Apr 11, 2023
Table of Contents
The European Lung Cancer Congress (ELCC 2023) is organized by leading multidisciplinary societies in the field of thoracic oncology, to advance scientific knowledge, provide education, and enhance the expertise of lung cancer specialists globally. The program for ELCC 2023 was held both in-person in Copenhagen, Denmark, and online from March 29th to April 1st, 2023. DelveInsight is featuring summary of key abstracts focusing on long term benefits presented at the conference that have noteworthy clinical importance and is able to differentiate the data on the basis of which the drug received the approval, with the follow-up data.
Highlights:
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During the ELCC 2023 conference, the latest findings from the EMPOWER-Lung 1 and EMPOWER-Lung 3 trials showed that LIBTAYO (cemiplimab) has continued to demonstrate strong and lasting efficacy as an immunotherapy for advanced stages of NSCLC without a targetable driver.
New data from a posthoc analysis of the international Phase III EMPOWER-Lung 1 trial (NCT03088540) showed that first-line treatment with LIBTAYO plus chemotherapy improved overall survival (OS) and progression-free survival (PFS) compared to chemotherapy chosen by the investigator for patients with metastatic NSCLC that is PD-L1-positive and has spread to the brain.
This analysis, which is one of the largest conducted in patients with stable brain metastases receiving PD-1 monotherapy in Phase III clinical trial, suggests that using LIBTAYO in this patient population is beneficial and challenges the notion that stable brain metastases should exclude patients from receiving immunotherapy.
At the ELCC 2023, it was also announced that the EMPOWER-Lung 3 trial had positive results from an additional 12-month follow-up, demonstrating the efficacy of LIBTAYO plus platinum-based chemotherapy in patients with NSCLC and any level of PD-L1 expression. The FDA approved this treatment regimen in November 2022 for use in adult patients with advanced NSCLC that lacks EGFR, ALK, or ROS1 aberrations, based on previous data from the EMPOWER-Lung 3 trial.
LIBTAYO has been approved as the second PD-1/L1 inhibitor, after KEYTRUDA, for use in combination with chemotherapy in the first-line treatment of non-small cell lung cancer, regardless of PD-L1 levels or histology. This adds to its previous approval as a monotherapy for patients with high levels of PD-L1 expression.
However, just because it has an indication that matches KEYTRUDA’s, it does not automatically mean that LIBTAYO will equally divide the market with KEYTRUDA, which is currently the leading PD-1 inhibitor.
A summary of extended analyses from these two regulatory Phase III trials is discussed below:
| EMPOWER-Lung 1 | EMPOWER-Lung 3 | |
| Subgroup | Cemiplimab (n = 45) vs. chemo (n = 42) | Cemiplimab + chemo (n = 45) vs. placebo + chemo (n = 24) |
| Median follow-up, months | 33.3 (range 24.0–50.3) | 28.4 months (range 20.5-35.9) |
| Median OS, months | NE vs. 20.7 | 21.1 months vs. 12.9 |
| Median PFS, months | 12.5 vs. 5.3 | 8.2 vs. 5.5 |
| ORR, % | 55.9% vs. 11.4% | 43.6% vs. 22.1% |
| Median DOR, months | 31.7 vs. 12.5 | 16.4 vs. 7.3 |
| Grade ≥3 AE | 35.3% vs. 60.0% | 48.7% vs. 32.7% |
Expert Opinion: “The data presented are reassuring. Cemiplimab is confirmed as an important option for the treatment of NSCLC without a targetable driver – it is particularly valuable because, unlike some other checkpoint inhibitors, its label includes locally advanced disease, which cannot be treated with definitive chemoradiotherapy, not just metastatic NSCLC”
Assistant Prof. Maastricht University, Netherlands
Patients with metastatic NSCLC who experience disease progression after receiving anti-PD-L1/PD-1 therapy in combination with or after platinum-based chemotherapy typically receive docetaxel or pemetrexed monotherapy, which provides limited clinical benefits and leaves a significant gap in medical treatment options.
