Early-Stage Lung Cancer: An Overview of the Clinical Trial Landscape
Although early-stage, resectable disease represents the best chance for meaningful long-term survival and cure for patients with lung cancer, there are still high rates of recurrence. According to Rajwanth Veluswamy, MD, MSCR, neoadjuvant and adjuvant treatments are needed to improve surgical outcomes in selected patients.
During the Quantitative Imaging Workshop XVII, Dr. Veluswamy, Assistant Professor of Medicine at the Tisch Cancer Institute, Mount Sinai, New York, provided an overview of current clinical trials in early-stage lung cancer and described the advantages and disadvantages of current neoadjuvant approaches.1
Even with complete resection, the 5-year survival rate for patients with small tumors is approximately 90%, and survival decreases significantly in those with larger tumors and with involvement of lymph nodes, said Dr. Veluswamy. He noted that the majority of recurrence is distant and provides rationale for adding systemic treatment with surgery to improve outcomes. Potential reasons for recurrence include occult micrometastatic disease and tumor seeding during surgery.
Rajwanth Veluswamy, MD, MSCR
Role of Adjuvant Chemotherapy
The majority of prior studies have focused on the use of adjuvant chemotherapies to reduce the risk of recurrence. Multiple phase III randomized controlled trials conducted in the 2000s demonstrated a benefit with cisplatin-based regimens for stage II and III cancers and a subgroup of stage IB disease.
The LACE meta-analysis combined individual patient data from five of the largest trials and included 4,584 patients with completely resected, non–small cell lung cancer (NSCLC).2 As Dr. Veluswamy reported, adjuvant chemotherapy was associated with a decreased risk of death of 5.4% at 5 years, which represents a number needed to treat of approximately 20.
The survival benefit varied by stage, however, with most of the benefit coming from those with stage II and III disease. “Adjuvant chemotherapy appeared to be detrimental for patients with stage IA disease. Stage IB disease has always been controversial, with a nonsignificant benefit observed in this group,” he said. The CALGB 9633 trial specifically enrolled patients with stage IB disease and found improved survival with adjuvant chemotherapy for a subset of patients with ≥ 4 cm tumors (hazard ratio [HR] = 0.69).3 Therefore, the standard of care is to consider adjuvant platinum-based chemotherapy for all tumors 4 cm or larger.
Neoadjuvant vs Adjuvant Treatment
The question of whether systemic treatment should be given prior to or after resection has been addressed by several phase III randomized controlled trials; they demonstrated no significant difference in survival outcomes between neoadjuvant and adjuvant approaches for chemotherapy. Across these studies, however, significantly more patients completed the planned chemotherapy in the neoadjuvant vs adjuvant groups (90% vs 60%), said Dr. Veluswamy. He suggests the lower rates of adjuvant chemotherapy compliance may be attributed to the potentially significant recovery period after surgery.4
In addition to better treatment compliance, Dr. Veluswamy noted several other advantages to neoadjuvant approaches. They include potential prevention or early treatment of micrometastatic disease, tumor downstaging, and in vivo assessment of treatment sensitivity.
As Dr. Veluswamy explained, however, these advantages need to be balanced with potential disadvantages, especially when designing a future early-phase trial. With neoadjuvant approaches, treatment-related toxicities may delay surgery, and treatment-related changes of the surgical field may complicate resection. The disease may also progress through treatment, and there can be patient anxiety while awaiting surgery.
Novel Adjuvant or Neoadjuvant Treatment Strategies
Adjuvant or neoadjuvant treatment for aggressive early-stage lung cancers has remained largely unchanged until the recent arrival of novel agents. “Immunotherapy and targeted therapies have resulted in unprecedented survival outcomes in the advanced-stage setting, and these agents are generally well tolerated,” said Dr. Valuswamy. “There’s been a lot of interest in moving these novel therapeutics forward in the early-stage lung cancer setting.”
Several important, early-phase, neoadjuvant immunotherapy studies have recently been published regarding the effectiveness of PD-1 or PD-L1 blockade. A pilot study of 20 patients with NSCLC (stage I to III) given two preoperative doses of nivolumab demonstrated a major pathologic response (< 10% viable tumor cells) in 45% of resected tumors.5 Responses occurred irrespective of PD-L1 expression, said Dr. Valuswamy, and there was some correlation with pretreatment tumor mutation burden.
A phase II trial of patients with stage IB to IIIA NSCLC who received neoadjuvant atezolizumab plus carboplatin and nab-paclitaxel showed a major pathologic response in 17 of 30 patients, with a median follow-up of 12.9 months.6 Treatment-related toxicity was manageable and did not compromise surgical resection, the study authors noted.
