Inevitably, at some point during their progression, small cell lung cancer (SCLC) tumors learn to dodge the bullets of treatment, no matter how rapidly they are fired, as effortlessly as Keanu Reeves’ character, Neo, dodges bullets from the Agents in the Matrix, shown above.
Despite remarkable initial sensitivity to first-line treatment with platinum-based chemotherapy plus an immune checkpoint inhibitor, either atezolizumab or durvalumab, responses are short-lived. SCLC inevitably relapses, and, when it does, all bets are off.
The use of topotecan, the only unconditionally approved second-line agent, is limited by concerns about its efficacy and an unfavorable safety profile. The chemotherapy agent, ZEPZELCA® (lurbinectedin), which in 2020 received conditional approval for second line SCLC based on a 35% overall response rate, failed to meet its endpoints in a confirmatory Phase 3 clinical trial.
No agent is specifically approved for third-line treatment of relapsed SCLC. The 3-year survival rate for patients with metastatic SCLC is 6%.
As dire as this situation is, patients with initial resistance to platinum chemotherapy are even worse off. Resistant SCLC is defined as relapse within 90 days of platinum-based treatment, and the survival of patients with platinum resistance is significantly shorter than the already short survival of patients with platinum sensitive disease, defined as relapse after 90 days.
In an ongoing Phase 3 clinical trial called REPLATINUM, RRx-001 (nibrozetone) is given in third line or beyond SCLC with platinum-based chemotherapy. The hypothesis of REPLATINUM is that RRx-001 (nibrozetone) specifically sensitizes platinum resistant tumors to platinum-based chemotherapy, which would upset the apple cart in the best possible way since these patients are currently without hope or help.
We’d like to imagine that platinum resistant SCLC reacts similarly to the Matrix’s supervillain, Agent Smith, when it encounters RRx-001 (nibrozetone) and platinum-based chemotherapy in the REPLATINUM clinical trial:
