Is immunotherapy all it’s cracked up to be?
The global spending on cancer drugs in 2020 grew 14.3% over the last five years to $164 billion. Some of the leading big pharma companies that saw an increase in revenue in their cancer drugs in 2020 include Merck & Co., Inc. (NYSE:MRK), Bristol-Myers Squibb Company (NYSE:BMY), Pfizer Inc. (NYSE:PFE), and Johnson & Johnson (NYSE:JNJ).The global spending on cancer care is projected to reach $200 billion in 2022, according to PwC. Immunotherapy is leading the way in cancer research, with many suggesting it is the way forward, over and above the existing standard of care, chemotherapy.But is immunotherapy all it’s cracked up to be?
Recent trial results highlight the benefits of immunotherapy over and above chemotherapy (SOC)
Recent trials results outlined by targetedonc.com on June 4, 2022 suggest immunotherapy is all it’s cracked up to be.
Findings from the Lung-MAP nonmatched phase 2 substudy S1800A show that treatment with pembrolizumab (Keytruda) plus ramucirumab (Cyramza) improved survival in patients with non–small cell lung cancer (NSCLC) previously treated with chemotherapy and immunotherapy compared with standard of care (SOC) therapy, according to a presentation given during the 2022 ASCO Annual Meeting.1
Despite similar progression-free survival (PFS) and objective response rates (ORRs) between the 2 groups, the PD-1/VEGFR2 inhibitor combination elicited a statistically significant improvement in median overall survival (OS) at 14.5 months (95% CI, 13.9-16.1) vs 11.6 months (95% CI, 9.9-13.0) with SOC therapies (HR, 0.69; 95% CI, 0.51-0.92; standard log-rank P = .05). This benefit was consistent across all subgroups examined, including those stratified by PD-L1 expression.
“Most patients with advanced non–small cell lung cancer will receive immunotherapy as part of their initial therapy. Though despite improved survival and clinical benefit, resistance develops.”
Karen L. Reckamp, MD, director of Medical Oncology, associate director of Clinical Research, and medical oncology director of the Lung Institute at Cedars-Sinai Medical Center in Los Angeles, California, said during a presentation of the data. “Developing therapies to overcome resistance to immunotherapy is a major area of unmet need for our patients.”
uptodate.com echoes these sentiments by noting that Checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the immune system, have substantially improved the prognosis for patients with advanced malignancy.
The primary targets for checkpoint inhibition include:
Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) – Multiple antibodies against PD-1 and PD-L1 have been approved by the US Food and Drug Administration (FDA) or are in development and have shown great promise in multiple malignancies. Nivolumab, pembrolizumab, cemiplimab, and dostarlimab, all of which target PD-1, and atezolizumab, avelumab, and durvalumab, all of which target PD-L1, have been approved for various indications.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) – Ipilimumab, an anti-CTLA-4 antibody, is approved by the FDA, with others in development.
Side effects and the difficulties in analysing immunotherapy alongside chemotherapy (SOC)
However in spite of these important clinical benefits, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest [1,2]. IrAEs include dermatologic, gastrointestinal, hepatic, endocrine, and other less common inflammatory events. IrAEs are believed to arise from general immunologic enhancement, and temporary immunosuppression with glucocorticoids, tumor necrosis factor-alpha antagonists, mycophenolate mofetil, or other agents can be an effective treatment in most cases.
Kevin Harrington, FRCP, FRCR, FRSB, PhD, The Institute of Cancer Research and Royal Marsden Hospital, London, UK, discusses the difficulties of using immunotherapy alongside standard-of-care (SOC) treatments of chemotherapy and radiotherapy for head and neck cancer in this video.
Without doubt immunotherapy like chemotherapy, can cause side effects within patients. It is important to note that as your immune system works harder than normal during immunotherapy treatment it may adversely effect your healthy cells and organs and cause whats called immune related side effects.
Phase 3 trials indicate immunotherapy line balling with chemotherapy (SOC)
So is immunotherapy all it’s cracked up to be?
Side effects are not the only concern when analysing immunotherapy treatment versus chemotherapy treatment arms. cancertreatmentreviews.com highlighted some of the difficulties in evaluating immunotherapy in treating cancer as opposed to chemotherapy when discussing a recent study designed to compare the effectiveness of single-agent immune-oncology (IO) compounds versus platinum-based chemotherapy in the first-line setting of aUC.