Finally, an open-label, phase II study conducted in 18 hospitals in Spain demonstrated a progression-free survival rate of 77.1% at 2 years in patients with resectable stage IIIA NSCLC receiving neoadjuvant chemotherapy and nivolumab.7
“Longer follow-up is going to be needed, but in the NADIM trial a major pathologic response in 83% of patients was striking, and 59% of patients had no viable tumor cells on resected tissue,” said Dr. Veluswamy.
There are also several adjuvant immunotherapy trials currently underway in NSCLC, but no data have yet been reported.
“There’s been a lot of interest in moving these novel therapeutics [immunotherapy and targeted therapies] forward in the early-stage lung cancer setting.”— Rajwanth Veluswamy, MD, MSCR
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Molecular Targeted Trials: EGFR Tyrosine Kinase Inhibitors
With respect to targeted approaches, the focus has been on EGFR, which is the most common driver mutation with a targeted treatment approved by the U.S. Food and Drug Administration. Five prospective clinical trials are evaluating EGFR tyrosine kinase inhibitors with adjuvant treatment, Dr. Veluswamy reported.
The BR19 trial showed no improved disease-free or overall survival with adjuvant gefitinib vs placebo in unselected patients whose EGFR mutation status was not known.8
The RADIANT trial showed no disease-free survival benefit with adjuvant erlotinib vs placebo in NSCLC patients with EGFR-protein expression by immunohistochemistry or EGFR-amplification by fluorescence in situ hybridization.9 In the post hoc analysis of the 16.5% of the cohort with known EGFR mutation status, a disease-free survival benefit was observed with adjuvant tyrosine kinase inhibitor therapy.
The SELECT trial was the first study to test the efficacy of adjuvant erlotinib in patients with EGFR-mutated NSCLC (stage IA to IIIA) after completion of standard adjuvant treatment.10 The disease-free survival was 90% at 2 years, and the median has not yet been reached. Although there was no comparison arm, survival rates are obviously better than those seen in historical data with nontargeted approaches, said Dr. Veluswamy.
The Chinese CTOG 1104 trial was the first phase III randomized controlled trial of adjuvant gefitinib vs vinorelbine plus cisplatin in patients with EGFR-mutated NSCLC (stage II to IIIA).11 Results showed significantly longer disease-free survival (~10 months) with targeted therapy vs chemotherapy in the adjuvant setting, with fewer adverse events. However, updated data showed no overall survival benefit.
“We may just be kicking the can down the road by simply delaying recurrence, but that may be okay,” said Dr. Veluswamy. “There could be significant quality-of-life benefits with adjuvant tyrosine kinase inhibitors.”
The recently published ADAURA trial showed significantly longer disease-free survival in patients with stage IB to IIIA EGFR mutation–positive NSCLC who received osimertinib vs placebo (HR = 0.21).12 The disease-free survival benefit was consistent across all subgroups analyzed, and notably there was a significant reduction in central nervous system recurrence in the osimertinib-treated group. Although overall survival has not yet been reported, Dr. Veluswamy noted this disease-free survival benefit should carry over to overall survival.
“Chemotherapy still has a role in the surgical management of NSCLC, but it appears to be in synergy with these novel agents,” he concluded. “We also need novel biomarkers to predict disease recurrence after surgery, so we can identify the patients who will derive the most benefit from these novel approaches.”
DISCLOSURE: Dr. Veluswamy has served as a consultant or advisor to AstraZeneca, Beigene, Bristol Myers Squibb, Merck, and Onconova Therapeutics; has participated in an unbranded speakers bureau for AstraZeneca; has received institutional research funding from Bristol Myers Squibb and Onconova Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by Bristol Myers Squibb.
1. Veluswamy R: Overview of current clinical trials for early-stage lung cancer. Quantitative Imaging Workshop XVII. Session 6. Presented October 30, 2020.
2. Pignon JP, Tribodet H, Scagliotti GV, et al: Lung adjuvant cisplatin evaluation. J Clin Oncol 26:3552-3559, 2008.
3. Strauss GM, Herndon JE 2nd, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB NSCLC. J Clin Oncol 26:5043-5051, 2008.
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9. Kelly K, Altorki NK, Eberhardt WEE, et al: Adjuvant erlotinib versus placebo in patients with stage IB-IIIA NSCLC. J Clin Oncol 33:4007-4014, 2015.
10. Pennell NA, et al: A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant NSCLC. J Clin Oncol 37:97-104, 2019.
11. Xu ST, Xi JJ, Zhong WZ, et al: The unique spatial-temporal treatment failure patterns of adjuvant gefitinib therapy). J Thorac Oncol 14:503-512, 2019.
12. Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.