Is the Nodule Malignant? Douglas Arenberg, MD, University of Michigan Health System, Ann Arbor, Michigan

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1 Questions were posed by attendees throughout the meeting using the interactive online question and answer platform. Some questions were addressed during the session, and some of our faculty were able to take extra time to respond in writing after their sessions had concluded. We hope that the information helps extend and enhance the learning experience for attendees. Audio for the Social Q and A during each session is available via the Virtual Meeting. General Session I: Screening, Diagnosis and Staging Is the Nodule Malignant? Douglas Arenberg, MD, University of Michigan Health System, Ann Arbor, Michigan Q: Where does Percepta fit in? A: Percepta is FDA approved but its place in the diagnostic workup of an indeterminate pulmonary nodule outside of a clinical trial is yet to be determined. There is a registry in progress that will help determine if this has sufficient negative predictive value, and if so, in whom. Q: When do you decide to biopsy for pure GGO? A: I don't. If it is pure GGO I advise serial observation with yearly CT and only recommend a biopsy or resection if a solid component develops that is greater than 5 mm. Q: Do you think there is much value in getting a PET scan for GG nodules, regardless of size, for risk assessment purposes given high likelihood of low SUV? A: I would not use a PET scan for GGO, ever. Keynote I: Personalized Surgical Approaches to Therapy Mark K. Ferguson, MD, University of Chicago, Chicago Q: Do surgeons use dye or Technetium 99m labeled sulfur colloid to detect the at risk pulmonary lymph nodes for dissection? A: Sentinel node mapping is performed in a clinical research setting but is not yet a routine part of clinical decision making. It is intended to identify target nodes for dissection and to determine which patients should undergo lymphadenectomy. The trial results demonstrate moderate predictive ability.

2 Plenary Session 3: Prospective Trial of Circulating Tumor Cells as a Biomarker for Early Detection of Recurrence in Patients with Locally Advanced Non-small Cell Lung Cancer Treated with Chemoradiation Chimbu Chinniah, University of Pennsylvania, Philadelphia Q: What is the amount of the blood sample needed each time? A: It was just a 10mL blood sample (1 tube) at each of the time points mentioned. Since all of our patients were treated with chemotherapy as well and required labs, it was quite easy to just add on this additional tube to assess for circulating tumor cells. 5: Reirradiation of Thoracic Cancers with Intensity Modulated Proton Therapy Jennifer Ho, MD, MD Anderson Cancer Center, Houston Q: Are initial treatment failures outside of primary field or within field, suggesting that higher doses are required? A: We had four patients (15%) with local failure, which was defined as anything within or overlapping with the original PTV, and notably these failures were all in patients who received <66 Gy (EQD2) reirradiation. We had eight patients overall with local-regional failures, defined as any failure in the thorax/mediastinum, including the above four patients with local failure. There was also an association with dose at one year. The freedom from LRR was 84% in the patients receiving 66 EQD2 and only 23% in those receiving <66 EQD2. These findings suggest that higher dose may be advantageous for control, as long as it is safe and organs-at-risk are kept within tolerance (typically we limit composite esophageal dose to <90 Gy and great vessels/bronchial tree <120 Gy). In our series, these escalated doses of 66 Gy or higher were typically given with an integrated boost to the GTV and the larger PTV typically received 60 Gy as a goal. General Session II: Early Stage Thoracic Cancers Adjuvant Therapy for Early-stage Lung Cancers Renato Martins, MD, MPH, University of Washington, Seattle Q: If good KPS, would you consider adjuvant chemo after SABR? A: I would discuss for tumors >4cm. Q: Have you considered adjuvant chemotherapy after SBRT for >4 cm tumors? A: I would absolutely consider it assuming no co-morbidities were the reason to choose SABR over surgery.

3 Q: What is the response rate of platinum doublet chemotherapy in the neoadjuvant setting? A: This would depend on the trial; from as low as 30% to as high as 60%, but generally higher than in the metastatic setting. General Session V: Advanced Non-small Cell Lung Cancer, Part I - Targeted Therapy and Immunotherapy Targeted Therapy and Management of Acquired Drug Resistance Lecia V. Sequist, MD, MPH, Massachusetts General Hospital, Boston Q: Does use of osinertinib and asetinib decrease the chance of future brain mets? A: I think they likely will, but we ll need the results from the first line randomized trials (FLAURA = osimertinib v erlotinib and ALEX = crizotinib v alectinib), both expected this year, to tell for sure. Q: In other cancers like CML, where multiple generations of TKIs are available, some oncologists use later generation TKIs up front. Do you anticipate something similar with molecular targeted therapy in lung cancer? A: Yes, I think we will transition to this strategy after the first line randomized trials (FLAURA = osimertinib v erlotinib and ALEX = crizotinib v alectinib), both expected this year. Immunotherapy: How to Apply in Practice, Choosing Patients and Management of Side Effects Hossein Borghaei, DO, Fox Chase Cancer Center, Philadelphia Q: I am seeing a number of patients with severe arthropathies. Comments? A: It is difficult to know as some lung cancer patients have arthropathy. Most side effects are of the "itis" variety. Q: Is underlying ILD a contraindication to immunotherapy? A: Yes, ILD is a contraindication in my view. Q: Has pituitary RT been tried for hypophysitis? A: Not as far as I know. Q: Do you consider collagen vascular disease as a contraindication? A: Any disorder with an autoimmune component could be a problem. In the absence of data, we should be very careful whom we treat.

