Thoracic Experts Review ESMO 2022 Data in NSCLC

D. Ross Camidge, MD, PhD

In a special OncLive video program, The Board, D. Ross Camidge, MD, PhD, director of thoracic oncology at the University of Colorado, led a discussion regarding key abstracts that were presented during the 2022 ESMO Congress in non–small cell lung cancer (NSCLC).

Camidge was joined by:

• David R. Gandara, MD: senior advisor to the director, UC Davis Comprehensive Cancer Center
• Jonathan W. Riess, MD: director of thoracic oncology, UC Davis Comprehensive Cancer Center
• Erminia Massarelli, MD, PhD: co-director of the Lung Cancer and Thoracic Oncology Program, and an associate professor in the Department of Medical Oncology & Therapeutics Research at City of Hope
• Julie R. Brahmer, MD: co-director of the Upper Aerodigestive Department within the Bloomberg-Kimmel Institute for Cancer Immunotherapy, and professor of oncology at Johns Hopkin Medicine
• Barbara Melosky, MD, FRCP(C): professor of medicine at the University of British Columbia
• Roy S. Herbst, MD, PhD: Ensign Professor of Medicine (Medical Oncology) and professor of pharmacology at Yale School of Medicine, and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital
• Enriqueta Felip, MD, PhD: head of the Lung Cancer Unit, Oncology Department at Vall d’Hebron University Hospital
• Mark G. Kris, MD: William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center

During the discussion, these experts discussed some of the stand-out studies that were presented at the meeting and how they may affect the current positioning of targeted therapy for patients with KRAS G12C, EGFR, and HER2 mutations and the use of checkpoint inhibitors across histological subtypes.

LBA10 - Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study¹

In this phase 3 study, 345 patients were randomly assigned to oral sotorasib (Lumakras) at 960 mg daily (n = 171) or intravenous (IV) docetaxel at 75 mg/m2 every 3 weeks (n = 174).

At a median follow-up of 17.7 months, the study met its primary end point, showing a statistically significant improvement in progression-free survival (PFS) with sotorasib vs docetaxel (HR, 0.66; 95% CI, 0.51-0.86; P = .002). The 1-year PFS rate was 24.8% with sotorasib vs 10.1% with docetaxel, and the PFS benefit was consistent across subgroups.

The objective response rate (ORR) was also significantly improved with sotorasib vs docetaxel, at 28.1% (95% CI, 21.5%-35.4%) vs 13.2% (95% CI, 8.6%-19.2%), respectively (P < .001). The disease control rate was 82.5% (95% CI, 75.9%-87.8%) with sotorasib vs 60.3% (95% CI, 52.7%-67.7%) with docetaxel. Overall survival (OS) was not significantly different between treatment arms (HR, 1.01; 95% CI, 0.77-1.33; 1-sided P = .53). However, the study was not powered to detect an OS improvement.

“This is an interesting trial. For us in the United States, it gives us more options,” Brahmer noted.

LBA47 Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): Updated results from ADAURA²

In the primary analysis of this phase 3 trial, adjuvant osimertinib (Tagrisso; n = 339) led to a significant improvement in disease-free survival (DFS) vs placebo (n = 343) in patients with completely resected EGFR-mutant NSCLC with or without adjuvant chemotherapy (stage II-IIIA DFS: HR, 0.17; 99.06% CI, 0.11-0.26; P < .001; stage IB-IIIA DFS: HR, 0.20; 99.12% CI, 0.14-0.30; P < .001).

Patients had received osimertinib at 80 mg once daily or placebo for up to 3 years.
With 2 years of additional follow-up, the DFS hazard ratio (HR) was 0.23 (95% CI 0.18-0.30) in patients with stage II to IIIA disease, and the 3-year DFS rate was 84% with osimertinib vs 34% with placebo. In the overall population of patients with stage IB to IIIA disease, the DFS HR was 0.27 (95% CI, 0.21-0.34), and the 3-year DFS rate was 85% with osimertinib vs 44% with placebo.

“At the 2-year mark, DFS remains quite strong,” Herbst said. “We don’t have crossover data. Patients were allowed to cross over after the initial result, but frankly, not many patients took advantage of that. The survival data are pending. Certainly, with these curves, one could be optimistic.”

LBA55 Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial³

Prior results from the phase 2 DESTINY-Lung01 trial (NCT03505710) showed durable activity with a 6.4-mg/kg dose of fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with previously treated HER2-mutant NSCLC.

In the phase 2 DESTINY-Lung02 trial (NCT04644237), 152 patients were randomly assigned 2:1 to 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50) of trastuzumab deruxtecan every 3 weeks. In the prespecified early cohort, results showed that the confirmed ORR by blinded independent central review was 53.8% (95% CI, 39.5%-67.8%) with the 5.4-mg/kg dose (n = 52) and 42.9% (95% CI, 24.5%-62.8%) with the 6.4-mg/kg dose (n = 28).

