October 2020 Edition Vol.11, Issue 10

Advances in Lung Cancer Treatment at the ESMO Virtual Congress

By Lynne Lederman, PhD

Two studies at this year’s virtual ESMO Congress addressed poor prognostic factors associated with non-small cell lung cancer (NSCLC): central nervous system (CNS) metastases in epidermal growth factor receptor-mutated (EGFRm) NSCLC, and advanced NSCLC with the KRAS p.G12C mutation.

The use of immune checkpoint inhibitors (ICI) in NSCLC continues to be refined: a study looked at the use of biomarkers to predict response or resistance to anti-PD1/L1 ICI, and two studies presented results of first-line ICI therapy in advanced NSCLC with PD-L1 tumor proportion score (TPS) ≥50%.

ADAURA: Adjuvant Osimertinib in Resected EGFRm NSCLC

Masahiro Tsuboi, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, presented results of ADAURA (LBA1), a phase 3, randomized, double-blind study of osimertinib as adjuvant therapy in resected EGFRm NSCLC.1 The ESMO presentation reported on pre-specified, exploratory endpoints of disease recurrence including CNS disease recurrence. Overall results were published simultaneously.2 Osimertinib is FDA-approved for metastatic NSCLC with specific EGFR mutations as first-line therapy or after progression on or after EGFR-tyrosine kinase inhibitors.3

Preventing CNS recurrence in patients with lung cancer is an unmet need. ADAURA randomly assigned patients with resected stage IB-IIIA EGFRm NSCLC, with or without adjuvant chemotherapy 1:1 to osimertinib 80 mg once-daily (n=339) or placebo (n=343) until recurrence or discontinuation or for up to 3 years of treatment.

Fewer recurrence events were observed in the osimertinib group (11%) versus placebo (46%). Recurrences were more likely to be local/regional in the osimertinib group, with 38% metastatic recurrence versus 61% metastatic recurrence in the placebo arm. In the osimertinib group, 1% (n=6) had CNS recurrence versus 10% (n=39) in the placebo group at a median follow-up 22 months.

Median CNS disease-free survival (DFS) was not reached with osimertinib versus 48.2 months with placebo (HR 0.18; 95% CI 0.10-0.33; P<.0001). The estimated probability of observing CNS recurrence (in the absence of non-CNS recurrence or death) at 18 months was <1% (95% CI 0.2%-2.5%) with osimertinib versus 9% (95% CI 5.9%-12.5%) with placebo. The cumulative incidence of CNS recurrence was consistently lower in the osimertinib arm than in the placebo arm.

Osimertinib reduced local/regional and distant relapses and was associated with a statistically significant and clinically meaningful improvement in CNS DFS, with an 82% reduction in risk of CNS disease recurrence or death in stage IB, II, or IIIA EGFRm NSCLC following complete tumor resection.

Alex Spira, MD, PhD, Virginia Cancer Specialists Research Institute, comments on the practice-changing potential of the ADAURA study:

CodeBreaK 100: Sotorasib in KRAS p.G12C NSCLC

David. S. Hong, MD, MD Anderson Cancer Center, Houston, Texas, presented results for patients with NSCLC from CodeBreaK 100 (Abstract 1257O). This phase 1, dose-escalation study looked at the durability of clinical benefit and biomarkers in tumors with the KRAS p.G12C mutation treated with the small molecule KRASG12C inhibitor sotorasib (AMG510).4 A simultaneous publication includes results in NSCLC and other tumors.5

The primary endpoint of the study was safety; key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). KRAS p.G12C mutant allele frequency (MAF), and PD-L1 expression levels, and tumor mutational burden (TMB) were investigated as potential biomarkers for sotorasib.

In patients with previously treated NSCLC (n=59), at a median follow-up of 11.7 months, no dose-limiting toxicities were observed and there were no fatal treatment-related adverse events (TRAE). The most common TRAE were diarrhea (25.4%), alanine aminotransferase (ALT) increase (20.3%), aspartate aminotransferase (AST) increase (20.3%), fatigue (10.2%), and nausea (10.2%). Eleven (18.6%) patients had grade 3 or higher TRAE, one of whom had grade 3 TRAE of ALT and AST increases that led to discontinuation of treatment. At data cutoff (June 1, 2020), 14 patients were continuing treatment; 35 discontinued due to disease progression, and five died.

The confirmed ORR was 32.2% overall and 35.3% in the 34 patients receiving the highest (960 mg) daily dose, which is the recommended phase 2 dose in NSCLC. DCR overall was 88.1% and 91.2% in the 960 mg dose group. Median DOR was 10.9 months for the 19 patients with confirmed partial response; median PFS was 6.3 months overall. The clinical activity of sotorasib was seen across a range of KRAS p.G12C MAF, PD-L1 tissue expression levels, and plasma TMB levels, as well as a range of tissue co-mutational profiles.

Editor’s Note: On October 5, 2020, Amgen announced positive topline results from a phase 2 trial of sotorasib in 129 patients with KRAS G12C-mutant advanced NSCLC after failure with two prior treatments. The company didn’t give specifics but said that the new data were “consistent” with the 35% response rate observed in the 34 patients who received the top dose in the earlier phase 1 trial for which data was announced at ESMO20. Details of the potentially registrational phase 2 study will be submitted to the IASLC 2020 World Congress on Lung Cancer taking place in January 2021.6

Dr. Hong discusses the phase 1 clinical trial investigating sotorasib (AMG 510):

KEYNOTE-024: 5-Year Update

Julie R. Brahmer, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, presented 5-year efficacy and safety from the open-label, pivotal phase 3 KEYNOTE-024 trial (LBA51) of frontline pembrolizumab versus platinum-based chemotherapy in patients with metastatic NSCLC with no EGFR or ALK genomic tumor aberrations and a PD-L1 TPS ≥50%.8

Patients randomly assigned to pembrolizumab (n=154) for 35 cycles (2 years) on study could receive an additional second course of 17 cycles (1 year) of therapy (12 of these 80 patients received subsequent anticancer therapy). Those randomly assigned to platinum-doublet chemotherapy (4 to 6 cycles; n=151) who experienced progressive disease could cross over to pembrolizumab for 2 years (n=83; 16 additional patients received subsequent anti-PD1/L1 therapy).

At five years (median follow-up of 59.9 months), OS was 26.3 months for pembrolizumab (31.9%) versus 13.4 months (16.3%) for chemotherapy (HR 0.62; 95% CI 0.48-0.81). PFS was 7.7 months for pembrolizumab and 5.5 months for chemotherapy (HR 0.50; 95% CI 0.39-0.65). ORR was 46.1% for pembrolizumab and 31.1% or chemotherapy. Median DOR for pembrolizumab was 29.1 months versus only 6.3 months for chemotherapy.

No new safety signals for pembrolizumab were reported. Among all patients who were treated, 31.2% of those who received pembrolizumab and 53.3% of those who received chemotherapy experienced grade 3-5 TRAE. Grade 3-5 TRAE occurred in 15.4% of patients completing two years of treatment with pembrolizumab (n=39).

With 5 years of follow up, pembrolizumab continues to show meaningful improvements in OS and durable responses versus chemotherapy. Despite the 66% effective crossover rate, the 5-year OS rate was approximately doubled in the pembrolizumab group. Patients who completed 35 cycles (2 years) of pembrolizumab experienced long-term OS. A second course of pembrolizumab at the time of disease progression was feasible and associated with antitumor activity. Pembrolizumab monotherapy is an effective first-line treatment regimen in patients with metastatic NSCLC and PD-L1 TPS ≥50%.