4 General Session V: Advanced Non-small Cell Lung Cancer, Part II Quality of Life Benjamin Movsas, MD, FASTRO, Henry Ford Hospital, Detroit Q: Does PRO-CTCAE have site-specific assessments and validation data (e.g., brain tumor, etc.). How much time does PRO-CTCAE require? A: It is very brief. PRO-CTCAE is validated and covers patient symptoms across many different sites and areas. Q: How do you deal with survey fatigue in clinical practice? A: By being very selective in how much we ask and how often. General Session VI: Other Thoracic Tumors Small Cell Lung Cancer Gregory P. Kalemkerian, MD, University of Michigan Health System, Ann Arbor, Michigan Q: Do you give PCI at the same time as consolidative chest RT in ESSCLC who respond well to chemo? A: Yes, for people deemed to be good candidates for both PCI and consolidative thoracic RT, we will treat both at the same time over a two-week course. Obviously, people getting such treatment need to have good PS and to have recovered well from initial chemotherapy. Q: Is there a standard of care for the rare stage 1 or 2 small cell lung cancer? A: Less than 5% of people with SCLC have true stage 1 (T1-2N0M0) disease. Hard to say that there is a standard of care, since there are no high-quality clinical trials purely in this subset. However, the recommendation based on trials of patients with limited stage disease and retrospective analyses of the stage 1 subset, is for mediastinal staging (EBUS, mediastinoscopy) followed by surgical resection (if mediastinal staging is negative), then followed by adjuvant chemotherapy with platinum/etoposide x 4 cycles. The role of PCI after surgery and adjuvant chemo is unclear, but recent studies suggest that the incidence of brain metastases is quite low for people with true stage 1 SCLC and that PCI may not be necessary. For people with known LN involvement before surgery, N1 (stage 2), N2 or N3 (stage 3), the recommended treatment is concurrent chemoradiation therapy, which is standard for limited stage SCLC. The only subgroup where surgery is recommended is true stage 1, T1-2 N0. After surgery, all patients should get adjuvant chemotherapy. The role of post-op radiation is not clear, but it is generally recommended for people found to have pathologic LN involvement. Some argue it should only be given for N2-3+ (stage 3), but I would also recommend it for N1+ (stage 2).

5 Q: What is the management of low-grade or intermediate-grade neuroendocrine pulmonary tumors? A: Low-grade pulmonary NET typical carcinoid: The vast majority are stage 1 with a high cure rate after surgical resection. For stage 2 or 3A, surgery is also the treatment of choice if all disease can be resected. There is no defined role for adjuvant therapy in typical carcinoid. For patients with locally advanced disease, stage 3A or 3B, there is considerable disagreement on treatment. I recommend concurrent chemo (platinum/etoposide) and thoracic RT while others would recommend RT alone. Although these tumors are not very sensitive to chemo, I would give it together with RT in a potentially curative setting such as stage 3 disease. For patients who have metastatic disease or more commonly multiple lung nodules, surveillance to determine the pace of disease is reasonable if they are asymptomatic. For significant progression or symptomatic disease, palliative RT can be used to manage localizable symptoms. Systemic therapy is challenging. If the tumor is positive on octreotide scan, then somatostatin analogues are a reasonable option not much data on benefit for bronchial carcinoids but improved PFS in GI NETs. Carcinoid syndrome is rare in bronchial carcinoids so there is rarely a symptomatic benefit for giving somatostatin analogues. My usual first-line treatment is now everolimus. Second-line is usually the combination of capecitabine and temozolomide. Intermediate-grade pulmonary NET atypical carcinoid: Again, most are stage 1 where surgery is the clear treatment of choice. These tumors are a bit more sensitive to chemotherapy (on the order of NSCLC), so if there is pathological LN involvement, I think that adjuvant chemotherapy (SCLC regimen platinum + etoposide x 4 cycles) is reasonable. Stage 2 and some stage 3A should also be managed with resection +/- adjuvant chemotherapy. For unresectable stage 3A or 3B, I recommend concurrent definitive chemoradiotherapy with platinum + etoposide. For metastatic disease, first-line systemic therapy should be platinum + etoposide. Somatostatin analogues and everolimus are unlikely to be effective, but could be attempted. Second-line options include capecitabine + temozolomide, single agent paclitaxel or topotecan (as used in SCLC). Q: How do you treat large cell neuroendocrine tumors (LCNEC)? A: Treatment of LCNEC is controversial because there are no good prospective trials. Some (NCCN) advocate that it be treated as NSCLC, while others treat it like SCLC. I agree more with the NCCN in that I use the NSCLC algorithms to guide treatment, but I do favor SCLC-type chemotherapy (platinum + etoposide). Specifically, for stage 1, surgical resection without adjuvant chemo (à la NSCLC). For stage 2, surgery followed by adjuvant chemo with platinum + etoposide x 4 cycles (a mix of NSCLC and SCLC guidance). For stage 3, concurrent chemo (platinum + etoposide) + thoracic RT (like NSCLC or LS-SCLC). I do not recommend PCI for LCNEC (as per NSCLC guidance). For stage 4, systemic therapy usually with platinum + etoposide (as in ES-SCLC) with second-line therapy with paclitaxel or topotecan. Overall, I think that LCNEC is the worst of both worlds; it can be as aggressive as SCLC, but response to treatment more like NSCLC. It is usually a bad disease. Q: What is the equivalent dose for 45 twice daily for thoracic radiation? A: The once-daily RT dose that is supposedly biologically equivalent to 45 Gy BID is between Gy. I am not a radiation oncologist, but this is what they tell me. These are the two arms on the recently reported CONVERT trial that demonstrated relative equivalence in survival and toxicity between 45 Gy BID and 66 Gy QD thoracic RT with chemotherapy in LS-SCLC.