Surgical and Radiotherapy Choices in Limited-Stage SCLC

Video content above is prompted by the following:

In your experience, what percentage of limited-stage disease is amenable to resection and does lobectomy remain the preferred procedure for stage I-IIA (T1-2, N0, M0) disease?

does a surgeon operate on a small cell nodule, and what is the next step in treatment? 

Under what circumstances would surgery vs radiotherapy (SABR ) be a preferred, definitive treatment choice for a patient with stage I-IIA small cell lung cancer (SCLC)? 

What factors inform your decision to select systemic treatment and 

ation factor into your treatment plan for patients with limited-stage SCLC?

Videos

Panelists discuss how the surgical approach to limited-stage small cell lung cancer varies, including the percentage of cases amenable to resection, the preference for lobectomy in stage I-IIA disease, and the role of mediastinal lymph node staging in shaping treatment strategies, alongside considerations for choosing between surgery and radiotherapy, the selection of systemic treatments, and the integration of prophylactic cranial irradiation in treatment plans.

Current Landscape of First-Line Treatment for Limited-Stage SCLC: Diagnostic Workup & Multidisciplinary Approaches

Briefly explore the current landscape of 

for limited-stage small cell lung cancer (LS-SCLC):

What clinical factors influence the initial diagnostic workup and managementof patients with LS-SCLC? 

approach adopted when developing a treatment plan for patients with LS-SCLC? 

Panelists discuss how the current landscape of first-line treatment for limited-stage small cell lung cancer is shaped by various clinical factors that influence the diagnostic workup and management, emphasizing the importance of a multidisciplinary team approach in developing effective treatment plans for these patients.

Wade T. Iams, MD, assistant professor of medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, discusses the potential for providing small cell lung cancer (SCLC) subtyping in clinical practice.

Current subtyping modalities are largely tumor-based, says Iams. Initial methodology bases classification on characteristic patterns of RNA expression, while more recent systems utilize immunohistochemical analysis of protein expression. Since SCLC tumors are primarily necrotic and patients rarely undergo surgical removal according to the standard of care, there is often a lack of viable tumor tissue for clinicians to study, Iams explains.

However, a recent collaborative study of cell-free DNA (cfDNA) methylome profiling in SCLC featured in Nature Cancer demonstrated that cfDNA assays, including blood tests, could detect SCLC subtypes through the analysis of specific DNA methylation signals. This breakthrough study indicates the potential use of blood-based assays to classify and accordingly treat clinically relevant subgroups of SCLC, Iams concludes.

Wade T. Iams, MD, discusses the potential for providing small cell lung cancer subtyping in clinical practice. 


Dr. Iams on Small Cell Lung Cancer Subtyping in Clinical Practice 

Wade T. Iams, MD, assistant professor of medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, discusses the evaluation of sotorasib (Lumakras) in 

 G12C–mutant solid tumors, including non–small cell lung cancer (NSCLC).

The phase 1/2 CodeBreaK-100 trial (NCT03600883) is evaluating the safety, tolerability, and efficacy of sotorasib as a single agent and in combination with other agents in patients with solid tumors harboring 

 G12C mutations. A cohort of patients with treatment-naïve advanced NSCLC is receiving sotorasib monotherapy.

Investigators are watching for hepatotoxicity, particularly in the combination approaches, and it was observed when pembrolizumab (Keytruda) was administered concurrently with sotorasib, Iams says. When sotorasib was given at higher doses in this cohort, grade 3 or higher hepatotoxicity occurred in more than75% of patients, Iams explains. However, when sotorasib was administered atdoses of 360 mg or less per day in combination with pembrolizumab, grade 3 or higher hepatotoxicity was observed in the range of 25% to 40% of patients, Iams adds.

Another method found to reduce the rates of hepatotoxicity in these patients was to conduct a 21- or 42-day lead-in with sotorasib at 360 mg or less before introducing pembrolizumab, Iams concludes.

Wade T. Iams, MD, discusses the evaluation of sotorasib in KRAS G12C–mutant solid tumors, including non–small cell lung cancer.


Dr. Iams on the Evaluation of Sotorasib in KRAS G12C–Mutant Solid Tumors

Wade T. Iams, MD, assistant professor of medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, discusses the need to establish the clinical utility of circulating tumor DNA (ctDNA) testing in lung cancer.

