Expert Discusses Benefits of Preoperative Therapy for NSCLC

Jamie E. Chaft, MD

Noeadjuvant therapy for lung cancer provides significant benefits compared with adjuvant therapy, according to Jamie E. Chaft, MD. In a presentation at the 14th AnnualNew York Lung Cancers Symposium^®, Chaft explained why neoadjuvant therapy is beneficial even though adjuvant therapy is still the standard of care at a number of cancer centers.¹

Preoperative treatment allows for earlier treatment of micrometastatic disease, reductions in surgical risk, improved tolerability and compliance with therapy, and also affords opportunities for use of surrogate endpoints and to study adaptive adjuvant therapy in nonresponders, said Chaft, who is an associate attending physician at Memorial Sloan Kettering Cancer Center.

Chaft said there is powerful logic for addressing cancer earlier in development, when tumor size is smaller and the prognosis is better. At stage IA3, a resected non—small cell lung cancer (NSCLC) tumor the size of a quarter has a roughly 20% recurrence-mortality rate at 5 years; at stage IIA, a tumor the size of a golf ball has a recurrence-mortality rate of around 35% at 5 years. With lymph node involvement, mortality increases to 40% to 75% at 5 years, “and that’s just not acceptable. We need to do better,” Chaft said.

In a meta-analysis of preoperative chemotherapy, including cisplatin and carboplatin, for patients with resectable NSCLC, investigators observed a 13% reduction in the relative risk of death (HR, 0.87; 95% CI, 0.78-0.96;P= .007), she noted. The analysis included 15 trials (n = 2385) and no evidence of difference was seen between trials (P= 0.18).²

The analysis demonstrated that preoperative chemotherapy in resectable NSCLC was a viable option for many of the patients, stage IB to IIIA, enrolled in these trials. Overall survival (OS), time to distant recurrence, and recurrence-free survival in resectable NSCLC were each significantly improved. “We clearly see the efficacy of cisplatin-based chemotherapy either preoperatively or postoperatively,” Chaft said.

She also noted a study of metastatic breast cancers in mice that she said demonstrated greater power of neoadjuvant versus adjuvant immunotherapies to eradicate distant metastases following primary resection. The combination of anti—PD-1 and CD137-directed antibodies improved survival when given preoperatively but not postoperatively. “I haven’t seen anything more compelling,” Chaft said. Authors of the study noted elevated and sustained peripheral tumor-specific immune responses, and speculated that blood sampling of tumor-specific CD8-positive T cells immediately before and after surgery may help to predict outcomes.³

In the phase II NADIM trial, neoadjuvant chemoimmunotherapy with nivolumab (Opdivo) induced an 83% rate of pathologic response in patients (n = 34) with stage IIIA NSCLC, and the complete response rate was 59% (n = 24).^1,4“I think this is truly a game changer,” Chaft commented. Progression-free survival (PFS) was 81% at 18 months in the intent-to-treat population.

By comparison, PFS in the PACIFIC trial was 52%, she noted, in which patients with locally advanced, unresectable NSCLC received durvalumab (Imfinzi) after ≥2 cycles of platinum chemotherapy.¹

In the NATCH trial, chemotherapy before surgery for early-stage NSCLC led to moderately higher survival rates than surgery alone, but the findings were not statistically significant.⁵

Chemotherapy before surgery for early-stage NSCLC led to moderately higher survival rates than surgery alone, but not enough to reach statistical significance. However, 90% of patients completed 3 cycles of preoperative paclitaxel and carboplatin.

“Chemotherapy, we know from the NATCH study, is better tolerated preoperatively, there’s greater compliance preoperatively, and we know there is benefit preoperatively versus postoperatively, so if it were me, I’d want my systemic therapy preoperatively rather than postoperatively,” Chaft said.

Although neoadjuvant treatment has potency in NSCLC, the potential for cure rests with surgery, and so “We should not be giving therapies that are likely to interfere with that,” she added. Patient selection is key to success with immunotherapies. “The big push to give immunotherapy to all is well-intentioned, but we have to respect both absolute and relative contraindications for this patient population.”

Low-grade toxicities should be observed but not treated, and all endocrinopathies should be investigated, particularly for thyroid dysfunction or adrenal insufficiency that could be exacerbated by the induction of anesthesia, she advised.

An ongoing trial slated to have practice-changing potential is the EA5142 study (NCT02595944) of nivolumab after surgery and chemotherapy in patients with stage Ib to stage IIIa NSCLC. The study, which Chaft is leading, will evaluate whether adjuvant therapy with nivolumab will result in improved OS and disease-free survival over standard observation following resection and standard adjuvant therapy. The trial just completed accrual and results will slowly read out over the next 7 years, Chaft said. “The practicality of adjuvant versus neoadjuvant with all of these amazing new therapies out there is that it’s going to take a really long time to understand how these drugs work.”

She also discussed the value of surrogate endpoints as substitutes for clinical endpoints, such as pathologic response in the neoadjuvant setting and cell-free DNA in the adjuvant setting.

Although evidence for neoadjuvant therapy is compelling, major international adjuvant anti—PD-1/PD-L1 trials are fully enrolled or enrolling currently. “In the next 3 years, we will have a plethora of data. Does that mean we should stop studying neoadjuvant chemotherapy and immunotherapy? Absolutely not,” given all of the data, neoadjuvant therapy “really is game-changing and probably better,” Chaft concluded.

References

1. Chaft JE. Neoadjuvant or adjuvant. Presented at: 14th Annual New York Lung Cancers Symposium; November 9, 2019; New York, New York.
2. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data.Lancet.2014;383(9928):1561-1571. doi: 10.1016/S0140-6736(13)62159-5.
3. Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.Cancer Discov.2016;6(12):1382-1399. doi: 10.1158/2159-8290.CD-16-0577.
4. Provencio M, Nadal E, Insa A, et al. Phase II Study of Neo-Adjuvant Chemo/ Immunotherapy for Resectable Stages IIIA Non-Small Cell Lung Cancer- Nadim Study-SLCG.J Thorac Oncol.2019;13(105):S320. doi: 10.1016/j.jtho.2018.08.236.
5. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non—small-cell lung cancer.J Clin Oncol.2010;28(19):3138-3145. doi: 10.1200/JCO.2009.27.6204.