Faculty Perspectives: Current Guidelines and Emerging Treatments in Nonmetastatic NSCLC

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A Multidisciplinary Approach to Screening, Staging, and Treating NSCLC

Stephen R. Broderick, MD

At Johns Hopkins Hospital, each specialist in my practice sees approximately 8 to 10 patients with nonmetastatic NSCLC per month, some of whom are not candidates for surgery based on physiologic parameters. In most cases, we follow the NCCN Guidelines or ASCO clinical practice guidelines in our management of patients with early-stage NSCLC, except in clinical scenarios where the patient may not fit into a particular category within the guidelines, or when we enroll a patient in a clinical trial. For example, we may determine that a neoadjuvant clinical study is appropriate for a patient with stage IB NSCLC, whereas this recommendation is not concordant with the NCCN Guidelines. There are also instances in which we apply recently published clinical study data when managing our patients—even before the NCCN Guidelines have been updated to reflect the most recent findings.

At our centers, we conduct reflex molecular biomarker testing, performed at the time of diagnosis, regardless of tumor stage. For all patients with the adenocarcinoma subtype, if adequate tissue is acquired at the initial biopsy, we perform next-generation sequencing—a panel of approximately 60 genes, which includes the most common driver mutations—EGFR, ALK fusion, KRAS, RET, and MET. We also test for PD-L1 expression. The standard next-generation sequencing panel and PD-L1 testing are conducted in-house. If additional biomarker tests are required, they are sent to an external testing laboratory. Test results from an outside laboratory generally take 2 to 3 weeks; this delay may be challenging for patients who want to start treatment immediately or for informed patients who prefer to get results quickly. In other cases, the delay is not a concern for many of our patients recovering from surgery who would not be starting therapy for several weeks. Moreover, patients for whom surgery is the first-line treatment usually receive adjuvant chemotherapy rather than targeted therapy or immunotherapy in the adjuvant setting, although this may change based on currently enrolling clinical trials.

Repeat biomarker testing for patients whose disease progresses after first-line or neoadjuvant therapy is generally ordered by the medical oncologist. For patients whose disease recurs or those whose disease has progressed on first-line therapy, I am sometimes asked to obtain additional tissue for molecular testing, possibly for additional assays or to detect changes since the initial molecular panel.

In the neoadjuvant setting, chemoradiation is our standard treatment. In addition, many of our patients are being placed on neoadjuvant immunotherapy protocols. With respect to treating patients with early-stage NSCLC, there is a marked difference between stage IA and stage IIIA disease. For patients with stage I disease who are candidates for resection, biomarker-driven treatment is not typically used. Nevertheless, we order biomarker tests and may use the results to discuss prognostic information with the patient, and then save the information and refer to it if the disease recurs. Biomarker information is useful for patients with stage II and III NSCLC who are being enrolled in clinical trials. And while we do not currently have a targeted therapy neoadjuvant trial, we look at PD-L1 expression, because it affects our immunotherapy focus.

Determining the resectability of early-stage NSCLC is based on 2 factors: anatomic considerations, which include the size and location of the tumor and what is required anatomically to remove the tumor entirely; and patient fitness for surgery, which includes the patient’s age, performance status, pulmonary reserve, cardiac comorbidities, and other factors.

At our institution, patients with stage I (particularly stage IA) and some patients with stage II disease are referred directly to thoracic surgeons, who perform a battery of staging tests and assess the patient’s physiologic reserve and medical suitability for surgery. Similarly, patients with stage IB NSCLC are first referred to thoracic surgeons, who consult with the medical oncologist to determine whether a clinical trial is appropriate for patients with tumors ≥4 cm but clinically node-negative, and then determine whether the patient will be enrolled in a trial or go straight to surgery.

