The study has taken around four and a half years to complete, with progression-free survival (PFS) data released in September last year. The benefit, as measured by overall survival, has delivered a substantially better outcome that the PFS result.
The median overall survival in the patients who received HER-Vaxx plus chemotherapy was 13.9 months compared to a median overall survival of 8.3 months in patients who received chemotherapy alone. In this study patients had not previously received HER2 binding antibody treatments such as Herceptin or Perjeta.
The one sided p-value for the study was 0.066. (A one-sided test provides more power in detecting an effect but excludes the possibility of a worse result from treatment compared to the control.) The consulting statistician for the study, Brent Blumenstein, said that the trial was designed with a relaxed false positive probability, meaning that the target was to achieve a p-value of less than 0.10 (which it did). This is not the standard measure expected by regulatory agencies (to gauge clinical success) according to Blumenstein (which is a two sided p-value of less than 0.05).
For such a small patient population, it's a very good outcome, warranting further clinical investigation. The PFS outcome delivered a p-value of 0.266 with the actual months not reported. There was the same relaxed false probability target for PFS (p<1.0) which was not met.
The hazard ratio for overall survival was 0.585, which equates to a 41.5% reduced risk of death. The hazard ratio for PFS was 0.719. Overall survival is a more important outcome measure than PFS.
(Last year interim results were reported on the first 27 patients. At that time, eight of the 13 patients in the control arm had died compared to four of the 14 in the active arm receiving HER-Vaxx. The hazard ratio for overall survival at that point was 0.418 with a p-value of 0.083.)
Importantly there was no added toxicity seen from the addition of HER-Vaxx to treatment. The doses of HER-Vaxx used in this study was 50µg with the dose cleared for subsequent studies to be twice that at 100µg. The patients who responded best to treatment with HER-Vaxx were those who were observed to have generated the stronger internal HER2 antibodies.
Where antibody drugs such as Herceptin and Perjeta are antibodies infused into patients to bind to the HER2 receptor and inhibit tumour growth, HER-Vaxx functions as a therapeutic vaccine stimulating the body to produce its own anti-HER2 antibodies.
Next studies with HER-Vaxx
One of the challenges for Imugene with this study has been to gain access to patients where Herceptin (or similar) therapy is considered the standard-of-care. This is why the above trial was conducted in India and parts of Eastern Europe where access to these therapies is more difficult for patients. However it also explains the long recruitment period for that study. To conduct a head-to-head pivotal study with Herceptin could take up to 15 years according to Imugene CEO Leslie Chong.
One of the next studies with HER-Vaxx will be in 30 patients with metastatic gastric cancer who have previously failed Herceptin therapy. This study should see more rapid recruitment with the primary completion date of the study expected to be reached just 15 months from trial commencement. Although the study is expected to take 3.5 years to fully complete.
The patients will also be receiving either chemotherapy or Keytruda (a PD-1 inhibitor). MSD (Merck) will supply Keytruda for the study. There will be no control arm in this study. Ethics approval to start the study was received in May at the Queen Elizabeth Hospital in Adelaide. Additional sites are expected to be opened in Australia, South Korea and the US.
Another study with HER-Vaxx is also planned in patients undergoing gastric cancer surgery. This study will be conducted in Germany and South Korea with the company seeking to enrol 72 patients. Patients will receive HER-Vaxx both before and after surgery. Product for subsequent studies has been manufactured and is available use in these trials.
Other Studies Underway
PD1-Vaxx
Using a similar approach to the HER-Vaxx program, Imugene is also seeking to promote patients to generate antibodies against PD-1. Injected monoclonal antibody drugs such as Keytruda and Opdivo also inhibit PD-1. A Phase Ia study has been completed in 12 subjects with lung cancer (NSCLC) who express PD-L1 on the tumours in patients who have failed checkpoint inhibitor therapy (with a PD-1 or PD-L1 inhibitor)
At the end of 2020, the company had completed the first low dose cohort at a dose of 10µg. Dosing of patients in the second cohort (50µg) started in February last year. Dosing of the third cohort (at 100µg) started in August last year and was completed in February this year.