During the 2023 ELCC, the Phase III CONTACT-01 trial (NCT04471428) presented the final analysis of overall survival, secondary endpoints, and safety. This study compared TECENTRIQ plus CABOMETYX with docetaxel in patients with metastatic NSCLC who had received platinum-based chemotherapy and an anti-PD (L) agent. The primary endpoint of OS was not met. Though PFS and DOR showed numerical improvements, the secondary efficacy endpoints did not demonstrate clinically significant improvements in favor of TECENTRIQ plus CABOMETYX.
| TECENTRIQ + CABOMETYX (n = 185) | Docetaxel (n = 180) | |
| Median OS, months | 10.7 | 10.5 |
| Median PFS, months | 4.6 | 4.0 |
| ORR, % | 11.8% | 13.3% |
| Median DOR, months | 5.6 | 4.3 |
| Grade ≥3 AE | 48% | 45% |
The combination of drugs from Roche and Ipsen has encountered difficulties this year, not only with this recent stumble but also in March when CABOMETYX and TECENTRIQ failed in a Phase III study against Bayer’s NEXAVAR for the treatment of newly-diagnosed liver cancer. This setback caused Exelixis to abandon plans to expand CABOMETYX’s approved uses for that indication.
As first-line treatment, immune checkpoint inhibitors are becoming more prevalent, but there is currently a deficit of effective second-line therapies to address the needs of patients who do not respond to the initial treatment.
Expert Opinion: “The CONTACT-01 trial is not the first phase III study that has failed to reach the survival endpoint following encouraging results from an exploratory phase II trial. The shift of immune checkpoint inhibitors to first-line therapy has left an unmet need for effective second-line therapies”
Prof. Hospital Clinic, Barcelona, Spain
Updated data from the Phase III CheckMate 816 trial (NCT02998528) has shown that neoadjuvant treatment with OPDIVO (nivolumab) plus chemotherapy resulted in long-term event-free survival (EFS) advantage compared to chemotherapy alone in patients with resectable NSCLC, regardless of the type of surgery performed (minimally invasive or thoracotomy) or the extent of lung resection (complete or partial).
During the 2023 ELCC, data was presented indicating that after a median follow-up of 41.4 months, the median EFS had not yet been reached for patients receiving OPDIVO plus chemotherapy, compared to 21.1 months for patients receiving chemotherapy alone. The 3-year EFS rates were reported to be 57% for patients receiving OPDIVO plus chemotherapy and 43% for those receiving chemotherapy alone.
Among patients who underwent surgery, the recurrence rates were 28% for patients who received OPDIVO plus chemotherapy and 42% for those who received chemotherapy alone.
The FDA approved OPDIVO plus platinum-doublet chemotherapy on March 4, 2022, for use in the neoadjuvant setting in adult patients with resectable (tumors ≥ 4 cm or node-positive NSCLC, based on earlier data from the CheckMate 816 trial. The previous findings from the study showed that OPDIVO plus chemotherapy resulted in a significant improvement in EFS compared to chemotherapy alone.
The 2022 AACR Annual Meeting presented the EFS and initial OS data, which indicated that the median EFS was 31.6 months with OPDIVO plus chemotherapy and 20.8 months with chemotherapy alone.
The CheckMate 816 trial showed an enhancement in EFS, which is frequently used as a substitute indicator for overall survival. This indicates that the likelihood is increasing that the trial outcomes will actually improve survival.
Expert Opinion: “An important issue for clinical practice will be to differentiate the results seen with pure neoadjuvant chemoimmunotherapy, as used in CheckMate 816, from those soon to be reported from the new generation of phase III trials investigating neoadjuvant plus adjuvant chemoimmunotherapy in resectable NSCLC”
Prof. Lung Clinic Grosshansdorf, Germany
The 2023 ELCC presented new long-term data from the CHRYSALIS study, which assessed the efficacy of RYBREVANT (amivantamab-vmjw) in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations. The study included patients whose disease had progressed after receiving platinum-based chemotherapy.
It’s been more than two years that the therapy has find its place in the market for this patient segment as RYBREVANT received accelerated approval from the FDA in May 2021 for this patient segment based on previous data from the CHRYSALIS study, which demonstrated that the drug induced an ORR of 40% and a median DOR of 11.1 months in this patient population.
