Dr Kotecha on the FDA Approval of Optune Lua in Metastatic NSCLC

Rupesh Rajesh Kotecha, MD, radiation oncologist, chief of Radiosurgery, director of Central Nervous System Metastasis, Miami Cancer Institute, discusses the FDA approval of Optune Lua, a tumor treating fields (TTF) device, in metastatic non–small cell lung cancer.

 for concurrent use with PD-1/PD-L1 inhibitors or docetaxel in adult patients with metastatic NSCLC whose disease has progressed on or after a platinum-based regimen.

The regulatory decision was based on the results of the 

which investigated TTFields plus standard-of-care (SOC) immune checkpoint inhibitors or docetaxel vs immune checkpoint inhibitors or docetaxel alone in patients with metastatic NSCLC. This trial was important for the NSCLC field, particularly in regard to the development of treatments outside of the traditional systemic therapy realm, Kotecha says.

The LUNAR trial demonstrated that patients given Optune Lua concurrently with a PD-1/PD-L1 inhibitor or docetaxel (n = 145) experienced a median overall survival (OS) of 13.2 months (95% CI, 10.3-15.5) compared with 9.9 months (95% CI, 8.2-12.2) for those given a PD-1/PD-L1 inhibitor or docetaxel alone (n = 146; 

The use of Optune Lua plus an immune checkpoint inhibitor (n = 66) generated a median OS of 18.5 months (95% CI, 10.6-30.3) vs 10.8 months (95% CI, 8.2-18.4) for a checkpoint inhibitor alone (n = 68; HR, 0.63; 95% CI, 0.41-0.96; 

 = .030). Optune Lua plus docetaxel (n = 71) produced a median OS of 11.1 months (95% CI, 8.2-14.1) vs 8.7 months (95% CI, 6.3-11.3) for docetaxel alone (HR, 0.81; 95% CI, 0.55-1.19; 

The addition of Optune Lua to the current SOC second-line treatment regimens for patients with NSCLC offers a new option for those whose disease has progressed on or after platinum-based therapy. Notably, the use of TTFields concurrently with SOC options was not associated with an increase in adverse effects that would impact quality of life, Kotecha concludes.

Videos

Rupesh Rajesh Kotecha, MD, discusses the FDA approval for Optune Lua in metastatic non–small cell lung cancer.

Rupesh Rajesh Kotecha, MD, chief, Radiosurgery, director, Central Nervous System Metastasis, Miami Cancer Institute, member, Baptist Health Group, member, Baptist Health Quality Network, discusses the use of magnetic resonance (MR)–guided radiotherapy in lung cancer.

Adverse effects associated with radiation therapy are typically confined to the treatment area, Kotecha says. Specifically regarding patients with lung cancer, damage to the lung following radiotherapy remains a primary concern, and preserving as much lung as possible remains the goal, Kotecha explains. These patients are considered high risk since they are generally inoperable or have comorbidities that may preclude surgery, Kotecha adds.

The use of MR-guided radiotherapy can help reduce damage to healthy parts of the lung around the tumor, when compared with radiation done with a computerized tomography (CT)–based approach, Kotecha notes. Since the position of the tumor changes when a patient breathes, CT-guided radiation is more likely to affect healthy tissue.

However, with MR-guided radiation therapy, the smaller radiation beam is activated only when the tumor moves within its range, allowing for a more targeted approach, Kotecha concludes.

Rupesh Rajesh Kotecha, MD, discusses the use of magnetic resonance–guided radiotherapy in lung cancer.


Dr. Kotecha on MR-Guided Radiotherapy in Lung Cancer


The development of brain metastases represents a common complication of a diagnosis of cancer occurring more frequently than primary tumors, with approximately 97,000 to 170,000 new cases diagnosed annually in the United States. In fact, approximately 10% to 30% of all patients with cancer will develop brain metastases at some point during the course of their systemic disease.