OS data from 2,068 individuals from 3 phase III trials investigating the role of IO vs chemotherapy were reconciled. Overall, patients receiving IO [n = 1,013 (49%)] or chemotherapy [n = 1,055 (51%)] had similar OS with a 24-month ΔRMST of −0.4 (95% CI: −1.1, 0.4; p = 0.2) months. In the cisplatin-ineligible population, patients receiving IO [n = 509 (49%)] or chemotherapy [n = 530 (51%)] had similar OS with a 24-month ΔRMST of 0.1 (95% CI: −0.9, 1.2; p = 0.7) months. In the cisplatin-ineligible population with PD-L1-high tumors, patients receiving IO [n = 226 (50%)] or chemotherapy [n = 226 (50%)] had similar OS with a 24-month ΔRMST of 1.1 (95% CI: −0.5, 2.7; p = 0.1) months.
In Conclusion the researchers and study found no OS benefit for patients treated with first-line immune checkpoint inhibition compared to chemotherapy among the overall population, cisplatin-ineligible patients, and PD-L1-high patients.
Are Overall Survival Rates (OSR) the best way to evaluate immunotherapy clinical trials?
ncbi.nlm.nih.gov believes some of the difficulties in assessing immunotherapy as opposed to chemotherapy may be found in the way immunotherapy trials are structured, with a focus on overall survival rates. Their findings highlight a fundamental challenge in the design of immunotherapeutic trials where OS is the most reliable indicator of efficacy. As the FDA guidance on clinical trial endpoints points out, despite being a universally accepted outcome measure, OS is significantly affected by subsequent therapies, crossover to the experimental immunotherapy following progression on the SOC is particularly difficult.
The field of cancer immunotherapy is rapidly expanding, and as numerous clinical trials with a dizzying array of agents, including cancer vaccines, checkpoint inhibitors and novel treatment strategies, are undertaken, so the broader cancer community must adjust to the unique challenges presented by these developments. The current clinical trial and drug development framework is, at times, ill-suited to the direct comparison of therapies with distinct mechanisms of action, response kinetics and impact on commonly accepted clinical outcomes. The SOC in each trial fundamentally affects the design, management and interpretation of these trials, and only effective communication between drug developers, researchers, clinicians and regulatory bodies will enable the development of a modern, ethical and responsive approach to clinical trial execution. In summary ncbi.nlm.nih.gov note that novel approaches to trial end point selection, definition and measurement will be required if we are to be able to rise to these challenges. They suggest we owe it to our patients to do just that.
The Cancer Research Institute is onboard when it comes to immunotherapy
We can start to see how mixed messages exist when it comes to immunotherapy versus chemotherapy. Though in the main regulatory authorities do espouse the virtues of immunotherapy. Take a look at this video which formed part of the 8th Annual Cancer Immunotherapy Month™ in June 2020, hosted by the Cancer Research Institute.
Immunotherapy patient stories are part of the Cancer Research Institute's Answer to Cancer Patient Education Program. Established in 1953, the Cancer Research Institute (CRI) is a 501(c)(3) nonprofit organization dedicated to harnessing our immune system’s power to control and potentially cure all cancers. Their mission: Save more lives by fueling the discovery and development of powerful immunotherapies for all types of cancer.
Let’s take a look at one such successful immunotherapy story
Oswald believes immunotherapy is all it’s cracked up to be.
On New Year’s Day 2017, Oswald woke up extremely sick. After a week of illness and wanting the best care possible, he left Brooklyn and went to Columbia University Medical Center where he was diagnosed with stage 4 non-small cell lung cancer. With a PD-L1 score of 80 percent, he was eligible for a newly approved first-line treatment with pembrolizumab (Keytruda), PD-L1 checkpoint immunotherapy. Almost immediately, he felt different; today, he has no evidence of disease. Now, every day is like a New Year’s Day for Oswald, and he looks forward to dancing in Trinidad's Carnival next year. https://www.cancerresearch.org/patients
This Drug Could Transform Breast Cancer Treatment - but is it a chemotherapy or immunotherapy drug?
The phase 3 Destiny-Breast04 study for AstraZeneca and Daiichi Sankyo’s drug Enhertu resulted in reduced the risk of disease progression or death by a whopping 50% and the risk of death by 36% in a group of patients with previously treated HER2-low metastatic breast cancer. Standing ovations are hard won at ASCO's annual meeting and recently Enhertu was the beneficiary of such plaudits from the 2022 conference members.