Results were published at ASCO this year. In the lowest dose, one patient had their tumour burden level reduced to zero at 16 months with one patient achieving stable disease. At the second dose, four patients achieved stable disease. And in the highest dose, there was one partial response and two patients with stable disease with one immune reaction causing discontinuation of treatment.
The study will progress into a Phase Ib trial in combination with the PD-1 inhibitor Tecentriq from Roche. Roche will supply product for the study.
An issue with PD1 and PD-L1 therapies is that primary or secondary resistance to treatment can occur. However using a chimeric cancer vaccine such as PD1-Vaxx that produces polyclonal B-cells in the body, B-cell and T-cell responses can be induced whilst limiting immune system evasion of the tumour and immune suppression (according to the ASCO paper).
Oncolytic virus CF33-hNIS
In May this year Imugene started dosing patients with its new oncolytic virus, CF33-hNIS, which was in-licensed from the City of Hope in 2019. CF33-hNIS is a new engineered virus (chimeric orthopox virus) that is highly aggressive and highly specific to tumours, with a potency orders of magnitude greater than other oncolytic viruses approved or in trials according to Chong. It's also been shown in preclinical studies to be effective against distant (non-injected) tumours (abscopal effect).
In a study against 60 different cancer cell lines (NCI-60), 97% were destroyed by this virus with the remaining 3% being retarded in growth says Chong. This includes cell lines for pancreatic cancer, lung, colon and lung cancer. The high specificity and high potency of the virus gives the therapy a high therapeutic window as well (which means a higher dose can be delivered with an acceptable side effect profile).
The program was cleared for studies in the US by the FDA in December last year. The trial will seek to recruit 100 patients with a range of solid tumours. Monotherapy with CF33-hNIS will be compared with combination therapy with Keytruda, as well as investigating the differences between injections directly into tumours and intravenous delivery.
It will be a dose escalation, open label study, with the primary completion date being the end of 2024. Safety and establishing the maximum tolerated dose are the two primary outcomes being sought, with changes in the tumours (Objective Response Rate) being one of the secondary measures.
CHECKvacc (CF33-hNIS-antiPDL1)
In June last year Imugene received approval from the FDA to start a clinical study with the novel CF33 oncolytic virus in the treatment of triple negative breast cancer. The virus has been genetically modified to also bind to PDL1, effectively acting also as a checkpoint inhibitor. The first patient was treated with this virus in October last year.
In March this year the company reported that the first three patients had been safely treated at the lowest dose and would move on to the second cohort of patients. Treatment of the second cohort started in April. Results from cohort one will be of considerable interest.
onCARlytics platform
The third platform for Imugene is to use its oncolytic virus CF33 as a delivery vehicle to solid tumours in conjunction with CAR T therapy. To date approved CAR T therapies have been limited to blood-based cancers targeting CD19. But CD19 is not present in solid tumours.
The novel concept here is to deliver the target of interest, CD19, to all tumour cells infected by the virus by re-engineering the virus to express CD19. The tumour cells can then be targeted with existing CD19 CAR T therapies. The inventors of the technology at the City of Hope believe this therapy could potentially be used for any type of solid tumour.
Chong said that to make cancer potentially the one disease with this approach is a revolutionary idea. The virus infiltrates the tumour, multiplies within the tumour, causes tumour lysis, and then puts up CD19 flags explained Chong, which will allow all tumours to then be targeted by CAR T CD19-directed therapies.
An FDA IND to initiate clinical studies is expected to be obtained by the end of this year with a Phase I trial expected to start next year.
Summary
In 2023 Imugene expects to have between nine to 10 clinical studies underway. The company had $109 million in cash at the end of March. It is capitalised at $1.3 billion.
Bioshares recommendation: Speculative Hold Class A
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