Faculty Perspectives: Current Guidelines and Emerging Treatments in Nonmetastatic NSCLC
Multiple Pathways and Resources for NSCLC Treatment in an Academic Medical Center
In my medical oncology practice at Johns Hopkins, I see approximately 4 patients with nonmetastatic NSCLC per week. Most of these patients are referrals from either pulmonary medicine or thoracic surgery. A patient with early stage disease initially sees a pulmonologist for diagnosis and may then be referred to a thoracic surgeon. The thoracic surgeon may refer the patient to us in medical oncology if there is an indication to enroll the patient in a clinical trial or for systemic therapy. In a community oncology practice, patients tend to go to surgery first and are then referred to the medical oncologist for adjuvant chemotherapy. In academic centers, it is more common for patients to be seen in a multidisciplinary setting.
For the most part, we follow the NCCN Guidelines closely when managing NSCLC. However, we may deviate from the guidelines in isolated settings; for example, a patient with stage IIIA NSCLC who is healthy might be offered postoperative concurrent chemoradiation rather than the sequential treatment that the NCCN Guidelines recommend. Overall, a majority of eligible patients would be enrolled in a clinical trial, because we have numerous open trials in the neoadjuvant and adjuvant setting.
Here at Johns Hopkins, we perform in-house reflexive biomarker testing on all patients with adenocarcinoma subtype of NSCLC, including patients with early-stage disease. However, most US centers are not conducting biomarker tests for early-stage NSCLC. We test for EGFR, ALK, ROS1, RET fusion, MET amplification, HER2 mutation, and mosaic zone 14 mutation. We also test all patients for PD-L1 expression. If additional biomarker testing is warranted (primarily at the time of disease relapse), we may send these tests to an external laboratory. Similarly, NTRK gene fusion tests are sent out because we do not currently test this biomarker in-house.
It takes approximately 2 to 4 weeks to obtain test results for our initial in-house biomarker panel. For early-stage disease, we proceed to treat the patient in the absence of biomarker test results because there is no clinical reason to wait for these results before treating the patient. Our rationale for testing patients reflexively is twofold: (1) when the pathologists are looking at the tissue sample, they may not know that the patient has early-stage versus late-stage disease; and (2) the results are available if and when the patient’s tumor relapses and a clinical trial may be available for the patient. Currently, outside of a clinical trial, there is no indication to use biomarker-driven treatment in early-stage NSCLC. We have several clinical trials that have completed accrual, and we are awaiting data from these trials to identify how PD-L1 expression may impact adjuvant or neoadjuvant immunotherapy in early-stage disease.
At Johns Hopkins, most patients with NSCLC are initially referred to a pulmonologist by either the emergency department or the primary care physician. The 2 most common initial pathways for patients are as follows:
- A patient with symptoms presents in the emergency department, has a chest x-ray showing a nodule, and has a workup done. The patient is then referred to a pulmonologist and may be diagnosed with lung cancer.
- The patient may present to the primary care physician with unresolving pneumonia or unresolving respiratory problems and is referred to a pulmonologist, who diagnoses lung cancer.
In some cases, when the patient has symptoms or has a nodule that is amenable to bronchoscopic biopsy, the pulmonologist can obtain a biopsy via bronchoscopy. In other cases, the patient may be referred directly to a thoracic surgeon. Patients with very early-stage NSCLC (ie, stage I) would receive a workup by the thoracic surgeon, who performs a tumor resection on appropriate patients. Depending on the results of the resection, the patient may be referred to the medical oncologist for postoperative adjuvant chemotherapy.
Here at Johns Hopkins, patients with stage I and most patients with stage II NSCLC are generally referred directly to the thoracic surgeon by either the pulmonologist or the primary care physician. The thoracic surgeon subsequently triages these patients based on the availability of a relevant clinical trial and may consult with the medical oncologist if a clinical trial is available. If a clinical trial is not appropriate, the patient would proceed to a workup with the thoracic surgeon, and appropriate patients would have surgery.
Patients with locally advanced disease (ie, stage III NSCLC) who may or may not be candidates for surgery are evaluated through our multidisciplinary clinic held once weekly; an oncology nurse navigator coordinates the clinic and guides the patient through the process. Most of the patients evaluated at the multidisciplinary clinic have complex cases where there is disagreement over the best treatment approach, and approximately half of the patients are seeking second opinions. The multidisciplinary team includes a medical oncologist, surgical oncologist, radiation oncologist, oncology nurse, nurse practitioner, a social worker (if appropriate), and others. Relevant members of the multidisciplinary team see the patient and recommend a joint plan, which may include neoadjuvant therapy followed by surgery, chemoradiation if the patient is not a candidate for surgery, or enrollment onto a clinical trial.
Typically, the physician who provides definitive treatment to the patient will continue to follow the patient. For instance, the thoracic surgeon who performs surgery as the definitive treatment may continue to monitor the patient for several years. Patients who receive definitive treatment with chemoradiation continue to be followed by the medical oncologist and radiation oncologist; those who receive chemotherapy and surgery are followed up by the medical oncologist and the surgeon. At our institution, we monitor the patients for 5 years and order scans intermittently. Community settings that do not have a multidisciplinary clinic may have a different pathway, such as a one-to-one referral from the surgeon to the medical oncologist, or from the pulmonologist to the surgeon, and the treating physicians have phone discussions about the patient.
The most important unmet need in NSCLC is improving outcomes for most patients with resectable disease. Of patients who have surgery, approximately 50% will experience a relapse of disease, and this relapse rate is higher than many other tumor types, including breast cancer and colorectal cancer. The last major advance in systemic therapy for lung cancer was approximately 15 years ago when adjuvant chemotherapy (4 cycles of platinum-based chemotherapy) was adopted as standard treatment.
A complicating factor is that the median age for lung cancer is 70 years. Many of these older patients, particularly those with comorbidities, do not receive the NCCN Guidelines recommended 4 cycles of platinum-based chemotherapy because of the perceived benefit/risk profile. The 5-year survival with chemotherapy is a modest 5%, and with surgery alone, 40%; thus, the overall benefit with surgery and chemotherapy is approximately 45% at 5 years. There remains a substantial need to improve survival for these patients.
Moving forward, the most promising prospect for early-stage NSCLC is immunotherapy at the time of surgery—either in the preoperative neoadjuvant setting or postoperative setting. It will be interesting to see the data from several large postoperative trials involving patients receiving single-agent immunotherapy for 1 year. Some of these postoperative trials take time because long-term disease-free survival and overall survival are being assessed. Several studies are investigating 3 or 4 cycles of chemotherapy plus immunotherapy prior to surgery. Early data suggest that combination therapy may lead to pathologic complete response (no residual disease when the tumor is surgically removed). Findings from these studies will show whether pathologic complete response translates into longer-term disease-free survival and overall survival.
On December 3, 2019, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to the biopharmaceutical company Adaptimmune Therapeutics for ADP-A2M4 for the treatment of synovial sarcoma. Earlier this year, the FDA granted Orphan Drug designation to the agent for the treatment of soft tissue sarcomas.
The PD-L1 inhibitor durvalumab (Imfinzi) showed an overall survival benefit in patients with unresectable stage III non–small-cell lung cancer (NSCLC) in the phase 3 PACIFIC trial.