Regarding safety, treatment-emergent adverse effects (TEAEs) were higher with the 6.4-mg/kg dose, as was any-grade adjudicated drug-related interstitial lung disease, which occurred in 5.9% of patients receiving the 5.4-mg/kg dose vs 14.0% of those receiving the 6.4 mg/kg dose.

“There really isn’t an agent that has jumped out for the treatment of this group, but this drug surely has,” Kris said. “Based on the aggregate of data that has been presented to the FDA so far, we have this approval now for trastuzumab deruxtecan at 5.4 mg/kg for patients with HER2-mutant cancers—and for better or worse, it’s the standard of care. There really isn’t a drug available to us [that is] as good. Is it tolerable? Yes. Is there pneumonitis? Yes, but there’s a learning curve.”

LBA52 - Tepotinib + osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: Initial results from the INSIGHT 2 study⁴

In this phase 2 study, 88 patients with advanced EGFR-mutant NSCLC with MET amplification after progression on frontline osimertinib received 500 mg of tepotinib (Tepmetko) plus 80 mg of osimertinib once daily.

The confirmed ORR was 54.5% (95% CI, 32.2%-75.6%) in patients who had at least 9 months of follow-up (n = 22). In those with at least 3 months of follow-up (n = 48), the confirmed ORR was 45.8% (95% CI, 31.4%-60.8%). However, approximately one-quarter of patients (23.9%) experienced grade 3 or greater AEs.

“There is a future for MET targeting in the 30% of patients who develop resistance to EGFR TKIs,” Massarelli said. “However, the other thing that I wonder is whether we can target MET resistance with chemotherapy because there is significant toxicity [with the addition of] tepotinib or capmatinib [Tabrecta].”

LBA11 IPSOS: Results from a phase III study of first-line (1L) atezolizumab (atezo) vs single-agent chemotherapy (chemo) in patients (pts) with NSCLC not eligible for a platinum-containing regimen⁵

Patients who were deemed ineligible for frontline platinum-based chemotherapy due to a poor performance status of 2 or greater or comorbidities were randomly assigned 2:1 to 1200 mg of IV atezolizumab (Tecentriq) every 3 weeks (n = 302) or investigator’s choice of single-agent vinorelbine or gemcitabine in 3- or 4-week cycles (n = 151).

At a median follow-up of 41.0 months, atezolizumab led to a significant improvement in OS vs chemotherapy (stratified HR, 0.78; 95% CI, 0.63-0.97; P = .028) regardless of PD-L1 expression level, performance status, and histology.

Notably, atezolizumab improved time to confirmed deterioration of chest pain vs chemotherapy (HR, 0.51; 95% CI, 0.27-0.97) and showed clinically meaningful improvements from baseline in appetite loss and cough.

“This regimen is going to be adopted for patients who don’t, won’t, or can’t have a platinum doublet, and those are usually patients in their late age,” Melosky said. “This study is going to change our management [of these patients].”

973MO - KEYNOTE-189 5-year update: First-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC⁶

In KEYNOTE-189, patients were randomly assigned 2:1 to receive 200 mg of pembrolizumab or placebo every 3 weeks for up to 2 years. All patients also received pemetrexed (Alimta) and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pemetrexed, until progressive disease or unacceptable toxicity.

At 5 years, the median OS was 22.0 months (95% CI, 19.5-24.5) with pembrolizumab vs 10.6 months (95% CI, 8.7-13.6) with chemotherapy alone in the intention-to-treat (ITT) population (HR, 0.60; 95% CI, 0.50-0.72). The 5-year OS rates were 19.4% and 11.3%, respectively. The median PFS was 9.0 months (95% CI, 8.1-10.4) vs 4.9 months (95% CI, 4.7-5.5), respectively (HR, 0.50; 95% CI, 0.42-0.60); the 5-year PFS rates were 7.5% and 0.6%, respectively.

“The hazard ratios for OS and PFS are almost identical to what they were at the time of the original presentation, around 0.6,” Gandara said. “Why is this important? It’s particularly important for immunotherapy because we’re learning that different regimens may affect the tail of the curve. There was some debate at the [time of the] ESMO presentation about whether there’s a plateau. I don’t think that’s as important as [this]: around 20% of people are still alive at 5 years with metastatic NSCLC.”

974MO - 5-year update from KEYNOTE-407: Pembrolizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC)⁷

Eligible patients were randomly assigned 1:1 to receive 200 mg of pembrolizumab or placebo plus carboplatin and paclitaxel or nab-paclitaxel (Abraxane) every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to 35 cycles.