At a median follow-up of 19.2 months, the median PFS with RYBREVANT was 6.9 months, with a 2-year PFS rate of 13.7%. The median OS with the drug was 23 months, and the 2-year landmark OS rate was 47.2%. Moreover, RYBREVANT elicited an ORR of 37%, with a median DOR of 12.5 months. Regardless of the patient’s prior treatments or their response to platinum-based chemotherapy, the efficacy of the drug remained consistent.
NSCLC caused by EGFR exon 20 insertion mutations has a worse prognosis and shorter survival rates compared to lung cancer caused by more common EGFR mutations like exon 19 deletions and L858R substitutions. EGFR tyrosine kinase inhibitors, which are the standard of care for lung cancers with common EGFR mutations, are generally ineffective against exon 20 insertion mutations and are not approved by the FDA for treating these types of patients.
RYBREVANT and EXKIVITY are currently the only two agents approved for treating pretreated non-small cell lung cancer (NSCLC), although several other agents are in development. Some of these agents, including zipalertinib, sunvozertinib, furmonertinib, BLU-451, and ORIC-114, show promise, with a particular interest in small-molecule inhibitors that can penetrate the central nervous system.
However, there is a need to determine how these inhibitors can be used in patients with untreated diseases. The Phase III PAPILLON study is investigating the effectiveness of RYBREVANT plus chemotherapy compared to chemotherapy alone in the frontline treatment of EGFR exon 20 insertion-mutated NSCLC.
Expert Opinion: “With these new data, amivantamab showed long-term consistent efficacy regardless of prior therapies or response to prior platinum chemotherapy. Due to the aggressive nature of NSCLC with EGFR exon 20 insertion mutations, treatment with targeted therapies is an important consideration when identifying a treatment option for patients.”
MD, Associate Prof. of Medical Oncology, Universidad de Alcalá, Head of Medical Oncology Department, the University Hospital Ramón y Cajal, Madrid
KRAS G12C, a subtype of KRAS that was previously considered impossible to target with drugs, accounts for 40-45% of all KRAS mutations in lung cancer patients.
A study called EAP Study-436, conducted across six countries, provided data on the use of LUMAKRAS (sotorasib) for patients with KRAS G12C-mutated advanced NSCLC through an expanded access program. The study reported a median OS of 9.5 months in 147 patients, with a follow-up of 13.6 months. Patients with a history of central nervous system metastases had a similar median OS to those without (9.5 months versus 10.3 months).
The PFS data, which had been previously reported at the ESMO Congress 2022, were comparable to those seen in the CodeBreaK 200 trial of LUMAKRAS versus docetaxel. The study also reported that 21.1% of patients experienced grade ≥3 treatment-related adverse events.
At ELCC 2023, an exploratory analysis of the Phase II KRYSTAL-1 study investigated the potential association between mutation allele frequency clearance (MAFC) and response to KRAZATI (adagrasib) in patients with advanced/metastatic KRAS G12C-mutated NSCLC. The study found that patients with a MAFC ≥90% by cycle 4 day 1 (C4D1), as measured by circulating tumor DNA (ctDNA) analysis, had a higher objective response rate compared to those with a MAFC <90%. Patients with a MAFC ≥90% at C4D1 also had a longer PFS.
Expert Opinion: “The OS findings from this extended access program are very informative, even though they are not collected in a clinical trial, and confirm that sotorasib works and can improve patient outcomes. The median OS is impressive in what is a very heavily pretreated population of patients, who had received up to eight lines of therapy. In addition, it is reassuring that the presence of brain metastases did not limit the effects of sotorasib, with similar survival being observed in patients with and[D3] without CNS metastases.”
Prof. HFR Fribourg, Kantonsspital, Switzerland
The use of MAFC as a measure of treatment response may allow for less frequent radiological imaging, which is often stressful for patients and resource-intensive for healthcare providers. Blood samples could be used to measure MAFC at intervening periods, potentially reducing the need for imaging beyond the baseline and the 3-month endpoint.
Combining immunotherapy with targeted therapy is a promising approach for treating KRAS mutations due to their immunogenicity. Combination therapy is likely to be important in improving treatment response. One example is the use of KRAZATI and the EGFR inhibitor cetuximab together, which is effective in treating metastatic colorectal cancer in patients who have undergone extensive prior treatment.
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