by ecancer reporter Janet Fricker

The combination of the PD-1 inhibitor durvalumab and the CTLA-4 inhibitor tremelimumab achieved higher anti tumour activity than either drug alone in non-small cell lung cancer (NSCLC), reports a phase 1b study.

The study, published in Lancet Oncology, showed that toxic effects but not antitumour activity increase with rising doses of tremelimumab, but that there were no differences in toxic effect among different doses of durvalumab when tremelimumab remained constant.

Evidence of anti tumour activity was found irrespective of patient PD-L1 status.

Early clinical trials suggest blockade of multiple immune checkpoints might have greater anti-tumour activity than blockade of one checkpoint in melanoma and NSCLC.

Drugs that block the PD-L1/ PD-1 pathway act in the tumour microenvironment and prevent inhibition of T-cell function; while drugs that block the CTLA4 pathway act in the lymphoid compartment to expand the number and repertoire of tumour-reactive T cells.

Such observations have led to the rationale that combined blockade of both compartments would achieve better results.

For the study Naiyer Rizvi, from Columbia University Medical Center, and colleagues assessed the tolerability and antitumour activity of the combination of durvalumab and tremelimumab in patients with advanced NSCLC irrespective of PD-L1 status.

Between October 2013 and April 2015, 102 patients from five US cancer centres with NSCLC were enrolled in to a dose escalation phase study using a standard 3 3 and modified zone-based design.

Further expansion of escalation cohorts were allowed for safety assessments.

Results showed investigator-reported confirmed objective responses were achieved by six (23%) of patients in the combined tremelimumab 1mg/kg cohort.

Of these six patients two were PD-L1 positive and four were PD-L1 negative.

The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20mg/kg every four weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose –limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase).

Discontinuations attributable to treatment-related adverse events occurred in 28% of patients, with treatment-related serious adverse events occurring in 36% of patients.

Altogether among the 102 patients three treatment related deaths occurred that were attributed to complications arising from myasthenia gravis, pericardial effusion and neuromuscular disorder.

“The tolerability profile and antitumour activity of the combination of durvalumab plus tremelimumab reported both in PD-L1 positive and PD-L1 negative patients in the dose-escalation phase of this study indicate that 1mg/kg tremelimumab is sufficient to augment the biological and antitumour activity of durvalumab,” conclude the authors.

The data, they add, suggest PD-L1 status might not predict response to durvalumab plus tremelimumab to the same extent as has been seen with durvalumab treatment alone.

“This observation also suggests that additional factors beyond PD-1 have a role in suppressing an active immune response,” write the authors.
Durvalumab 20 mg/kg every four weeks plus tremelimumab 1mg/kg showed a manageable tolerability profile and has been selected as the dose for a phase 3 study which is currently ongoing.

Reference

S Antonia, S Goldberg, A Balmanoukian, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre phase 1b study. Lancet Oncology. Published online February 5, 2016.