New immunotherapy options lead to a paradigm shift in the treatment of NSCLC


This change came in the form of immunotherapy, which has since seen significant progress – mainly over the past decade, Herbst, professor of medicine, professor of pharmacology, director of the Center for Thoracic Cancers and chief of medical oncology at the Yale Cancer Center. and Smilow Cancer Hospital, noted during a presentation at the 3rd annual Precision Medicine Symposium: An Illustrated Tumor Board, a program developed by Physicians’ Education Resource® LLC.

One of the first studies to demonstrate this was the phase 1 trial CA209-003 (NCT00730639), which looked at 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

“It’s amazing,” Herbst said. “It’s only 16% of patients, but it really shows that we are probably 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, problems persist with the biomarker, such as heterogeneity, interval between biopsy and treatment, differences between primary disease and metastatic disease, and antibody and staining conditions.4

In addition, the definition of a positive PD-L1 result depends on the type of cell expressing the marker (immune vs tumor), the place of expression (cell surface vs intracellular vs stromal), the intensity or the percentage of cells. positive and distribution.

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

This was indicated in the Phase 2/3 KEYNOTE-010 trial (NCT01905657), which examined pembrolizumab (Keytruda) versus docetaxel in previously treated patients with advanced PD-L1 positive NSCLC. Patients in the trial were required to have a PD-L1 Tumor Proportion (TPS) score of at least 1%. Results showed that among patients with PD-L1 TPS of 50% or greater, the median OS was 16.9 months (95% CI, 12.3-21.4) with pembrolizumab versus 8.2 months (95% CI, 6.4-9.8) with docetaxel. In patients with PD-L1 TPS of 1% or greater, the median OS in the investigation 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 PD-L1 TPS of 50% or greater 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 PD-L1 TPS of 1% or greater.

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

The OS rate at 3 years after the end of 35 cycles of pembrolizumab treatment was 83.0%, and 15.6% of patients with PD-L1 TPS of 1% or greater were alive at approximately 5 years later. randomization, which was similar to what had been seen with nivolumab, Herbst noted.

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

Move immunotherapy to the first-line setting

Immunotherapy has shifted from second-line to first-line with the launch of the Phase 3 KEYNOTE-024 (NCT02142738) trial, which examined pembrolizumab versus platinum doublet chemotherapy in patients who were naive to treatment with metastatic NSCLC. Patients included in this trial had to have a PD-L1 TPS of 50% or more and an ECOG performance index of 0 or 1. They could not have activation. EGFR mutations or ALK translocations, untreated brain metastases or active autoimmune disease requiring systemic treatment.

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

The results showed that the median OS at 5 years was 26.3 months (95% CI, 18.3-40.4) with pembrolizumab vs 13.4 months (95% CI, 9.4-18 , 3) with chemotherapy (RR: 0.62; 95% CI: 0.48-0.81) .6 In addition, the median 3-year PFS with pembrolizumab was 7.7 months (95% CI %, 6.1-10.2) versus 5.5 months (95% CI, 4.2-6.2) with chemotherapy (RR: 0.50; 95% CI: 0.39-0, 65), and the ORRs were 46.1% versus 31.1%, respectively.

“The operating system 3 years from the end [of treatment] was 81.4% and the ORR was 82.1%, ”Herbst noted. “[The CR rate was] 10.3%, the RP rate was 71.8% and there was a more stable disease that lasted a long time.7

Other trials looking at immunotherapy in this setting include the phase 3 IMpower110 trial (NCT02409342) which compared aezolizumab (Tecentriq) to chemotherapy in patients with stage IV non-squamous or squamous NSCLC, and ‘EMPOWER-Lung1 phase 3 trial (NCT03088540) which compared cemiplimab (Libtayo) with chemotherapy in patients with metastatic NSCLC.

The results of IMpower110 demonstrated that aezolizumab (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).

In addition, the median OS for aitzolizumab was 20.2 months (95% CI: 16.5 – not evaluable [NE]) vs. 13.1 months (95% CI, 7.4 to 16.5) with chemotherapy (RR: 0.59; 95% CI, 0.40 to 0.89; P = .0106). The results of an updated exploratory analysis showed a median OS of 20.2 months (95% CI, 17.2-27.9) versus 14.7 months (95% CI, 7.4-17 , 7), respectively (HR, 0.76; 95% CI, 0.54-1.09).8,9.11

EMPOWER-Lung1 data demonstrated that cemiplimab caused an ORR of 39.2% (95% CI, 33.5% to 45.2%) versus 20.4% (95% CI, 15, 8% to 25.6%) with chemotherapy in the population of patients with MP-L1 of 50% or more (n = 563). The median PFS was 8.2 months (95% CI, 6.1 to 8.8) with cemiplimab versus 5.7 months (95% CI, 4.5 to 6.2) with chemotherapy (RR : 0.54; 95% CI: 0.43 to 0.68; P <.0001 in addition median os with cemiplimab was not achieved ci: ne compared to months chemotherapy>P = .0002).ten

The current first-line treatment algorithm

For patients with advanced NSCLC without targetable motor mutations, the current first-line treatment landscape includes 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 greater than 50%: pembrolizumab; pembrolizumab plus chemotherapy; aezolizumab; nivolumab plus ipilimumab; nivolumab / ipilimumab plus chemotherapy; and cemiplimab.
  • Non-squamous cell, PD-L1 expression less than 1%: pembrolizumab plus chemotherapy; atezolizumab plus chemotherapy with or without bevacizumab (Avastin); and nivolumab / ipilimumab plus chemotherapy.
  • Non-squamous 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.
  • Non-squamous cell, PD-L1 expression greater than 50%: pembrolizumab; pembrolizumab plus chemotherapy; atezolizumab plus chemotherapy with or without bevacizumab; aezolizumab; nivolumab plus ipilimumab; nivolumab / ipilimumab plus chemotherapy; and cemiplimab.

“There are a lot of options,” Herbst said. “Yes [a patient doesn’t] have a driver [mutation, they are] will receive immunotherapy unless [they] have some kind of autoimmune process.

The references

  1. Herbst RS. First-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 English 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 study CA209-003. 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 DW et al. Updated five-year survival of KEYNOTE-010: pembrolizumab versus docetaxel for previously treated advanced programmed death-Ligand 1 positive 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 OS update at 5 years: first-line pembrolizumab (pembro) (1L) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and proportion score tumor (TPS) PD-L1 ≥ 50%. Anne Oncol. 2020; 31 (4): S1142-S1215. doi: 10.1016 / advert / advert325
  7. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Five-year outcome with pembrolizumab versus chemotherapy for metastatic non-small cell lung cancer with a 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. Arezolizumab for the first-line treatment of selected PD-L1 patients with NSCLC. N English J Med. 2020; 383 (14): 1328-1339. doi: 10.1056 / NEJMoa1917346
  9. Spigel D, de Marinis F, Giaccone G, et al. IMpower110: Interim analysis of overall survival (OS) of a phase III study comparing atezolizumab (atezo) to platinum-based chemotherapy (chemo) as first-line treatment (1L) (tx) in NSCLC selected PD-L1. Anne Oncol. 2019; 30 (5): V915. doi: 10.1093 / advert / mdz293
  10. Sezer A, Kilickap S, Gümüs M, et al. Cemiplimab as monotherapy for the first-line treatment of advanced non-small cell lung cancer with at least 50% PD-L1: a multicenter, open-label, global, phase 3, randomized, 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 naïve programmed death NSCLC with selected ligand 1. J Thorac Oncol. Published online July 12, 2021. doi: 10.1016 / j.jtho.2021.06.019

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