acceptable within the standard of care,” she said. “But I’m not sure there’s going to be just 1 standard of care going forward.”

Even if these new strategies show equal or better success rates compared with the current standard ofcare, patients who undergo deintensified therapy might avoid the toxicities of more intense therapy at the cost of unexpected long-term AEs.

The 2 key takeaways from the study we put together are that, 1, there are a lot of different deintensification strategies, and in the short term, a lot of these different strategies don’t show any differences in outcomes or toxicity,” Patel said. “But the second point that is crucial is that longer-term follow-up is necessary for making judgments as to whether or not to do deintensified treatments.”

Nathan said 1 major concern is that patients with deintensified treatment regimens might facea higher risk of a subsequent cancer diagnosis. “HPV- associated cancers still have the same distant metastasis rate as HPV-negative cancers,” she said. “And the distant metastasis is occurring years later and sometimes in unusual locations.”

For example, lack of systemic therapy might not affect the current oropharyngeal tumor, but years later, could it lead to a cancer that might have been prevented? That type of question is impossible to answer at thispoint, andNathan says it is problematic to assume the answer is no.

Nathan also raised concerns about changes to the American Joint Commission on Cancer (AJCC) staging system. In the eighth edition of the AJCC Cancer Staging Manual, HPV-associated cancers were restaged because staging is generally meant to match prognoses, and HPV-associated cancers had been shown to have better prognoses, she said.The end result of the restaging, she said, is that some cancers previously deemed stage IV might now be reclassified as stage I or II. Nathan worries that the lower staging will result in even more deintensification because clinicians will not consider cases as serious as they once did, which would be a mistake, she said. “All the patients who did so well and have such good survival [in the existing de-escalation literature] were being treated like they were stage III or IV,” she said. “So, until you have the results of [ongoing clinical trials], you shouldn’t be doing it.”

Clearly, some level of deintensification is occurring withinclinics inthe United States.If itturnsout that 1 or more of the new, lower-intensity strategies is effective, the treatment paradigm for patients will be drastically different, Yom said:“To start talking about things like patient preferences and quality of life is foreign and different in oropharyngeal cancer.”

Patient preference is a key consideration,Patel said: “That’s why the data and being able to share with patients that these outcomes aren’t different at longer-term follow-ups is important.”

Different types of patients will likely favor different approaches, even if de-escalation is validated as a standard option, according to Yom. “I have patients who come to my clinic, and they’re like, ‘I have 2 kids. I’m staying alive. Hit me with everything you have,’” she said.

A large spectrum of Yom’s patient population is very highly educated about their cancers, she said, and that knowledge can inform the strategies they prefer. In many cases, education leads patients to be less concerned about mortality and more concerned about the impact of therapy on quality of life.

“There’s a large proportion of that population where their driving concern is this fear of long-term consequences,” she said.

Yom said radiation oncologists will need to better help patients, who until now had few treatment choices, think through their options. “We don’t have good structures and instruments to help people sort through the decision-making process ina way that makes sense to them,” she said. “I don’t think anybody does.”

Even if the data from the current trialsare positive, Nathan cautioned, the time horizon to evaluate outcomes must be longer than a few years. “Most of these trials are looking good, but follow-up is only about 3 to 4 years, she said. “A lot of our toxicities [that we have seen] have occurred 5 and 8 years later.”

That will require oncologists to be involved in decisions that might be thornier than those patients previously faced. “You’re going to have to be a much better oncologist,” Yom said.

Still, she and others say the challenge will be well worth it, but only if the ongoing scientific study findings support the optimism now shared by many in the field. “This deintensification movement will have huge implications [for] how the majority of patients with head and neck cancers will be treated in this country going forward,” Yom said.

Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. 

. 2008;100(4):261-269. doi: 10.1093/jnci/djn011

Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. 

. 2010;363(1):24-35. doi: 10.1056/NEJMoa0912217

Viens LJ, Henley SJ, Watson M, et al. Human papillomavirus-associated Cancers - United States, 2008-2012. 

. 2016;65(26):661-666. doi: 10.15585/mmwr.mm6526a1

https://www.cdc.gov/mmwr/volumes/65/wr/mm6526a1.htm

Yom SS, Saavedra-Torres P, Caudell JJ, et al. NRG-HN002: a randomized phase II trial for patients with p16-positive, non-smoking-associated, locoregionally advanced oropharyngeal cancer. 

. 2019:105(3):684-685. doi: 10.1016/j.ijrobp.2019.08.038

Deintensification of Treatment in HPV-Associated Cancers Holds Promise, But With Caveats

Using liquid biopsy assays to guide precision therapy in different cancer types is more relevant than ever before, and their use has even been incorporated into multiple national guidelines. Where these assays are particularly useful is for treatment selection in patients with little or no tumor tissue for sequencing or for whom repeatbiopsy is not feasible.

“Liquid biopsy is useful at any time when a physician needs genomic information about their patient’s cancer in order to make a treatment decision,” said Becky Nagy, MS, LGS, senior director of medical affairs at Guardant Health, in an interview withTargeted Therapies in Oncology. “Right now, this is largely used in patients with advanced cancers, although the potential uses will likely expand in the future.”

The ability to detect DNA derived from a tumor in the total cell-free DNA from all cells present in a patient’s blood is the basis of liquid biopsy assays.1As methods of detecting oncogenic drivers in circulating tumor DNA (ctDNA) advance, testing methods have been developed with increasingly enhanced clinical sensitivity (smallest amount of a substance in a sample that can accurately be measured by an assay) and specificity (ability of an assay to measure a particular substance versus others in a sample).

Moreover, shed ctDNA is derived from cancer cells occurring anywhere in the body; this contrasts with tumor tissue, which can be usedto identify cancer-associated aberrations at only 1 sample location.

"Liquid biopsy is useful at any time when a physician needs genomic information about their patient’s cancer in order to make a treatment decision."

May 1 2020

Oncogene Identification and Treatment Advances Guide Lung Cancer Meeting

Protocol Management, Off-the-Shelf Therapies Help Bring CAR T Into More Settings

Trametinib Shows Promising Benefit for Low-Grade Serous Ovarian Cancer

Medical Meeting Planners Pivot to Share Advances With the Oncology

Deintensification of Treatment in HPV-Associated Cancers Holds Promise, But With Caveats

Hitting the Target: Rapid Evolution of Plasma Assays Continues to Move Genomic Profiling Toward More Efficient Testing Methods

With Patients’ Safety Top of Mind, Oncologists Develop Innovative Care Plans During Pandemic

COVID-19 Presents an Opportunity for Precision Medicine to Play Expanded Role in Care