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NADIM II IMpower010 CALGB 140503 Yorkshire Enhanced Stop Smoking Study (YESS)

NADIM II validates the addition of nivolumab to neoadjuvant chemotherapy for stage IIIA NSCLC

 

In the initial NADIM (NCT03081689) trial, the addition of nivolumab to neoadjuvant chemotherapy was shown to be highly effective in resectable stage IIIA non-small cell lung cancer (NSCLC).1 These findings were confirmed in the Phase III CheckMate 816 (NCT02998528) trial, demonstrating a higher rate of pathologic complete response (pCR) and event-free survival (EFS) with neoadjuvant chemoimmunotherapy over chemotherapy alone in resectable stage IIIB NSCLC.2 The Phase II NADIM II (NCT03838159) trial is the second prospective randomized trial in this setting, which validates the addition of nivolumab to neoadjuvant chemotherapy as superior to chemotherapy alone in patients with resectable stage IIIA-B NSCLC.3  The results of the NADIM II trial were presented at the IASLC 2022 World Conference on Lung Cancer (WCLC) in Vienna, Austria.

Patients with resectable clinical stage IIIA NSCLC with no known EGFR or ALK alterations were randomized to receive 3 cycles of neoadjuvant chemotherapy alone (n=29), consisting of paclitaxel and carboplatin, or in combination with nivolumab (n=57).

 

Following completion of neoadjuvant treatment, patients underwent surgery. Patients with R0 resection, confirmed by pathological evaluation, recieved adjuvant nivolumab. The primary endpoint of the NADIM II trial was pCR and secondary endpoints included progression-free survival (PFS), overall-survival (OS) and biomarker analysis.2

The median follow-up time was 21.9 months (95%CI: 18.7-23.3). At the time of data cut-off, PFS was 67.3% (95%CI: 55.5-81.6) for patients treated with nivolumab in combination with chemotherapy, compared to 52.6% (95%CI: 36.8-75.2) for patients treated with chemotherapy alone (HR, 0.56; 95%CI: 0.28-1.15; P= 0.117). The rate of OS at 24 months for patients treated with nivolumab plus chemotherapy was 85.3% (95%CI: 75.7-96.1) versus 64.8% (95%CI: 47.4-86.4) with chemotherapy alone (HR, 0.37; 95%CI, 0.14-0.93; P=0.003).4

Patients who were treated with neoadjuvant chemoimmunotherapy with a higher PD-L1 expression, based on tumor proportion score (TPS) ≥ 1%, were more likely to achieve pCR. pCR rate was 36.2% in the combination arm versus 6.8% in the chemotherapy arm (P=0.007). None of the patients showing a pCR has progressed or deceased (P LogRank <0.001 and P LogRank= 0.013 for PFS and OS, respectively). The safety profile was tolerable, and most toxicities were manageable with dose reduction or interruption, with a moderate increase in grade 3–4 adverse events with the addition of nivolumab.

Conclusively, the NADIM II trial supports the efficacy of adding nivolumab to neoadjuvant chemotherapy in patients with resectable stage IIIA NSCLC, confirmed by a significantly higher pCR with no impediment to the feasibility of surgery. Following the results of this trial, it is likely neoadjuvant chemoimmunotherapy will become the new standard of care for this patient population.

IMpower010: OS trend in favor of adjuvant atezolizumab over best supportive care observed in PD-L1+ resected NSCLC

Previous findings from the Phase III IMpower010 (NCT02486718) trial demonstrated a statistically significant improved disease-free survival (DFS) with atezolizumab compared to best supportive care (BSC) in patients with resected PD-L1 TC ≥1% stage II-IIIA non-small cell lung cancer (NSCLC) following platinum-based chemotherapy.5 The significance boundary for DFS was not crossed in the intent-to-treat population, including stage IB-IIIA NSCLC. Following these results, atezolizumab was approved as adjuvant treatment in patients with PD-L1 tumor cell ≥1% stage II-IIIA NSCLC in the US, China, and other countries; as well as for PD-L1 TC ≥50% stage II-IIIA NSCLC in the EU and other countries.6,7

The Phase III IMpower010 trial was designed to compare atezolizumab with best supportive care in patients with completely resected IB to IIIA NSCLC. Patients had initially received platinum-based chemotherapy and were then randomized 1:1 to receive either atezolizumab for 1 year or best supportive care. The primary endpoint was hierarchically tested disease-free survival (DFS); key secondary endpoints included overall-survival (OS) in the intention-to-treat (ITT) population, DFS in the PD-L1 population and safety outcomes. OS biomarker analysis was additionally performed as part of an experimental endpoint.