The median OS in the ITT population was 17.2 months (95% CI, 14.4-19.7) with pembrolizumab vs 11.6 months (95% CI, 10.1-13.7) with chemotherapy alone (HR, 0.71; 95% CI, 0.59-0.85). The 5-year OS rates were 18.4% and 9.7%, respectively.

Notably, in the subset of patients with a PD-L1 tumor proportion score (TPS) of less than 1%, the 5-year OS rate was 10.7% with pembrolizumab (n = 95) vs 13.1% with chemotherapy alone (n = 99; HR, 0.83; 95% CI, 0.61-1.13).

“The subset analysis is noteworthy, because the subset of patients with PD-L1 expression of 50% or higher and 1% and 49% showed a clear benefit for OS but did not show one for the subset of patients with PD-L1 negativity,” Riess explained. The HR for OS in the subset of patients with a PD-L1 TPS of 50% or higher was 0.68 (95% CI, 0.47-0.97); in the subset of patients with a PD-L1 TPS of 1% to 49%, the HR was 0.61 (95% CI, 0.45-0.83).

LBA54 - Three years survival outcome and continued cemiplimab (CEMI) beyond progression with the addition of chemotherapy (chemo) for patients (pts) with advanced non-small cell lung cancer (NSCLC): The EMPOWER-Lung 1 trial⁸

For EMPOWER-Lung 1, patients were randomly assigned 1:1 to 350 mg of IV cemiplimab-rwlc (Libtayo) every 3 weeks for 2 years (n = 357) or investigator’s choice of chemotherapy (n = 355). Patients who were randomized to cemiplimab and had progressive disease were allowed to continue cemiplimab with the addition of up to 4 cycles of chemotherapy.

Continued treatment with cemiplimab and chemotherapy (n = 64) led to a median OS of 15.1 months (95% CI, 11.3-18.7) and an ORR of 31.3% (95% CI, 20.2%-44.1%).

“In the original arm, there were 357 patients and only 64 patients received chemotherapy added to cemiplimab,” Melosky said. “[Even so,] there’s a signal that that might be the right thing to do. In the United States, you do this all the time. You start with single-agent pembrolizumab [Keytruda], and if it’s not working, you add chemotherapy to it, but I’m not allowed to do that [in Canada].”

References

1. Johnson ML, de Langen AJ, Waterhouse DM, et al. Sotorasib versus docetaxel for previously treated non-small cell lung cancer with KRAS G12C mutation: CodeBreaK 200 phase III study. Ann Oncol. 2022;33(suppl 7):S1417-S1418. doi:10.1016/j.annonc.2022.08.051
2. Tsuboi M, Wu YL, Grohe C, et al. Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): updated results from ADAURA. Ann Oncol. 2022;33(suppl 7):S1413-S1414. doi:10.1016/j.annonc.2022.08.047
3. Goto K, Sang-We K, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol. 2022;33(suppl 7):S1422. doi:10.1016/j.annonc.2022.08.057
4. Mazieres J, Kim TM, Lim BK, et al. Tepotinib + Osimertinib for EGFRm NSCLC with MET amplification (METamp) after progression on first-line (1L) osimertinib: initial results from the INSIGHT 2 study. Ann Oncol. 2022;33(suppl 7):S1419-S1420. doi:10.1016/j.annonc.2022.08.054
5. Lee SM, Schulz C, Prabhash K, et al. IPSOS: results from a phase III study of first-line (1L) atezolizumab (atezo) vs single-agent chemotherapy (chemo) in patients (pts) with NSCLC not eligible for a platinum-containing regimen. Ann Oncol. 2022;33(suppl 7):S1418-S1419. doi:10.1016/j.annonc.2022.08.052
6. Garassino MC, Gadgeel SM, Speranza G, et al. KEYNOTE-189 5-year update: first-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC. Ann Oncol. 2022;33(suppl 7):S992-S993. doi:10.1016/j.annonc.2022.07.1101
7. Novello S, Kowalski DM, Luft A, et al. 5-year update from KEYNOTE-407: pembrolizumab plus chemotherapy in squamous non-small cell lung cancer (NSCLC). Ann Oncol. 2022;33(suppl 7):S993-S994. doi:10.1016/j.annonc.2022.07.1102
8. Özgüroğlu M, Kilickap S, Sezer A, et al. Three years survival outcome and continued cemiplimab (CEMI) beyond progression with the addition of chemotherapy (chemo) for patients (pts) with advanced non-small cell lung cancer (NSCLC): the EMPOWER-Lung 1 trial. Ann Oncol. 2022;33(suppl 7):S1421. doi:10.1016/j.annonc.2022.08.056