 The incidence of brain metastases has increased over the past 10 years as a result of heightened screening in patients who are asymptomatic but deemed high-risk, improvements in diagnostic imaging, the increased availability and efficacy of systemic therapies, and improved survival of patients with cancer. These principles are especially important for patients with breast cancer who represent the second-highest proportion of patients with brain metastases, second to only lung cancer.

The overall relative incidence of patients with brain metastases related to breast cancer is 15%; approximately only 5% of patients who receive a diagnosis of breast cancer will develop brain metastases.

 Certain subgroups of patients, such as those with triple-negative disease, are at higher risk as are those with 

-amplified disease. In patients with breast cancer who develop brain metastases, the peak incidence of diagnosis occurs in those aged 50 to 59 years.

The diagnosis-specific graded prognostic assessment (DS-GPA) was developed as an objective means of estimating the survival of patients with newly diagnosed brain metastases. The prognostic criteria vary by tumor subtype. Specifically for patients with breast cancer, prognostic features include age, performance status, and tumor subtype.

 In general, the prognosis of patients with breast cancer who develop brain metastases has substantially improved over the past 20 years. The 5-year survival rate was approximately 1.3% in 2000 compared with 12% in 2020.

 During this time period, the DS-GPA has continued to stratify patients into prognostic groups, with median survival ranging from 6 to 36 months.

Prognosis and treatment recommendations for patients with breast cancer and brain metastases rely heavily on the tumor subtype; however, evolving evidence demonstrates that receptor expression and subtype grouping may change during the course of the patient’s disease. Whole exome sequencing of brain metastases compared with primary breast tumors as well as other visceral metastases have demonstrated that approximately 50% of brain metastases may exhibit actionable mutations that are not detected in the primary tumor.

Patterns of tumor subtype switching has been observed in several studies; the most common discordances are estrogen receptor loss, progesterone receptor loss, and amplification of 

 Given the increasing availability of systemic therapies with the ability for intracranial penetration, a more comprehensive understanding of the biology of brain metastases has developed. This will be important for personalizing and tailoring therapy for patients at the time of intracranial progression.

There are number of management considerations to take into consideration for a patient who receives a diagnosis of brain metastasis, including performance status, number of brain metastases, size and location of the lesions, presence of neurologic deficits, age, the extent of the primary tumor or extracranial disease, overall stability on systemic therapy, and patient input.

Similarly, there are a range of treatment strategies for this patient population, from corticosteroids and medical management alone, to whole brain radiation therapy with or without hippocampal-avoidance, stereotactic radiosurgery (SRS), resection, or combination approaches. Evidence has shown the risk of neurocognitive decline in the setting of whole brain radiation therapy and therefore there has been a paradigm shift toward offering SRS for the majority of patients with brain metastases including those with multiple lesions or larger brain metastases. Additionally, SRS should be considered before or after surgery for patients requiring resection, or as a boost to reduce the bulk of leptomeningeal disease in those patients who will undergo intrathecal systemic therapy.

Efficacy Outcomes from the RTOG 1119 Trial8

Primary SRS is an effective local therapy with many advantages for patients with brain metastases, including its ability to target surgically inaccessible areas of the brain; shorter recovery time compared with resection; shorter treatment schedules that allow expeditious treatment in between systemic therapy cycles for patients receiving standard cytotoxic chemotherapy; an effective management strategy for patients who develop metachronous lesions; and potentially a synergistic treatment along with targeted therapy or immunotherapy in select patients. Notably, the response to SRS for patients with brain metastases in different breast cancer subtypes mirrors the outcomes of patients treated with lumpectomy and adjuvant radiation therapy for early-stage disease. For example, results showed that patients with luminal B or HER2-positive disease subtypes experience the highest risk of local failure compared to those with luminal A disease.

It is important to consider the timing and sequencing of systemic therapy around the time of radiosurgery for patients who are receiving treatment for their metastatic disease as well as local therapy with SRS. Several systemic therapy agents have been safely combined with SRS and results of retrospective studies have demonstrated favorable safety profiles with concurrent immunotherapy, capecitabine, temozolomide, trastuzumab (Herceptin), hormonal agents, and lapatinib (Tykerb).

