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Novel Cytotoxic Drugs Still Play an Important Role in the Treatment of Lung Cancer

TOP - February 2017, Vol 10, No 1 - Lung Cancer

Vienna, Austria—Targeted agents and immunotherapy are displacing chemotherapy in certain subgroups of the treatment of lung cancer, but chemotherapy remains a key therapeutic pillar in the daily management of patients with this disease, according to Jean-Charles Soria, MD, PhD, Head of the Drug Development Department, Gustave Roussy, Villejuif, France.

“Cytotoxic chemotherapies remain the dominant alternative for more than 50% of patients with lung cancer. Therefore, there is still a need to develop novel cytotoxic drugs,” he told attendees at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer.

Dr Soria elaborated on 2 novel compounds in particular, PM1183 and TAS-114, both of which have shown promise in phase 1/2 studies.

“I have found these 2 new cytotoxic compounds to be pretty fascinating for the future, and they are likely to emerge as new players in the field of lung cancer management,” he added. The first, PM1183, has activity in small-cell lung cancer (SCLC), and the other, TAS-114, has activity in non–small-cell lung cancer (NSCLC).

PM1183 in SCLC

PM1183 (lurbinectedin) is a DNA-binding chemotherapy with a unique mechanism of action. In living cells it inhibits active transcription, and it has been associated with antitumor activity in patients resistant to platinum compounds.

PM1183 in combination with doxorubicin has been tested in a phase 1B dose-escalation and expansion trial in patients with SCLC. The recommended dose was defined as either a PM1183 4.0-mg flat dose or 2.0 mg/m2 plus doxorubicin 50 mg/m2, both on day 1 every 3 weeks. Reversible myelosuppression was the most frequent dose-limiting adverse event, but compelling activity was observed during the escalation phase.

It was especially remarkable as second-line treatment in patients with SCLC; 5 of 7 (71%) evaluable patients had objective partial response, and in an expansion cohort of 21 second-line SCLC patients, PM1183 and doxorubicin showed outstanding clinical activity with a 67% objective response rate, including 10% complete responses. Dr Soria called these results “impressive.”

The recommended dose appears to be feasible, he added, and, a randomized phase 3 study is ongoing to better define the role of this combination as second-line treatment for patients with SCLC.

TAS-114 in NSCLC

TAS-114 is a first-in-class oral de­oxyuridine triphosphatase (dUTPase) inhibitor that acts by enhancing the incorporation of uracil and fluorouracil into DNA. dUTPase prevents fluorouracil drugs from being incorporated into a patient’s DNA; when dUTPase is blocked, fluorouracil is more highly concentrated in DNA, and therefore higher cytotoxic activity is observed.

The enzyme dUTPase is strongly associated with colorectal cancer, but recent data have demonstrated that dUTPase is present in a significant number of tumor samples in the NSCLC setting, whereas it is absent in the majority of normal lung samples.

A phase 1 clinical trial of TAS-114 in combination with the antitumor drug S-1 is ongoing to investigate safety and determine the maximum tolerated dose and recommended dose in patients with advanced refractory solid tumors. TAS-114 and S-1 are administered orally twice daily for 14 days, followed by a 7-day resting period for a 21-day cycle. TAS-114 at 240 mg/m2 plus S-1 at 30 mg/m2 was determined to be the maximum tolerated dose and the recommended dose.

As of October 2016, among the 8 evaluable patients with NSCLC in the expansion phase of the study, an objective response rate of 25% (2/8) has been observed, with 2 confirmed partial responses and a disease control rate of 88% (7/8). Pharmacodynamics analyses performed on tumor specimens from patients treated with the maximum tolerated dose indicated reductions in the amount of a metabolite indicative of dUTPase inhibition following administration of the TAS-114/S-1 combination, compared with S-1 administration alone.

A global phase 2 study of TAS-114/S-1 is currently in development. The study will evaluate progression-free survival for third-line and beyond patients with squamous or nonsquamous NSCLC.

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Last modified: April 27, 2020