Why was Enhertu lauded with such praise at ASCO 2022?
In patients with HR-positive disease, which constitutes the trial’s primary endpoint analysis, Enhertu cut the risk of disease progression or death by 49%. The drug nearly doubled the median progression-free survival (PFS) to 10.1 months, versus 5.4 months for chemo.
So where does Enhertu sit on the immunotherapy versus chemotherapy spectrum. Well just to complicate analysis even further Enhertu is somewhat of a hybrid, or a cross between a chemotherapy and immunotherapy drug. Enhertu (Fam-trastuzumab deruxtecan-nxki) is a chemo drug (chemotherapy) and it is also a targeted therapy anti-cancer drug.
Enhertu fights cancer in two ways:
- the antibody (trastuzumab) part is designed to find and attach to the HER2 receptor on cancer cells
- once attached to the receptor the chemotherapy (deruxtecan) part of it is released into the cancer cells which destroys the cancer cells and any surrounding cancer cells
Enhertu has been made by joining two different types of anti-cancer drugs together to make one drug called antibody-drug conjugate (ADC). Whilst being a chemotherapy drug, Enhertu is also a targeted immunotherapy medicine. As we now know immunotherapy drugs utilize the body’s immune system to fight cancer cells by stimulating the natural defenses of the body’s immune system, and this is exactly what Enhertu does.
Symptomatic of chemotherapy drugs and as we now recognise many immunotherapy drugs, there are many side effects with Enhertu. Mild side effects of Enhertu can include:
- nausea and vomiting
- fatigue (lack of energy)
- headache
- upper respiratory infection, such as the common cold
- decreased appetite
- cough
- mouth sores
- hair loss
- digestive problems, including indigestion (upset stomach), constipation, and diarrhea
Beyond efficacy, Enhertu has also been linked to a potentially dangerous side effect known as interstitial lung disease (ILD), which causes scarring of the lungs. In Destiny-Breast04, 45 Enhertu patients (12.1%) experienced drug-related interstitial lung disease, according to an independent review committee, including 3 (0.8%) deaths. By comparison, only 1 patient in the chemo arm experienced a low, grade 1 case of the lung problem.
So what does this all mean for Imugene?
So what does all this mean for Imugene, a company founded upon immunotherapy treatment? In essence it means Imugene must to continue to strive, as they are, to develop cancer drugs that are safe and low in toxicity. Drugs which produce relatively small or inconsequential side effects in patients.To this end they are succeeding. Her Vaxx, PD1 Vaxx, and now CF33 trials have all been deemed safe, low in toxicity and inconsequential when it comes to side effects in patients, when monitored by Independent Review Committees worldwide. As an example recruitment for the phase 2 trial of HER-Vaxx completed in January 2021, after the independent data monitoring committee (IDMC) recommended a lower number of patients would be needed for study completion.The Committee at the time deemed it unethical to continue with the trials existing number of patients, given Her Vaxx’s outstanding safety results when compared to the existing standard of care, chemotherapy.The median overall survival for HER-Vaxx-treated patients in the interim analysis was higher than the chemotherapy group – 14.2 months versus 8.8 months, respectively.
Perhaps even more importantly Imugene does need to continue designing and formulating clinical trials in a framework that enables independent committees to properly assess and evaluate the benefits of their immunotherapy treatments against that ofchemotherapy. In their current trials there has been a focus on treating late stage cancer patients, who have already undertaken several chemotherapy and alternate immunotherapy treatment programs. Many of these patients have failed in their existing treatment regeimes. As such they come to existing Imugene trials with depressed and weak immune systems, and are therefore compromised from an independent evaluation perspective. With this in mind Imugene is working hard to commence clinical trials wherein early stage cancer patients are recruited. Patients with stronger immune systems that have not already been subjected to chemotherapy and other treatment programs. The phase 2 Her Vaxx combination trials with Merck Germany and Pfizer, and the current phase 1 Vaxinia trial in the US, are trials aiming to recruit earlier stage cancer patients.
Most recently Imugene’s PD1 Vaxx phase 1 trial results exhibited a stabilsation response from many patients with non small cell lung cancer (NSCLC). This gives us faith their existing B Cell immunotherapy platform is working as planned, and that in conjunction with Her Vaxx, and now CF33, Imugene can offer patients safe and effective immunotherapy treatment without excess side effects. Treatments that indeed stimulate the immune system, without compromising our healthy cells and organs in the process.
Best of luck to all LTH’s - DYOR
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