The interim-analysis results of OS data of the IMpower010 trial were presented at the IASLC 2022 World Conference on Lung Cancer (WCLC) in Vienna, Austria. Following an additional 13 months of follow-up evaluating OS and safety, an OS trend (OS HR, 0.71 [95% CI: 0.49, 1.03]) in favor of atezolizumab over best supportive care was demonstrated in patients with a PD-L1 expression of tumor proportion score (TPS) 1% or more, but not in all of the intent-to-treat population. Additionally, a clinically meaningful improvement in OS was observed in the PD-L1 TC ≥50%, stage II–IIIA population with atezolizumab.8

Grade 3-4 adverse events occurred in 22% of patients receiving atezolizumab and 11.5% of patients receiving best supportive care, leading to atezolizumab discontinuation in 18.2% of patients. Grade 5 treatment-related adverse events occurred in 0.8% and 0% of patients receiving atezolizumab and best supportive care, respectfully.

Previously, biomarker testing has only been routinely performed for NSCLC in the advanced-stage setting, however, the results of the IMpower010 trial highlight the importance of biomarker testing for early-stage NSCLC, specifically for PD-L1. In this update of IMpower010, a trend towards improved OS with atezolizumab over best supportive care at the first OS interim-analysis was demonstrated in patients with PD-L1-positive stage II-IIIA NSCLC, and no new safety signals were observed with additional follow-up. IMpower010 is set to continue to the final DFS and OS analysis.8

 

 

CALGB 140503 (Alliance): sub-lobar resection new standard of care for early-stage NSCLC

Lobar resection has been the standard of care for the surgical treatment of early node negative (cT1N0) non-small cell lung cancer (NSCLC) since 1995, based on the results of a single randomized trial.9,10 Sub-lobar resection is a less invasive form of resection and associated with a better quality of life, reduced operative risk and better preservation compared to standard lobar resection.11

An increasing amount of evidence indicates sub-lobar resection to produce outcomes just as effective as lobular resection in appropriate patient populations. Additionally, notable advances in clinical staging and imaging modalities with the ability to detect small tumors via CT scans have reestablished an appeal for sub-lobar resection in early-stage NSCLC.12

The Phase III CALGB 140503 (Alliance) (NCT00499330) trial is a multicenter, non-inferiority study designed to determine whether sub-lobar resection is just as effective as a standard lobectomy for the treatment of patients with early non-small cell lung cancer (NSCLC), clinically staged as T1aN0 with tumors no larger than 2cm.

The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS) and difference in pulmonary functions at 6 months postoperatively between arms.13 A total of 697 patients were intraoperatively randomized to receive lobar (n=357) or sub-lobar (segmentectomy or wedge resection at the surgeon’s discretion; n=340) resection. Randomization was stratified by tumor size (1.5-2 cm), smoking status (never, former, current) and histology (squamous, adenocarcinoma, other).

With a median follow-up of 7-years, DFS for sub-lobar resection was noninferior to lobar resection (HR 1.01, 90% CI 0.83-1.24, P=0.0176 for non-inferiority), with a 63.6% and 64.1% 5-year DFS among patients in the sub-lobar versus lobar group, respectively. OS was also comparable between the two arms (HR 0.95, 90% CI 0.75-1.21, P=0.014 for noninferiority), with 95 deaths in the sub-lobar arm and 103 in the lobar arm. Five-year OS was 80.3% and 78.9% in the sub-lobar and lobar arms, respectively.14

The findings from the CALGB 140503 study, together with the recent Phase III JCOG 0802 trial conducted in Japan demonstrating segmentectomy to be noninferior to lobectomy in a similar patient population 15 , and establishes sub-lobar as the new standard of care for patients with early-stage NSCLC.

YESS: personalized smoking cessation study achieves smoking abstinence rate of more than 30%

Low-dose computed tomography (LDCT) screening was approved in the US for lung cancer in 2013, with other nations set to follow suit shortly.16 The vast majority of lung cancer cases are caused by smoking tobacco.17 However, there is no standard of care currently offering smoking cessation within lung cancer screening programs, despite lung cancer screening offering a teachable opportunity. Evidence has highlighted the efficacy of using personalized risk information as part of a smoking cessation intervention. The Yorkshire Enhanced Stop Smoking Study (YESS) was designed to test the efficacy of a personalized approach to smoking cessation on an opt-out basis offered to all eligible smokers who attended a lung health check.18

The YESS study is a double-blind, randomized, controlled trial of an enhanced, personalized smoking cessation support package including a booklet containing CT images of the participants’ own heart and lungs, annotated where appropriate, to highlight emphysema or coronary artery calcification (CAC) with accompanying explanatory text, and scripted behavioral support delivered by a trained smoking cessation practitioner, compared to continued standard best practice.18 The primary outcome was validated carbon monoxide cessation at seven days (self-reported) by point prevalence three months after the lung health assessment event and two months after enrollment in the YESS study. Secondary outcomes include carbon monoxide validated cessation at 4 weeks and 12 months and self-reported control at four weeks, three months, and 12 months after the event.