Roy Herbst, MD, PhD, Yale Cancer Center, shares his thoughts on the update to the Keynote-024 trial presented at ESMO20:

EMPOWER-Lung 1: Cemiplimab in Advanced NSCLC

Ahmet Sezer, MD, Baskent University, Adana, Turkey, presented data from the pivotal phase 3 EMPOWER-Lung 1 study (LBA52) of first-line cemiplimab monotherapy versus platinum-doublet chemotherapy in advanced NSCLC with PD-L1 expression ≥50%.9 Cemiplimab is a PD-1-blocking antibody FDA-approved for treatment of metastatic cutaneous squamous cell carcinoma (CSCC) or CSCC in patients who are not candidates for curative surgery or curative radiation.10

Patients with treatment-naïve NSCLC that were PD-L1 ≥50%, with no EGFR, ALK or ROS1 mutations, were randomly assigned 1:1 to cemiplimab (n=356) or investigator’s choice of platinum-doublet chemotherapy (n-354). Patients on the cemiplimab arm who had progressive disease could continue cemiplimab plus four cycles of chemotherapy. Patients on the chemotherapy arm with disease progression could cross over to cemiplimab. The primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR, health-related quality of life (HRQoL), and safety.

Data were presented from the second interim analysis as of March 1, 2020. Of 203 patients who had progression on chemotherapy, 150 (73.9%) received cemiplimab as crossover treatment and 50 of 158 patients (31.6%) who had progression on cemiplimab received extended cemiplimab plus chemotherapy. Patients were retested for PD-L1 due to tests prior to August 2018 not being done correctly. Results from those who were retested and had PD-L1 ≥50% confirmed were analyzed separately.

Median follow-up was 13 months in the intent-to-treat (ITT) population. Median OS for cemiplimab was 22.1 months (n=356) versus 14.3 months for chemotherapy (n=354; HR=0.68; 95% CI: 0.53-0.87; P=.0022). For those in the ITT population with PD-L1 ≥50%, median OS was not reached for cemiplimab (n=283) and was 14.2 months for chemotherapy (n=280; HR=0.57; 95% CI: 0.42-0.77; P=.0002).

Median PFS in the ITT population was 6.2 months for cemiplimab and 5.6 months for chemotherapy (HR=0.59; 95% CI: 0.49-0.72; P<.0001). In the PD-L1 ≥50% ITT population, median PFS was 8.2 months for cemiplimab and 5.7 months for chemotherapy (HR=0.54; 95% CI: 0.43-0.68; P<.0001). A subgroup analysis for OS and PFS favored cemiplimab for most subgroups.

In the ITT population, ORR was 36.5% for cemiplimab and 20.6% for chemotherapy. In the PD-L1 ≥50% ITT population ORR was 39.2% for cemiplimab and 20.4% for chemotherapy (P<.0001 for both comparisons). Median DOR for the ITT population was 21.0 months for cemiplimab and 6.0 months for chemotherapy; in the PD-L1 ≥50% ITT population median DOR was 16.7 months versus 6.0 months, respectively.

On average patients receiving cemiplimab experienced early clinically meaningful improvements in HRQoL that were sustained over the course of the study, whereas HRQoL tended to remain the same or deteriorate for patients receiving chemotherapy.

Adverse events (AEs) were more frequent with chemotherapy, except for immune-related AEs, which were more frequent with cemiplimab and led to discontinuation for 14 patients and death of one. The safety profile of cemiplimab was consistent with that seen in previous trials. Cemiplimab was associated with fewer AEs overall than chemotherapy despite substantially longer treatment exposure.

EMPOWER-Lung 1 met its primary and secondary endpoints. Dr. Sezer concluded that these data provide the rationale for cemiplimab as a new first-line monotherapy option for patients with advanced NSCLC with PD-L1 ≥50%.

Dr. Herbst elaborates on the design and outcomes of the EMPOWER-lung 1 trial:

PIONeerR: Response/Resistance Predictive Biomarkers for PD1/L1 ICI

Fabrice Barlesi, MD, PhD, Gustave Roussy Cancer Campus, Marseille, France, presented results of the preliminary analysis of the first 100 patients enrolled in the biomarker component of the PIOneeR study (LBA53), an assessment of over 400 biomarkers for predictive value in advanced NSCLC treated with anti-PD-1/L1 immunotherapy.11,12 The rationale for this study is that although ICI significantly improves long-term outcome in 20% of patients with advanced NSCLC, there are no robust biomarkers predictive of primary or secondary resistance.