 Results of a study of 445 patients with brain metastasis treated with SRS and concurrent systemic therapy showed an incidence of radiographic radiation necrosis of approximately 8%, which was comparable to those treated with radiosurgery alone.

Further, the addition of systemic therapies, such as lapatinib may improve the control rates over SRS alone. In results from a retrospective study, investigators observed a reduction in the risk of local failure as well as a trend to decreased risk of distant intracranial failure with the addition of lapatinib to SRS.

The RTOG 1119 trial (NCT01622868), which evaluated radiation therapy with or without concurrent lapatinib for patients with HER2-positive breast cancer with brain metastases, reported results at the 2020 Society for Neuro-Oncology Virtual Meeting (

). Although concurrent lapatinib improved the 4-week overall response rate, concurrent treatment did not improve the 12-week complete response rate, the primary end point of the study. Moreover, the use of central nervous system (CNS)–penetrating therapy, presence of fewer lesions, and higher DS-GPA score were associated with a higher 12-week complete response rate. Finally, fewer lesions and the receipt of any CNS-penetrating systemic therapy were also associated with improved CNS progression-free survival. We await the publication of this and other studies to determine the synergistic benefit of concurrent treatment.

Although several agents for patients with breast cancer can be safely combined with radiosurgery, there is growing concern about the use of ado-trastuzumab emtansine (Kadclya; T-DM1) for those with HER2-positive disease with brain metastases who received prior stereotactic radiation therapy. Investigators have observed that patients who receive either concurrent or sequential radiosurgery with T-DM1 are at significantly higher risk of radiation necrosis. Therefore, caution is warranted in this patient population until additional data are collected.

In conclusion, advances in radiotherapy techniques and systemic therapy have allowed for improved survival and quality of life for patients with breast cancer and brain metastases. Further study is needed to optimize personalized management based on brain metastasis biology. 

Rupesh R. Kotecha, MD, is chief of radiosurgery and director of central nervous system metastasis at the Miami Cancer Institute at Baptist Health South Florida.

Articles

Prognosis and treatment recommendations for patients with breast cancer and brain metastases rely heavily on the tumor subtype; however, evolving evidence demonstrates that receptor expression and subtype grouping may change during the course of the patient’s disease.

Modern Approaches to Brain Cancer Metastases in Breast Cancer

Brain metastases are a significant and growing healthcare burden. With the growth and aging of populations worldwide, the global cancer burden is expected to increase to nearly 22 million by 2030, at which time cancer will be the leading cause of death in the United States.

 Large-scale studies of brain metastases are lacking, but reported percentages of patients with systemic disease who develop brain metastases range from 9% to 50%.

 The cost of treating brain metastases is also rising. The growth in the incidence and cost of treating brain metastases creates a critical challenge for physicians and cancer care centers: how to optimize and ensure access to high-quality care to improve patient quality of life and survival while simultaneously implementing cost-effective clinical workflows and processes.

Stereotactic Radiosurgery Improves Brain Metastasis Treatment

Recent advances in the delivery of technology and treatment regimens for stereotactic radiosurgery (SRS) enable new approaches to improve patient outcomes and clinical efficiency. These technology advances are enabling new precision radiation medicine regimens that have been shown to improve local tumor control rates with minimal toxicity. Key to the success of treating brain metastases with SRS is using a regimen tailored to the size of the lesion and individual patient need.

Table. Miami Cancer Institute Brain Metastases SRS Guidelines

, SRS is currently being used in single-session, hypofractionated, and multisession (staged) regimens, depending on the clinical scenario. Single-session regimens can be used to treat lesions up to 3 cm in diameter and offer patients the greatest convenience. Hypofractionated regimens are the most versatile and can be used across the greatest range of lesion size. Although lesions greater than 3 cm are usually treated with multisession SRS administered over several weeks, Miami Cancer Institute in Kendall, Florida, has successfully used hypofractionated regimens in these cases for improved patient convenience. Regardless of regimen, dose reduction is performed for lesions in specific locations, such as those in the brainstem or in proximity to the optic pathway.

