Novel Immunotherapy Options Prompt Paradigm Shift in NSCLC Treatment

Roy Herbst, MD, PhD

Just over 20 years ago, the prognosis for patients with non­–small cell lung cancer (NSCLC) was dismal. Chemotherapy regimens were the only options available, and although they did improve survival for patients, all doublets demonstrated similar efficacy, no predictive factors had been identified for response, and there was significant associated toxicity. With 1-year survival rates of 33%, and a median survival of just 7.9 months, it was clear that a paradigm shift was needed, according to Roy Herbst, MD, PhD.^1,2

This shift came in the form of immunotherapy, which has since seen significant progress—mostly in the past decade, Herbst, the Ensign Professor of Medicine, professor of Pharmacology, director of Center for Thoracic Cancers, and chief of Medical Oncology at Yale Cancer Center and Smilow Cancer Hospital, noted during a presentation during the 3rd Annual Precision Medicine Symposium: An Illustrated Tumor Board, a program developed by Physicians’ Education Resource® LLC.

One of the first studies to showcase this was the phase 1 CA209-003 trial (NCT00730639), which examined nivolumab (Opdivo) in patients with previously treated, advanced NSCLC. The median overall survival for those treated with the agent was 9.9 months (95% CI, 7.8-12.4), and the 5-year OS rate was 16%.³

“This is incredible,” Herbst said. “It is only 16% of patients, but it really does speak to the fact that we probably are curing lung cancer.”

What is the Best Biomarker?

PD-L1 remains an important biomarker in this patient population, due to its high positive predictive value. However, issue still exist with the biomarker, such as heterogeneity, the interval between biopsy and treatment, differences in primary vs metastatic disease, and antibody and staining conditions.⁴

Additionally, defining a positive PD-L1 result depends on the cell type expressing the marker (immune vs tumor), the location of expression (cell surface vs intracellular vs stromal), the intensity or percent of positive cells, and the distribution.

“PD-L1 is a good marker, but it’s a difficult marker due to heterogeneity, [as well as] different ways of measuring and scoring it,” Herbst said. “But it certainly can be useful.”

This was indicated in the phase 2/3 KEYNOTE-010 trial (NCT01905657), which examined pembrolizumab (Keytruda) vs docetaxel in previously treated, patients with PD-L1–positive, advanced NSCLC. Patients on the trial were required to have a PD-L1 tumor proportion score (TPS) of at least 1%. Results showed that among patients with a PD-L1 TPS of 50% or higher, the median OS was 16.9 months (95% CI, 12.3-21.4) with pembrolizumab vs 8.2 months (95% CI, 6.4-9.8) with docetaxel. In patients with a PD-L1 TPS of 1% or higher, the median OS in the investigative and control arms was 11.8 months (95% CI, 10.4-13.1) vs 8.4 months (95% CI, 7.6-9.5), respectively.⁵

In terms of progression-free survival (PFS), those who received pembrolizumab who had a PD-L1 TPS of 50% or higher had a median PFS of 5.3 months (95% CI, 4.2-6.5) vs 4.0 months (95% CI, 3.1-4.1) in those with a PD-L1 TPS of 1% or higher.

The objective response rate (ORR) achieved with pembrolizumab was also higher among patients with the higher PD-L1 TPS, at 33.1% (95% CI, 27.7%-38.8%) vs 21.1% (95% CI, 18.2%-24.4%) in those with a PD-L1 TPS of 1% or higher. Both groups had a median duration of response (DOR) of 68.4 months.

The 3-year OS rate from completion of 35 cycles of treatment with pembrolizumab was 83.0%, and 15.6% of patients with a PD-L1 TPS of 1% or higher were alive at approximately 5 years from randomization, which was similar to what had been observed with nivolumab, Herbst noted.

“[Additionally, among 21 patients who progressed], 11 of them had a response when retreated with pembrolizumab,” Herbst says. “[There was also] 1 complete response [CR], 10 partial responses [PRs], and 6 [patients] with stable disease. All but 3 patients had some benefit, so there was still some gas in the tank to use immunotherapy, which is something to think about for the future.”

Moving Immunotherapy to the First-Line Setting

Immunotherapy moved from the second-line setting to the frontline with the launch of the phase 3 KEYNOTE-024 trial (NCT02142738), which examined pembrolizumab vs platinum doublet chemotherapy in treatment naïve patients with metastatic NSCLC. Patients enrolled on this trial were required to have a PD-L1 TPS of 50% or higher and an ECOG performance status of 0 or 1. They could not have activating EGFR mutations or ALK translocations, untreated brain metastases, or active autoimmune disease requiring systemic therapy.

Study participants were randomized 1:1 to receive either pembrolizumab at 200 mg every 3 weeks for 35 cycles or platinum doublet chemotherapy for 4 to 6 cycles. Those on the investigative arm went on to receive a second course of pembrolizumab at 200 mg every 3 weeks for 17 cycles. Those on the control arm who experienced progressive disease crossed over to pembrolizumab, which they received at 200 mg every 3 weeks for 2 years.

Results showed that the 5-year median OS was 26.3 months (95% CI, 18.3-40.4) with pembrolizumab vs 13.4 months (95% CI, 9.4-18.3) with chemotherapy (HR, 0.62; 95% CI, 0.48-0.81).6 Additionally, the 3-year median PFS with pembrolizumab was 7.7 months (95% CI, 6.1-10.2) vs 5.5 months (95% CI, 4.2-6.2) with chemotherapy (HR, 0.50; 95% CI, 0.39-0.65), and the ORRs were 46.1% vs 31.1%, respectively.