During the lung health check, 2150 people reported a history of smoking and were offered the opportunity to see a smoking cessation specialist. 1,905 (88.6%) accepted the referral and 1,609 (84.5%) accepted ongoing support. The validated 7-day abstinence rate among those receiving support was 16.5%, measured 4 weeks after the lung health check event (12.4% of all eligible smokers). Of the participants in the lung health check, 1003 smokers participated in the YESS study and 52.5% of these patients were allocated to the intervention group.

The validated 7-day abstinence rates were 33.6% in the intervention group, 30.0% in the control group (unadjusted OR 1.17, 95% CI 0.90-1.54) 3 months after the LHC and 29.2% and 28.6% (unadjusted OR 1.03, 95% CI 0.78-1.36) 12 months after LHC. Subgroup analysis showed significant gender interaction at 3 and 12 months (p=0.002 and p=0.001, respectively), with the intervention being effective in females (3-month abstinence rates in female participants were 33.9% for the intervention vs. 23 .1% in control, unadjusted OR 1.70, 95% CI 1.15–2.53). There was no significant effect of brochure content (presence/absence of emphysema or CAC) on dropout rates.18

The presence of a co-located stop smoking service and offer of an opt-out delivery of behavioral and pharmacological support for quitting smoking was demonstrated to result in a high uptake by people who smoke attending a lung health check. Females were significantly more likely to quit smoking if they received the intervention versus usual care, whereas no significant difference was observed in males, raising the question of whether gender-specific interventions are necessary.18

References

  1. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. The Lancet Oncology. 2020;21(11):1413-1422.
  2. Forde P, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in Lung Cancer. New England Journal of Medicine. 2022;387(6):571-573.
  3. Provencio-Pulla M, Nadal E, Larriba J, et al. Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: Primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial. Journal of Clinical Oncology. 2022;40(16_suppl):8501-8501.
  4. Provencio M, Serna R, Nadal E, et al. Progression-free survival and overall survival in NADIM II study. Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract 1988.
  5. Felip E, Altorki N, Zhou C, Csőszi T, Vynnychenko I, Goloborodko O et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. The Lancet. 2021;398(10308):1344-1357.
  6. FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. U.S. Food and Drug Administration. 2022. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-non-small-cell-lung-cancer
  7. Ltd F. European Commission approves Roche’s Tecentriq as adjuvant treatment for a subset of people with early-stage non-small cell lung cancer. GlobeNewswire News Room. 2022. Available from: https://www.globenewswire.com/news-release/2022/06/09/2459297/0/en/European-Commission-approves-Roche-s-Tecentriq-as-adjuvant-treatment-for-a-subset-of-people-with-early-stage-non-small-cell-lung-cancer.html
  8. Felip E, Altorki N, Vallieres E, et al. IMpower010: overall survival interim analysis of a phase III study of atezolizumab vs best supportive care in resected NSCLC. Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; PL03.09.
  9. Varlotto J, Emmerick I, Voland R, et al. The Incidence of Node-Positive Non-small-Cell Lung Cancer Undergoing Sublobar Resection and the Role of Radiation in Its Management. Frontiers in Oncology. 2020;10.
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  11. Yang F, Sui X, Chen X, Zhang L, Wang X, Wang S et al. Sublobar resection versus lobectomy in Surgical Treatment of Elderly Patients with early-stage non-small cell lung cancer (STEPS): study protocol for a randomized controlled trial. Trials. 2016;17(1).
  12. Altorki N, Yip R, Hanaoka T, Bauer T, Aye R, Kohman L et al. Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules. The Journal of Thoracic and Cardiovascular Surgery. 2014;147(2):754-764.
  13. Altorki N, Wang X, Wigle D, Gu L, Darling G, Ashrafi A et al. Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503). The Lancet Respiratory Medicine. 2018;6(12):915-924.
  14. Wakelee H, Altorki N, Vallieres E, et al. Lobar or Sub-lobar Resection for Peripheral Clinical Stage IA = 2 cm Non-small Cell Lung Cancer (NSCLC): Results From an International Randomized Phase III Trial (CALGB 140503 [Alliance]). Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; PL03.06
  15. Saji H, Okada M, Tsuboi M, et al. Segmentectomy versus lobectomy in small-sized peripheral non-small-cell lung cancer (JCOG0802/WJOG4607L): a multicentre, open-label, phase 3, randomised, controlled, non-inferiority trial. The Lancet. 2022;399(10335):1607-1617.
  16. Moyer V. Screening for Lung Cancer: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. 2014;160(5):330-338.
  17.  Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021;71(3):209-249.
  18. Personalised Smoking Cessation Support in a Lung Cancer Screening Programme: The Yorkshire Enhanced Stop Smoking Study (YESS). Brain K, Britton J, Lewis S, Thorley R. Presented at the 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; PL03.03

Written by Ellie Jackson

The content of VJOncology is intended for healthcare professionals