Patients with clinical stage II and III NSCLC undergo a multidisciplinary evaluation, either via direct referral from the surgeon to the medical oncologist, or if they see the medical oncologist first, they are referred by the medical oncologist to the surgeon. Most patients with stage II and III NSCLC are reviewed by our multidisciplinary clinic mechanism or discussed in our multidisciplinary tumor board.

Some patients who are not candidates for surgery may be amenable to stereotactic radiation, depending on the size and location of the tumor. If the patient is suitable for stereotactic radiation, we typically stage the mediastinum, and if the mediastinum is negative, treatment with stereotactic radiation would be initiated. Patients with unresectable disease who are not suitable for stereotactic radiation may be treated with radiation and chemotherapy and are therefore seen by radiation oncologists and medical oncologists.

Our multidisciplinary team (MDT) includes an oncology nurse navigator or oncology nurse practitioner, medical oncologist, radiation oncologist, thoracic surgeon, radiologist, pathologist, social worker, and smoking cessation expert. On a weekly basis, we hold a 1-day multidisciplinary clinic to evaluate newly diagnosed patients at the Johns Hopkins Sidney Kimmel Cancer Center and those that were diagnosed elsewhere who are seeking a second opinion (approximately 50% of our patients). The clinic is organized by an oncology nurse navigator who handles intake, gathers clinical study data, and conducts educational sessions with the patients and families. On the morning of the clinic, patients are seen by the oncology nurse navigator, or by either a medical oncology fellow or radiation oncology fellow, or by an internal medicine resident. The patient’s history and physical are prepared for the oncologist, surgeon, and radiation oncologist. The MDT meets for lunch to discuss the patients’ cases: the radiologist presents the patients’ films; the pathologist reviews the pathology findings; and the research nurse who screened the patients conveys the patients’ eligibility for clinical trials. For patients seeking second opinions, we generally review existing imaging studies if they are high-quality scans but may re-review the pathology findings and have a radiologist re-interpret the images.

Our goal for the MDT clinic is to arrive at a patient-­tailored, multidisciplinary treatment recommendation. By the conclusion of the meeting, we know which patients need to be seen by which physicians. After the meeting, physicians meet with the patients to discuss treatment recommendations and options. Afterward, the physicians regroup with the nurse navigator, who ensures that all patients have a defined management plan and coordinates the execution of that plan. This one-day MDT clinic appeals to many patients because they can come in for a single, one-day evaluation and treatment recommendation rather than several individual visits with different specialists. Moreover, it helps avert delays and reduce costs.

One of the greatest unmet needs in early-stage NSCLC is providing consistent high-quality surgical resection on a nationwide basis. Improvement is needed toward ensuring that resections are performed when indicated and that appropriate preoperative and pathologic staging metrics are used. There is also a marked need for broader screening of eligible patients, which can lead to earlier identification of tumors, earlier intervention, and better outcomes.

In my view, the most notable advance in NSCLC treatment over the past 10 to 15 years is immunotherapy, which has shown remarkable results in metastatic disease and may have similar responses and improvements in survival for patients with stage II and III disease. Early data on immunotherapy in the neoadjuvant setting is promising. I look forward to seeing data over the next few years on prospective neoadjuvant immunotherapy studies powered for survival. Another major step will be to identify a biomarker that shows which patients benefit from neoadjuvant checkpoint inhibition before surgery rather than proceeding straight to surgery or receiving neoadjuvant chemoradiation.

In the surgical setting, the aim is to continue exploring minimally invasive approaches with minimal morbidity and mortality so patients can recover quickly and move on to their next therapy if indicated. We have seen substantial progress across all treatment modalities for lung cancer, and these advances continue.

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Current Guidelines and Emerging Treatments in Nonmetastatic NSCLC

Non–small-cell lung cancer (NSCLC)—including squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma—accounts for 80% to 85% of all lung cancers. Of patients diagnosed with lung cancer (all types), 17% have localized disease (confined to the primary site), 22% have regional disease (spread to regional lymph nodes), 57% have metastatic disease, and 4% have an unknown stage.