“The 3-year OS from completion [of treatment] was 81.4%, and the ORR was 82.1%,” Herbst noted. “[The CR rate was] 10.3%, the PR rate was 71.8%, and there was more stable disease that lasted for a long period of time.”⁷

Other trials examining immunotherapy in this setting include the phase 3 IMpower110 trial (NCT02409342) that compared atezolizumab (Tecentriq) with chemotherapy in patients with stage IV nonsquamous or squamous NSCLC, and the phase 3 EMPOWER-Lung1 trial (NCT03088540) that compared cemiplimab (Libtayo) with chemotherapy in patients with metastatic NSCLC.

Results from IMpower110 demonstrated that atezolizumab (n = 107) induced an ORR of 38.3% vs 28.6% with chemotherapy (n = 98), and a median PFS of 8.1 months (95% CI, 6.8-11.0) vs 5.0 months (95% CI, 4.2-5.7), respectively (HR, 0.63; 95% CI, 0.45-0.88; P = .007).

Moreover, the median OS for atezolizumab was 20.2 months (95% CI, 16.5–not evaluable [NE]) vs 13.1 months (95% CI, 7.4-16.5) with chemotherapy (HR, 0.59; 95% CI, 0.40-0.89; P = .0106). Results from an updated exploratory analysis showed a median OS of 20.2 months (95% CI, 17.2-27.9) vs 14.7 months (95% CI, 7.4-17.7), respectively (HR, 0.76; 95% CI, 0.54-1.09).^8,9,11

Data from EMPOWER-Lung1 demonstrated that cemiplimab elicited an ORR of 39.2% (95% CI, 33.5%-45.2%) vs 20.4% (95% CI, 15.8%-25.6%) with chemotherapy in the population of patients with a PD-L1 of 50% or higher (n = 563). The median PFS was 8.2 months (95% CI, 6.1-8.8) with cemiplimab vs 5.7 months (95% CI, 4.5-6.2) with chemotherapy (HR, 0.54; 95% CI, 0.43-0.68; P < .0001). Moreover, the median OS with cemiplimab was not reached (95% CI, 17.9–NE) compared with 14.2 months (95% CI, 11.2-17.5) with chemotherapy (HR, 0.57; 95% CI, 0.42-0.77; P = .0002).¹⁰

The Current Frontline Treatment Algorithm

For patients with advanced NSCLC without targetable driver mutations, the current frontline treatment landscape consists of the following:¹¹

• Squamous cell, PD-L1 expression less than 1%: pembrolizumab plus chemotherapy; nivolumab/ipilimumab (Yervoy) plus chemotherapy.
• Squamous cell, PD-L1 expression 1% to 49%: pembrolizumab; pembrolizumab plus chemotherapy; nivolumab plus ipilimumab; and nivolumab/ipilimumab plus chemotherapy.
• Squamous cell, PD-L1 expression more than 50%: pembrolizumab; pembrolizumab plus chemotherapy; atezolizumab; nivolumab plus ipilimumab; nivolumab/ipilimumab plus chemotherapy; and cemiplimab.
• Nonsquamous cell, PD-L1 expression less than 1%: pembrolizumab plus chemotherapy; atezolizumab plus chemotherapy with or without bevacizumab (Avastin); and nivolumab/ipilimumab plus chemotherapy.
• Nonsquamous cell, PD-L1 expression 1% to 49%: pembrolizumab; pembrolizumab plus chemotherapy; atezolizumab plus chemotherapy with or without bevacizumab; nivolumab plus ipilimumab; and nivolumab/ipilimumab plus chemotherapy.
• Nonsquamous cell, PD-L1 expression more than 50%: pembrolizumab; pembrolizumab plus chemotherapy; atezolizumab plus chemotherapy with or without bevacizumab; atezolizumab; nivolumab plus ipilimumab; nivolumab/ipilimumab plus chemotherapy; and cemiplimab.

“There are many options,” Herbst said. “If [a patient doesn’t] have a driver [mutation, they are] going to get immunotherapy unless [they] have some sort of autoimmune process.”

References

1. Herbst RS. Front Line Immunotherapy for NSCLC. Presented at: 3rd Annual Precision Medicine Symposium; September 17-18, 2021.
2. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non–small-cell lung cancer. N Engl J Med. 2002;346(2):92-98. doi:10.1056/NEJMoa011954
3. Gettinger S, Horn L, Jackman D, et al. Five-year follow-up of nivolumab in previously treated advanced non–small-cell lung cancer: results from the CA209-003 study. J Clin Oncol. 2018;36(17):1675-1684. doi:10.1200/JCO.2017.77.0412
4. McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non–small-cell lung cancer. JAMA Oncol. 2016;2(1):46-54. doi:10.1001/jamaoncol.2015.3638
5. Herbst RS, Garon EB, Kim D-W, et al. Five year survival update from KEYNOTE-010: pembrolizumab versus docetaxel for previously treated, Programmed Death-Ligand 1–positive advanced NSCLC. J Thorac Oncol. Published online May 25, 2021. doi:10.1016/j.jtho.2021.05.001
6. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. LBA51 - KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol. 2020;31(4):S1142-S1215. doi:10.1016/annonc/annonc325
7. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non–small-cell lung cancer with PD-L1 tumor proportion score ≥ 50%. J Clin Oncol. 2021.39(21):2339-2349. doi:10.1200/JCO.21.00174
8. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1–selected patients with NSCLC. N Engl J Med. 2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346
9. Spigel D, de Marinis F, Giaccone G, et al. IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC. Ann Oncol. 2019;30(5):V915. doi:10.1093/annonc/mdz293
10. Sezer A, Kilickap S, Gümüs M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021;379(10274):592-604. doi:10.1016/S0140-6736(21)00228-2
11. Jassem J, de Marinis F, Giaccone G, et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1–selected NSCLC. J Thorac Oncol. Published online July 12, 2021. doi:10.1016/j.jtho.2021.06.019