Therapeutics: anticancer agent

There has been a lot of interest in anti-programmed death ligand 1 (anti-PD-1) therapies to treat cancers. Another, dostarlimab, is under development at GlaxoSmithKline

It is a humanised monoclonal antibody and binds to PD ligand 1. This has the effect of increasing the immune response; the ligand is prevented from blocking the CD8+ T cells and it therefore has potential in the treatment of a wide range of cancers, particularly solid tumours.

In a multi-part, open label Phase Ib dose finding trial, it was investigated as a potential treatment for advanced cancers in combination with the PARP inhibitor niraparib or with platinum-based chemotherapy (with or without bevacizumab in both cases).1

In all, 55 patients with solid tumours who had progressed on standard therapy were given 500 mg intravenous doses of dostarlimab every 3 weeks for four cycles, then 1000 mg every 6 weeks in combinations involving niraparib or paclitaxel plus carboplatin, either with or without 3-weekly doses of bevacizumab.

In early reports, one complete response has been achieved in a patient with endometrial cancer in combination with carboplatin plus paclitaxel without bevacizumab, and there were confirmed partial responses across all different treatment regimens in a variety of tumour types, including breast, ovarian, liver, pancreatic, head and neck, and gall bladder. At the data cut-off point, 24 patients remained on treatment. All the combinations were well tolerated.

It is also being investigated in patients with mismatch repair deficient tumours. As part of a wider trial, those 48 patients with this form of cancer, 42 of which was some form of gastrointestinal tumour, were included.2

They had all progressed after previous systemic therapy for advanced disease. Patients were given 500 mg dostarlimab doses every 3 weeks for four cycles, and 1000 mg 6-weekly thereafter. The confirmed objective response rate was 44% and the complete response rate 8.3%.

The median duration of response was not reached and the probability of response being maintained at 12 months was 86%. It had an acceptable safety profile.

As part of the same trial, patient-reported outcomes were assessed for 43 patients with advanced or recurrent mismatch repair deficient endometrial cancer.3

They reported meaningful improvements in insomnia, pain and both emotional and social functioning during the trial, whereas side-effects such as nausea, vomiting, constipation and diarrhoea were stable.

Several other trials are under way, including a randomised, double-blind, adaptive Phase III trial in non-mucinous epithelial ovarian cancer, comparing the combination of dostarlimab plus the PARP inhibitor niraparib with standard of care.4

Also under way is a randomised, double-blind, adaptive Phase III study comparing standard of care platinum based therapy either with or without dostarlimab, followed by niraparib plus dostarlimab maintenance as first line treatment of stage 3 or 4 ovarian cancer.5

References

  1. N.Y. Gabrail, et al., J. Clin. Oncol. 37(Suppl.), Abst. 2560 (2019).
  2. T. Andre, J. Clin. Oncol. 38(Suppl. 4), Abst. 218 (2020).
  3. R.S. Kristeleit, et al., J. Clin. Oncol. 38(Suppl.), Abst. e18032 (2020).
  4. M.R. Mirza, et al., J. Clin. Oncol. 38(Suppl.), Abst. TPS 6107 (2020).
  5. A-C. Hardy-Bessard, J. Clin. Oncol. 38(Suppl.), Abst. TPS 6101 (2020).

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