At ESMO 2022, oncology experts gathered in Paris and online to share and debate the new developments in the field of medical oncology. This year’s program featured more than 20 tracks covering all tumor types, therapeutic innovations, translational research, patient advocacy, public policy, and more…
Discover our summary of three compelling talks showcasing the journey towards precision therapy in various tumor types.
Genomic profiling and molecular targeting of lung cancer brain metastases1
Haiying Cheng, Dept. Medical Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
Approximately 57% of patients with non–small-cell lung cancer (NSCLC) present with metastatic disease2. Among them, brain metastases (BM) affect up to 45% of all cancer patients and arise from lung cancers in 40-50% of the cases3. There have been limited studies investigating the genetic signatures of LC BM, and with small cohorts so far.
Assembling a large number of lung cancer cases (47215 NSCLC; 29438 lung adenocarcinoma), Dr Cheng and colleagues looked for key genetic alterations in loco-regional lesions (Loco), extracranial metastases (EM), and BM with comprehensive genomic profiling (CGP). They found significantly more genetic alterations in the PI3K/AKT/mTOR pathway in BM (Loco 13.0% vs EM 14.5% vs BM 18.1%), primarily driven by RICTOR amplification (Loco 3.6% vs EM 6.2% vs BM 8.6%).
RICTOR amplification is the most enriched actionable genomic target in NSCLC brain metastases.
Furthermore, in vitro genetic knockdown and pharmacological inhibition of RICTOR significantly reduced migration and invasion in RICTOR-amplified NSCLC cells, whereas RICTOR upregulation promoted these processes, modulating the AKT, MET, EMT, and CXCL12 chemokine-CXCR4 pathways. Finally, in vivo studies in orthotopic mouse models revealed that both RICTOR and mTOR1/2 inhibition significantly reduced lung cancer tumor growth and spread in the brain.
Dr Cheng provided evidence for the benefit of further investigation on the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of lung cancer BM. This study is a good example of how genomic profiling, combined with functional analyses, can identify new potential therapeutic targets.
Neoadjuvant immune checkpoint inhibition in locally advanced MMR-deficient colon cancer: The NICHE-2 study4.
Myriam Chalabi, Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands
Mismatch repair deficiency (dMMR) is observed in ~15% of colorectal cancers (CC)5 and 1/3 is associated with Lynch Syndrome. This characteristic genetic signature is marked by high levels of microsatellite instability (MSI) and resistance to standard-of-care neoadjuvant chemotherapy (5-7% pathological response (≤50% residual viable tumor; PR)). NICHE-1 exploratory study showed the potential of neoadjuvant immunotherapy in patients with dMMR CC with extraordinary PR in 100% of the patients6.
Dr Chalabi presented the NICHE-2 investigator-initiated study, conducted in 6 hospitals in the Netherlands. 107 patients with non-metastatic untreated dMMR CC and mainly high-risk tumors received injections of nivolumab and ipilimumab within 6 weeks prior surgery. The impressive pathological tumor regression was shown in a waterfall plot that led to a standing ovation! 95% of the treated patients showed PR, and 67% had no residual viable tumor (complete PR; cPR), contrasting with the neoadjuvant chemotherapies in the same patient population. Only 4% experienced grade 3-4 immune-related adverse events and 98% of patients underwent timely surgery, meeting the safety primary endpoint. To date, no disease recurrence has been observed and the 3 years disease-free survival data are expected next year.
Neoadjuvant immunotherapy has the potential to become standard of care for patients with dMMR colon cancer.
NICHE-2 trial opens the possibility that a surveillance approach may be possible for some patients with early dMMR CC and gives a glimpse at the potential of translational research to identify predictive biomarkers in pre- and post-treatment samples. While those preliminary results are extremely promising and we surely wait for the longer-term follow-up data to confirm them, patient selection remains crucial. Indeed, neoadjuvant decisions are based on radiological assessment of the tumor, particularly difficult in dMMR cancers, as well as the biopsy, and Dr Chalabi highlighted the need for improvement in the imaging techniques and circulating DNA analyses.
Final overall survival results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer7.
Isabelle Ray-Coquard, Department Of Medical Oncology, Centre Léon Bérard, and GINECO, Lyon, France
The late diagnosis of advanced ovarian cancer (AOC) is often accompanied by relapse, despite surgery and platinum-based chemotherapy. Treatment with olaparib (ola), a poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi), provided progression-free survival (PFS) benefit as maintenance therapy in patients with AOC carrying mutations in BRCA1 or BRCA2 (BRCAm)8. Besides, the incorporation of the antiangiogenic agent bevacizumab (bev) is a recognized option in addition to chemotherapies9.
PAOLA-1 investigators conducted a phase III trial where 806 patients with AOC and after first-line platinum-based chemotherapy plus bev were randomly assigned in a 2:1 ratio to ola + bev or placebo (pbo) + bev treatment. The primary endpoint was the PFS. They showed that combined treatment with ola + bev reduced the risk of relapse by 41% compared to bev alone, reducing by 67% in HRD+ patients (exhibiting BRCAm and/or genomic instability score ≥42)10.
Here, Dr Ray-Coquard presented the final overall survival (OS) results, a key secondary endpoint. She showed that the OS rate after 5 years was not different between the two arms (47.3% vs 41.5%) but significantly increased for HRD+ patients treated with ola + bev (65.5% vs 48.4%), regardless of BRCAm status. Also, PFS was significantly increased in the same population (46.1% vs 19.2%).
Maintenance therapy with olaparib plus bevacizumab improved survival in HRD+ patients with newly diagnosed advanced ovarian cancer.
With the absence of new safety signals and major adverse effects, these data confirmed the benefit of olaparib and bevacizumab combination as a standard of care for HRD+ patients and reinforced the importance of precision medicine and biomarker testing to guide treatment decisions.
- Ernani V, Stinchcombe TE. Management of Brain Metastases in Non-Small-Cell Lung Cancer. J Oncol Pract. 2019 Nov;15(11):563-570.
- Nieblas-Bedolla E, Zuccato J, et al. Central Nervous System Metastases. Hematol Oncol Clin North Am. 2022 Feb;36(1):161-188.
- Jin Z, Sinicrope FA. Prognostic and Predictive Values of Mismatch Repair Deficiency in Non-Metastatic Colorectal Cancer. Cancers (Basel). 2021 Jan 15;13(2):300.
- Chalabi M, Fanchi LF, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020 Apr;26(4):566-576.
- Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505.
- Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-2483.
- Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N Engl J Med. 2019 Dec 19;381(25):2416-2428.