SRS: Cost-Efficient and Clinically Effective

Noninvasive SRS methods offer a cost-efficient and clinically effective treatment that can be used in addition to or as an alternative to intracranial surgery.

 SRS can also be readily incorporated into multimodal treatment regimens that may include surgery, chemotherapy, targeted therapy, or immunotherapy. SRS is flexible in terms of how and when it can be utilized, and this enables the development of highly personalized treatment regimens based on the stage of the patient’s disease, the histology of the tumor, and even the molecular profile of the tumor. Importantly, the availability of a radiation delivery system that can be used for single-treatment, hypofractionated, and staged radiation therapy regimens, such as Gamma Knife, allows cancer centers to optimize SRS treatment plans to best meet each patient’s needs while streamlining clinical workflows and maximizing the value of their device investment.

In July 2017, Miami Cancer Institute established a dedicated SRS clinic to facilitate access to this important therapeutic option and to effectively integrate SRS into its clinical workflows for treating brain metastases. The decision to establish the SRS clinic was based on 4 key factors. First, a growing body of data supports the clinical benefits of SRS in treating brain metastases. Second, SRS offers clinicians the opportunity to provide patients with precision radiation medicine regimens that are well tolerated and can provide durable local tumor control. Third, the availability of an SRS system that could be used to provide single-session, hypofractionated, and staged SRS regimens enabled the center to purchase a single device that could be used to treat all patients undergoing SRS, offering a greater return on its investment in technology. Finally, the establishment of the dedicated SRS clinical team helped to differentiate Miami Cancer Institute from other cancer centers in the region, allowing it to attract more patients and recruit staff members who want to be on the cutting edge of cancer therapy.

Once the decision to establish the SRS clinic was made, Miami Cancer Institute developed a variety of processes and procedures designed to optimize the use and outcomes of SRS in the treatment of brain metastases. Critical to the success of the program was implementing processes to ensure effective integration and coordination among neurologists, radiation oncologists, and medical oncologists for patients receiving complex, multimodal care. This included establishing a weekly meeting of a multidisciplinary team. This team helped to ensure effective coordination with medical oncology with respect to the timing of systemic therapy (targeted therapy or immunotherapy) relative to other treatments, including SRS, and to reduce delays in initiating or continuing cytotoxic chemotherapy by timing SRS around optimized chemotherapy cycles.

In addition to facilitating coordination and data sharing among its care providers, it is also important to establish SRS clinical workflows that streamline and optimize the patient journey while increasing patient volume and supporting cost-effective operations. Key to achieving this is implementing multidisciplinary treatment guidelines and care paths that ensure appropriate evidence-based treatment. The multidisciplinary guideline that Miami Cancer Institute developed and implemented to determine if a metastatic lesion is eligible for SRS treatment is shown in 

Another important factor in successfully integrating SRS into the brain metastasis treatment paradigm is ensuring that every patient with a brain tumor or brain metastasis undergoes a planning magnetic resonance imaging (MRI) at the time of imaging. This is done to facilitate the downstream workflow for those patients who will, in fact, undergo SRS. Gamma Knife MRI sequences are used rather than diagnostic sequences because the former can be used for target volume delineation for radiation treatments, not just for SRS. This approach streamlines downstream clinical workflow for SRS patients and allows a more rapid response if the patient develops a new metastatic lesion.

Figure 1. Miami Cancer Institute's Multidisciplinary Treatment Guideline

Figure 2. Form Used for Triaging Patients to the SRS Workflow at Miami Cancer Institute

To ensure that all patients who could potentially benefit from SRS are appropriately evaluated, the medical oncology, neurology, radiation oncology, and neuro-oncology departments can all triage directly to the SRS workflow. Additionally, the use of a standard form for all patients with brain metastases (

) helps to simplify and facilitate scheduling of pretreatment scans, SRS mask customization, and other care.