Clinical validity is how representative a specific measurement is of what information is trying to be captured, Iams explains. Measurements of clinical validity include sensitivity, specificity, and positive or negative predictive values of clinical measurements like laboratory values, radiography, or physical exam findings.

ctDNA testing has established clinical validity in a variety of circumstances and has specific clinical applications, Iams says. However, the clinical utility of ctDNA remains unestablished as the field has not proven that acting on the clinically valid measurements of ctDNA testing improves outcomes and prolongs survival for patients with lung cancer, Iams concludes.

Wade T. Iams, MD, discusses the need to establish the clinical utility of circulating tumor DNA testing in lung cancer.  



Dr. Iams on Establishing the Clinical Utility of ctDNA Testing in Lung Cancer 

Wade T. Iams, MD, assistant professor of medicine, Vanderbilt University Medical Center, discusses the emergence of TKIs and antibody-drug conjugates (ADCs) in 

-mutant non–small cell lung cancer (NSCLC), TKIs, such as mobocertinib and poziotinib, and ADCs, such as fam-trastuzumab deruxtecan-nxki (Enhertu), are emerging as potential treatment options for patients, says Iams.

Although mobocertinib and poziotinib have demonstrated efficacy in this patient population, the field appears to be moving toward implementing ADCs before TKIs, Iams explains. In May 2020, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for the treatment of patients with previously treated, 

-mutant, metastatic NSCLC. Most recently, on March 11, 2021, the FDA granted a fast track designation to poziotinib for the treatment of patients with previously treated, 

Wade T. Iams, MD, discusses the emergence of TKIs and antibody-drug conjugates in HER2-mutant lung cancer.   



Dr. Iams on Emerging TKIs and ADCs in HER2-Mutant Lung Cancer 

Vanderbilt-Ingram Cancer Center Nashville, TN

Current Standard of Care: Are Outcomes Satisfactory?

Neoadjuvant chemotherapy with or without radiation has become the preferred treatment in patients with resectable stage IIIA non—small cell lung cancer (NSCLC).

 However, results from studies have not shown a similar survival benefit for patients with early-stage (I or II) NSCLC who are candidates for upfront resection.

This may be changing with the introduction of neoadjuvant immunotherapy, as described in the plenary presentation “Immunotherapy Combinations: The New Frontline in Lung Cancer” at the 2018 American Association for Cancer Research meeting and in a study by Forde et al published in the 

Neoadjuvant Nivolumab Improves Major Pathologic Response Rate

The multidisciplinary interest in improving the standard of care for patients with surgically resectable NSCLC stems from higher-than-desired local and systemic recurrence rates after resection1 and low 5-year survival.3 Improvement in outcomes for these patients is a major need.

In their recent publication, Forde et al demonstrated an impressive major pathologic response in 45% (9 of 20) of patients treated with 2 preoperative doses of nivolumab (Opdivo) with no delays in surgical resection.4 Major pathologic response is defined as <10% viable residual tumor at the time of resection. In the study, a major pathologic response was identified in 6 patients with adenocarcinoma, 2 patients with squamous cell carcinoma, and 1 patient with pleomorphic carcinoma. By stage, these were 2 patients with stage I disease, 5 patients with stage II disease, and 2 patients with stage IIIA disease.

Does Major Pathologic Response Really Matter?

Interestingly, of the 9 patients with a major pathologic response, only 2 had a partial response on preoperative imaging, which calls into question the reliability of imaging as a marker for pathologic response to neoadjuvant nivolumab.

Many studies use “major pathologic response” as a surrogate endpoint. But is this clinically meaningful?

Although this endpoint has not been fully evaluated in the context of neoadjuvant immunotherapy, it has been well defined for neoadjuvant chemotherapy administered to patients with resectable NSCLC.

 Results from neoadjuvant chemotherapy clinical trials with populations analogous to those in the pilot trial by Forde et al have shown that rates of major pathologic response correlate strongly with overall survival (OS).

 This finding is not unique to NSCLC, as rates of pathologic response correlate with OS in other malignancies, such as neoadjuvant chemotherapy in patients with breast cancer.

