Prima BioMed — Preliminary LAG-3 combo data in breast cancer

Prima presented encouraging data from the safety run-in phase of its AIPAC Phase IIb breast cancer trial at the American Society of Clinical Oncology (ASCO) meeting held in Chicago on 2-6 June 2017. The trial is testing the effect of combining the IMP321 soluble LAG-3 fusion protein with paclitaxel in women with hormone receptor positive metastatic breast cancer (mBC) who have not previously received chemotherapy for metastatic disease. Women with HER2 positive tumours who are eligible for treatment with trastuzumab (Herceptin) are excluded from the trial.

In the safety-run-in phase 15 women were treated with either 6mg or 30mg of IMP321 in combination with weekly paclitaxel chemotherapy (80mg/m2 in three weeks out of every four). Both doses of IMP321 were found to be safe and well tolerated when used in combination with paclitaxel, with no dose-limiting toxicities reported. Cytokine release syndrome grade 1 was the only serious adverse event related to IMP321 (occurring twice in the same patient in the higher dose group). There were no grade 4 (life-threatening) adverse events related to either IMP321 or paclitaxel. The dose escalation committee confirmed the 30mg dose as the recommended Phase II dose (RP2D) for use in the randomised, placebo-controlled component of the trial.

The pooled preliminary efficacy data from the 15 patients in the safety run-in study are summarised in Exhibit 1. The overall response rate (ORR) was 47% and the disease control rate (DCR, tumour response or stable disease) was 87%. The 47% ORR from the AIPAC safety run-in was consistent with the 50% response rate reported from an earlier Phase I trial,1 which tested the 6mg dose of IMP321 in combination with weekly paclitaxel in 30 patients.

The company has previously compared the ORR in IMP321/paclitaxel studies to a randomised Phase III study of weekly paclitaxel (days 1, 8 and 15 of a 28-day cycle) as first-line therapy in HER2-negative subjects (Gray2 et al. 2009), which reported an ORR in patients treated with single-agent paclitaxel of 23%.

We have identified a Phase II study sponsored by Amgen (Martin3 et al 2011) with a similar design and paclitaxel regimen to the study above. The ORR in HER2-negative patients receiving weekly paclitaxel as first-line chemotherapy treatment for metastatic or locally advanced breast cancer in this study was 41%.

The average of the response rate in the Gray and Martin studies was 32%. While acknowledging the uncertainty inherent in cross-trial comparisons, it is encouraging to see that the response rate to IMP321/paclitaxel combination therapy is higher than the response rate to paclitaxel monotherapy in either of these two trials.

We note that there were minor differences between the Gray and Martin studies and Prima’s trials. The published studies used a slightly higher dose of paclitaxel (90mg/m2 vs 80mg/m2) and about 30% of subjects in the two published studies cited above were hormone receptor negative whereas these patients are ineligible for enrolment in the AIPAC study. Despite these differences, the two published studies are likely to be a reasonable guide to the response rate that could be anticipated in the control arm of the Phase IIb AIPAC study.

Prima also presented evidence of sustained proliferation and activation of circulating white blood cells over the course of IMP321/paclitaxel combination therapy. This included sustained increases in circulating antigen-presenting cells (APCs) and subsequent activation of effector cells including CD8 T-cells and natural killer cells.

Exhibit 2 shows that the treatment led to proliferation of APCs, including monocytes and dendritic cells, which was sustained over the 24-week course of treatment (panels A and B). Panels C and D show that injection of IMP321 prompted activation of circulating monocytes from the very first dose, and that monocyte activation was higher at week 22 than at the start of the study.

These data show that IMP321 was effective at activating APCs, in line with its proposed mechanism of action.

Prima also showed that the activation of the APC network by IMP321 was associated with sustained increases in absolute numbers of effector cells like CD8 T-cells and natural killer cells, as well as sustained increase in Th1 helper T-cell biomarkers like IFN gamma and IP-10.

These changes are suggestive of a stronger cytotoxic cellular response and improved helper T-cell immune status, which are both needed for a potent immune response against the tumour cells.

Prima’s chief medical officer Dr Frédéric Triebel pointed out that the increase in APC numbers and their activation has not previously been seen with other immune checkpoint inhibitors. He also viewed the increased numbers of CD8 T-cells and natural killer cells and the effect on Th1 cells to be indicators of potential efficacy of IMP321, as these are known to be related to anti-tumour efficacy in patients.

Prima dosed the first patient in the randomised Phase IIb component of AIPAC in January 2017. The randomised double-blind phase will enrol 226 patients, with half receiving standard paclitaxel chemotherapy on days 1, 8 and 15, plus 30mg of IMP321 on days 2 and 16 of each four-week cycle; the other half will receive paclitaxel plus placebo.

The record of the AIPAC trial on clinicaltrials.gov (NCT02614833) indicates that final data for the progression-free survival (PFS) primary endpoint are expected to be collected in June 2019. Depending on the recruitment rate and PFS observed, we estimate that top-line PFS data could mature sometime between late 2018 and mid-2019.

The European regulator (EMA) has indicated that this trial could be sufficient to support a marketing authorisation if it achieves certain (undisclosed) clinical endpoints.

In May the US FDA granted accelerated approval for the immune checkpoint inhibitor (ICI) Keytruda (pembrolizumab) in combination with the chemotherapy drugs pemetrexed plus carboplatin as a front-line treatment for non-small cell lung cancer (NSCLC). The Keytruda/chemo combo elicited a 55% ORR vs 29% for the chemo combo alone. Median PFS was 13 months for the Keytruda combo vs 8.9 months for chemo alone.

This is the first approval for chemotherapy plus immunotherapy combination treatment.

Part of the rationale for the chemo-immunotherapy approach is that the cellular debris created when the chemotherapy drug kills cancer cells stimulates an immune response, and that this immune response can be strengthened by including an immunotherapy drug in the treatment regimen. In the case of ICI drugs like Keytruda the immunotherapy strengthens the immune response by taking the brakes off the immune effector cells including cytotoxic T-cells.

Prima is similarly seeking to strengthen the immune response by combining chemotherapy with its IMP321 APC activator. In this case IMP321 acts earlier in the process by up-regulating the extent to which APC cells process the cellular debris and present tumour antigens to T- and B-cells, thereby strengthening the overall immune response.