Oleclumab (MEDI9447) is a human IgG1λ mAb that inhibits the function of cluster of differentiation 73 (CD73).8 CD73 is an enzyme found on the surfaces of cancer and immune cells and is involved in conversion of adenosine monophosphate to extracellular adenosine, which has an immunosuppressive effect on the tumor environment.9 CD73 upregulation by tumors has been shown to increase extracellular adenosine production and result in subsequent local immunosuppression in multiple cancers.
Monalizumab (IPH2201) is a first-in-class, humanized, IgG4 mAb that specifically binds to and blocks the inhibitory receptor NKG2A from binding to the major histocompatibility complex E (HLA-E), thereby reducing inhibition of natural killer and CD8+ T cells.14 HLA-E is overexpressed in multiple tumor types and, once bound to NKG2A, triggers inhibitory signals that suppress cytokine secretion and direct cytotoxicity of T lymphocytes and natural killer cells.15 Monalizumab binds specifically and with high affinity to NKG2A, thereby suppressing inhibitory signals and enhancing antitumor immunity.
Both seems to have synergy with PD-1/PDL-1 inhibitors without significant added toxicity.
Durvalumab significantly improves overall survival for patients with unresectable stage III non–smallcell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting.
Patients with unresectable stage III non–small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, # 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1).
Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade $ 3 treatmentemergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively.
Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.
Another possible option for first line NSCLC EGFR mutated (non-exon 20) is Osimertinib (osi). Osi and chemotherapy had less brain metastases. And with Amivantamab and Lazertinib (EGFR inhibitor), the combination had better PFS and OS (HR0.8). Higher toxicity though with 10% discontinuation vs 3% for Osimertinib. This is interim analysis, toxicity was EGFR related mostly.
Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo in the EGFR mutated patients. Osmiertinib shows efficacy in patients with EGFR mutation who underwent curative surgery or chemoradiotherapy.
Perioperative nivolumab (Nivo) showed a 20% 18-month EFPS improvement. This is another option to consider for your patients with stage IIA-IIIB NSCLC. Of note, the study arm received chemo + Nivo x 4 cycles preoperatively, then 12 months of Nivo therapy, and toxicities were as expected.
FCS medical oncologist and hematologist Ernesto Bustinza-Linares, MD has co-authored an abstract published in the American Society of Clinical Oncology Journal, JCO Precision Oncology, that uncovers a new testing method to determine personalized care options for patients with metastatic non-small cell lung cancer (NSCLC). The abstract’s authors address the limitations of existing guidelines that recommend checkpoint immunotherapy, sometimes in combination with chemotherapy, for treating NSCLC, which often discounts patient variability and immune factors. The findings from the study show that by incorporating additional plasma proteome-based testing, combined with the standard protein inhibitor testing, clear differences in patient outcomes were observed after applying targeted treatments based on the testing results.
This is another target for adjuvant therapy. The results are impressive. Notice that there was no chemotherapy in the study arm. Patients started on alectinib after surgery. Chemotherapy is losing ground to more tolerable treatments, more to follow, most likely, in the future.
FCS Hematology Oncology Review creates a platform for our physician network to observe the most recent articles and studies available in the oncology and hematology world. By sharing these articles we are building our wealth of knowledge of new observations and treatments as they come available.