Putting the pilot trial results in the context of resectable cancer, major pathologic response seems to be establishing itself as a good surrogate and predictor of survival in patients with NSCLC.

Most studies evaluating the efficacy of neoadjuvant chemotherapy in patients with resectable NSCLC reported a pathologic complete response rate of 0% to 20%,

 with the highest reported response rate in the literature being 27% (in 11 of 41 patients) after 3 doses of neoadjuvant bevacizumab.

In the historical context of neoadjuvant chemotherapy, the major pathologic response rate of 45% achieved by Forde et al is impressive.

Who Benefits Most From Neoadjuvant Immunotherapy?

But many questions remain: Will this continue to be well tolerated? Will it remain as effective in larger groups of patients? Will neoadjuvant nivolumab decrease recurrence rates, and will it decrease the efficacy of immunotherapy in the relapse setting? Will it translate to improved long-term survival?

Although 45% of patients had a major pathologic response, the majority did not. Can response to neoadjuvant immunotherapy be predicted? Forde et al found that there was a positive correlation between pretreatment tumor mutational burden (TMB) and major pathologic response to nivolumab. In addition, TMB performed better than tumor PD-L1 expression as a predictive biomarker in this setting.

 If adjuvant therapy options being studied in patients with resectable NSCLC succeed, initial biopsy TMB may help determine the ideal perioperative timing (preoperative vs postoperative vs both) for immunotherapy treatment.

Biomarkers predictive of treatment efficacy are an essential companion to new therapies; equally important is predicting which patients are likely to suffer adverse events. In this small pilot study, there were few adverse events—the only grade >2 adverse event was 1 instance of grade 3 pneumonia.

The long-term sequelae of patients receiving neoadjuvant immunotherapy are unknown, and although patients who achieve a major pathologic response are likely to fare better than those in historical controls, the prognosis of patients who did not respond to neoadjuvant immunotherapy is not defined.

Does the FDA consider major pathologic response a valid surrogate endpoint? The FDA defines an acceptable surrogate endpoint as one that is “reasonably likely to predict clinical benefit.”

 In the context of neoadjuvant systemic therapy for resectable cancer, pertuzumab (Perjeta) in HER2-positive breast cancer provided a precedent. In 2013, pertuzumab was granted accelerated FDA approval as neoadjuvant therapy in patients with HER2-amplified breast cancer based on pathologic response and the documented correlation between pathologic response and OS in patients with breast cancer.

 This precedent suggests that there is a promising regulatory future for neoadjuvant immunotherapy in patients with resectable NSCLC based on improvements in major pathologic response rates. Whether nivolumab will be the first agent approved in this setting remains unsettled.

Nivolumab monotherapy is not the only immune checkpoint inhibitor being applied in the neoadjuvant setting in patients with resectable NSCLC. Both atezolizumab (Tecentriq) (LCMC3; NCT02927301) and combination nivolumab and ipilimumab (Yervoy) (CheckMate 816; NCT02998528) are in clinical trials as neoadjuvant therapy in patients with resectable NSCLC. The phase II atezolizumab trial began in April 2017, and it will also evaluate TMB as a predictor of response to neoadjuvant immunotherapy. The phase III CheckMate 816 trial started in January 2017 and will enroll 642 patients from North America, South America, Europe, and Asia. Neither of these trials has reported results, but it will be important to compare both efficacy and toxicity among the various emerging neoadjuvant immunotherapy treatment strategies.

The field of neoadjuvant systemic therapy in patients with resectable NSCLC has received a breath of hope for improvement with the publication of the initial data in patients treated with 2 doses of neoadjuvant nivolumab.4 These results will need to be validated in a larger cohort of patients with special attention to perioperative toxicity profiles.

Head-to-head trials comparing neoadjuvant chemotherapy, immunotherapy, and combination chemotherapy plus immunotherapy will be essential in helping to establish neoadjuvant treatment protocols. Despite the research that still needs to be done, the future looks promising for neoadjuvant immunotherapy.

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Articles

Wade T. Iams, MD, and Erin A. Gillaspie, MD, MPH, discuss the impact that immunotherapy has had on the treatment of patients with early-stage non–small cell lung cancer.

Wade T. Iams, MD