More than 700 metastatic lesions have been treated with SRS since the establishment of the SRS clinic in July 2017, demonstrating that a coordinated, integrated approach can increase utilization of this important form of radiation therapy. A key to this success was the support and commitment of clinicians across multiple departments, as evidenced by a 98% physician attendance rate at the weekly multidisciplinary meeting in 2018 and a 100% attendance rate thus far in 2019. Effective integration of SRS into the brain metastasis care path has allowed 20 patients to date to receive same-day service and immediate treatment for new brain metastases. The ability to treat these patients with SRS within 24 hours of new lesion detection eliminated delays for initiating systemic therapy and costs for additional MRI while reducing patient anxiety.

Delays in initiating SRS can decrease both clinical efficacy and clinical efficiency. A recent study found that 41% of patients require a change in management if the planning MRI is performed within 7 days of initiating SRS and that 78% require a change in management if SRS is initiated more than 7 days after the planning MRI.6 With an integrated and defined process for triaging patients to the SRS care path and tight coordination between diagnostic imaging and SRS, the median time between the planning MRI and initiation of SRS treatment at Miami Cancer Institute is only 2 days. Similarly, close coordination between the neurosurgery and radiation oncology departments has increased the proportion of patients with radiation oncology/neurology dual SRS plans from 44% to 78%. This again helps to reduce treatment delays and improve clinical efficiency.

The establishment of the dedicated SRS clinic has been so successful that Miami Cancer Institute has created a multidisciplinary annual symposium in order to build awareness of the program within the regional medical community and to support other care centers seeking to integrate SRS into their brain metastasis treatment paradigms.

SRS is a flexible and effective tool for developing precision radiation medicine regimens to treat brain metastases. Importantly, evolving SRS treatment regimens can improve local tumor control and survival, even for patients with large and complex metastases not previously considered amenable to radiation therapy. Realizing the potential of SRS to improve the care and outcomes for patients with brain metastases requires a dedicated and multidisciplinary approach that utilizes evidence-based medicine to evaluate and triage these patients to the regimen most likely to provide clinical benefit.

Global Cancer Facts & Figures 3rd Edition. American Cancer Society website. cancer.org/research/cancer-facts-statistics/global. html. Published 2015. Accessed September 4, 2019.

American Society of Clinical Oncology. The state of cancer care in America, 2014: a report by the American Society of Clinical Oncology. 

. 2014;10(2):119-142. doi: 10.1200/ JOP.2014.001386.

Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study. 

. 2017;19(11):1511-1521. doi:  10.1093/neuonc/nox077.

Lal LS, Byfield SD, Chang EL, et al. Cost-effectiveness analysis of a randomized study comparing radiosurgery with radiosurgery and whole brain radiation therapy in patients with 1 to 3 brain metastases. 

. 2012;35(1):45-50. doi: 10.1097/ COC.0b013e3182005a8f.

Salkeld AL, Hau EKC, Nahar N, et al. Changes in brain metastasis during radiosurgical planning. 

. 2018;102(4):727-733. doi: 10.1016/j.ijrobp.2018.06.021.

Kotecha R, Mehta MP. The complexity of managing large brain metastasis. 

. 2019;104(3):483-484. doi: 10.1016/j.ijrobp.2018.02.160.

The growth in the incidence and cost of treating brain metastases creates a critical challenge for physicians and cancer care centers.

Rupesh Kotecha, MD

Articles

Dr Kotecha on the FDA Approval of Optune Lua in Metastatic NSCLC

Dr. Kotecha on MR-Guided Radiotherapy in Lung Cancer

Modern Approaches to Brain Cancer Metastases in Breast Cancer

Stereotactic Radiosurgery Can Improve Control of Brain Metastases