This ongoing study is enrolling patients with advanced NSCLC treated with anti-PD1/L1 therapy alone or in combination with chemotherapy who had available archived tumor tissue and who had re-biopsies and blood samples taken at 6 weeks of treatment. ORR, circulating and tumor infiltrating immune cells, PD-L1-mediated inhibition, endothelial activation, blood soluble factors, pharmacokinetics, and TMB were assessed.

The first 100 patients have been followed for a median of 6.55 months. ORR is 13%, median PFS is 3.0 months, and median OS is 11.0 months. Neither sex, age, ECOG performance status, histologic subtypes, smoking status, line of therapy, nor type of PD-1/L1 drug were found to have a significant influence on the likelihood of response.

ECOG performance status was the best predictor of OS following immunotherapy. Dr. Barlesi said that biomarkers are mandatory for PD1/L1 trials. Biomarkers that appear to have predictive value include PD-L1 tumor expression, with possible superiority of PD-L1-positive cell density; density of cytotoxic T cells in the tumor; and density of immunosuppressive cells, e.g. regulatory T cells or myeloid-derived suppressor cells.

Dr. Barlesi suggested the identified biomarkers could be used to generate an “immunogram” that could eventually be used to guide personalized, precision therapy.

Dr. Herbst reviews some details on the PIONeeR study:

In Conclusion

Roy S. Herbst, MD, PhD, Yale Cancer Center, New Haven, Connecticut, discussed abstracts LBA51, LBA52, and LBA53. He called the results of KEYNOTE-024 even with crossover as profound. Even with an impressive OS and PFS, Dr. Herbst pointed out that with an ORR of 46.1%, even with high PD-L1expression and targeted therapy, there are many patients with primary resistant disease. Dr. Herbst characterized the patient population in EMPOWER-Lung 1 as “more real world,” not only because it enrolled only smokers world-wide, but because patients were allowed to have clinically stable CNS metastases, and that compelling responses were seen even in these patients. PIONeeR is a public-private partnership that Dr. Herbst, who is a co-author, called innovative. Testing for “biomarkers pre- and post-treatment is something we all have to do worldwide,” because there are too many trials run without biomarkers, he said, adding that “PD-L1 is here to stay and others are needed.” Dr. Herbst concluded that the results from KEYNOTE-024 and EMPOWER-Lung 1 suggest that metastatic NSCLC can be cured with immunotherapy. This therapy needs to be personalized with better biomarkers and combinations.


  1. https://doi.org/10.1016/j.annonc.2020.08.2279
  2. Wu Y-L, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small cell lung cancer. N Engl J Med. September 19, 2020. DOI: 10.1056/NEJMoa2027071
  3. Tagrisso (osimertinib) Prescribing Information. AstraZeneca, Wilmington, Delaware. June 2020
  4. https://doi.org/10.1016/j.annonc.2020.08.1571
  5. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020; 383:1207-1217. DOI: 10.1056/NEJMoa1917239
  6. https://www.amgen.com/media/news-releases/2020/10/amgen-announces-positive-topline-phase-2-results-for-investigational-kras-g12c-inhibitor-sotorasib-in-advanced-non-small-cell-lung-cancer/
  7. https://clinicaltrials.gov/ct2/show/NCT04303780?term=sotorasib&cond=NSCLC&draw=2&rank=1
  8. https://doi.org/10.1016/j.annonc.2020.08.2284
  9. https://doi.org/10.1016/j.annonc.2020.08.2285
  10. Libtayo (cemiplimab-rwlc) Prescribing Information. Regeneron Pharmaceuticals, Inc. Tarrytown, New York. June 2020
  11. https://doi.org/10.1016/j.annonc.2020.08.2286
  12. https://marseille-immunopole.org/en/mi-live-en/the-pioneer-project-presents-a-biomarker-analysis-for-its-first-100-patients-at-the-esmo-2020-congress/

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