Immunotherapy stepped onto the hall of fame by winning the 2018 Nobel prize for medicine. Through their landmark discovery, Professor James P Allison from the US and Professor Tasuku Honjo from Japan have outlined how immune checkpoints can be effectively targeted to deal with the toughest of cancers.
Their seminal work on cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death receptor-1 (PD-1) mechanism led to a new class of therapeutics called immune checkpoint inhibitors. These drugs have brought remarkable outcomes by radically changing the treatment approach to cancer and made immunotherapy one of the hottest areas of cancer research.
“If you really want to do something paradigm shifting, then you really have to probe basic mechanisms,” says Dr Vishva M Dixit, Vice President and Staff Scientist, Physiological Chemistry at Genentech, San Francisco, CA, commenting on the Nobel-winning work in basic science.
Unlike conventional therapeutic modalities that directly target cancer cells, these drugs block the checkpoints of the host immune systems to unleash an outright attack on cancer cells.
Since the approval of ipilimumab, a CTLA-4 blocker, for melanoma by the USFDA in 2011, checkpoint inhibitors have fundamentally changed the outcome for certain subsets of patients with advanced forms of cancers, which were hitherto considered largely untreatable. This paved the way for US regulatory approval of checkpoint inhibitors with a broader range – PD-1 and PD-L1 – to treat over a dozen cancers.
Of the two treatment strategies, checkpoint therapy against PD-1 has proven to be more effective for the carcinoma of the lung. As a group of malignancies, lung cancer offers the lowest survival rates. Lung cancer has an incidence rate of 11.6% – the highest among all cancers — and a mortality rate of 18.4%, the highest of all cancer-specific deaths, according to the Globocan 2018 report.
Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway, such as nivolumab, pembrolizumab and atezolizumab, have been rapidly adopted into clinical practice as a standard treatment option for patients with advanced non-small-cell lung cancer (NSCLC).
Exploring PD-1/PD-L1 pathways
Nivolumab, a fully human monoclonal immunoglobulin G4 antibody to PD-1 intended for the treatment of squamous cell lung cancer, won US FDA approval in March 2015. Marketed by Bristol-Myers Squibb under the brand name Opdivo, its efficacy to treat squamous NSCLC was established in a randomized trial of 272 participants, 135 of whom received nivolumab and 137 received docetaxel.
In October 2015, FDA expanded nivolumab’s approval to advanced (metastatic) nonsquamous non-small cell lung cancer patients whose disease progressed during or after platinum-based chemotherapy.
“We are continuing to explore the potential of nivolumab through our broad development programme in thoracic malignancies, including early and late-stage NSCLC, SCLC and malignant pleural mesothelioma,” says Sabine Maier, M D, Development Lead, Thoracic Cancers at Bristol-Myers Squibb.
Pembrolizumab is an alternative, highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptor.
Pembrolizumab got approval from the US FDA on October 2015 for the treatment of metastatic NSCLC in patients whose tumours express PD-L1 and who have failed treatment with other chemotherapeutic agents.
Merck sells the drug under the brand name Keytruda.
Merck is evaluating pembrolizumab in both neoadjuvant and adjuvant settings; for example, in Keynote-091 (adjuvant) and Keynote-671 (neoadjuvant and adjuvant), which are currently recruiting patients, said a Merck spokesperson.
Cemiplimab (Libtayo) is another PD-1 blocker, developed by Regeneron and Sanofi. The drug is being investigated presently for NSCLC as a monotherapy and in combination in first-line patients in different trial settings.
Atezolizumab, marketed as Tecentriq by F Hoffmann-La Roche/Genentech, works through the PD-L1 pathway. The drug is approved in Europe and the USA for second-line treatment of NSCLC following platinum-based chemotherapy.
Currently, Roche has eight Phase III lung cancer studies underway, evaluating atezolizumab alone or in combination with other medicines.
Other PD-L1 inhibitors in late-stage development for NSCLC include durvalumab (Imfinzi, AstraZeneca) and avelumab (Bavencio, EMD Serono and Pfizer).
Checkpoint therapy has really worked wonders. It brought remarkable results in patients who are deemed untreatable otherwise. It resulted in the complete remission of disease even in cases of melanoma which has metastasised. However, it fails to do the trick in all patients with the same condition.
PD-1/PD-L1 inhibitors also share some of the debilitating adverse effects which are common to this class of immunotherapies.
“There’s a substantial toxicity because when we remove the brakes, the immune system will also attack normal tissue. There is, especially with the anti-CTLA4 therapy, a tendency to get autoimmune diseases like thyroiditis and hypopituitarism,” points out Dr Dixit. But that, fortunately, has been largely managed by dose alterations and other supportive care, he adds.
Uncertainty about which patients with NSCLC are most likely to benefit from anti-PD-1/PD-L1 therapy, however, continues to be the biggest concern for oncologists treating lung carcinoma.
Researchers point to the many limitations of using the PD-L1 expression as a biomarker. Anti-PD-1/PD-L1 drugs do not inhibit every co-inhibitory interaction that may play a role in anti-tumour T-cell responses. This could be a contributing factor to the failure of PD-L1 expression to fully differentiate responders and nonresponders, they opine. The anti-PD-1/PD-L1 drug is co-developed with its own PD-L1 immunohistochemistry (IHC) diagnostic assay. The US FDA has mandated that pembrolizumab be used only in conjunction with its companion PD-L1 test, while the assays for nivolumab and atezolizumab are considered complementary.
Too many subsets
The carcinoma of the lung has high mutational burden. Mutations in EGFR and ALK genes are considered key to the development of NSCLC. These driver mutations are seen to occur in approximately 10%–35% and 3%–7% of patients respectively. KRAS mutations are found in around 30% of NSCLC cases. They are more common in patients with adenocarcinomas and smokers. At present, there is no approved targeted treatment for KRAS mutant NSCLC. Trials are underway to determine the efficacy of anti-PD-1/PD-L1 therapy according to KRAS mutation status in a subgroup.
It has also been found that high-level MET (exon 14 skipping mutations) amplification and BRAF and ROS1 mutations are driving events in NSCLC. They occur in 1%–3% of lung cancers.
Carcinoma of the lung, which appears as a single disease entity at the outset, is actually a composite of several pathologies, avers Dr K Govind Babu, Professor of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru.
“If a cell has a very high number of mutations, we call it a hot tumour. These cells can initiate a response from our immune system. But the tumour cells have a blanket to prevent the immune system from working. With the help of these drugs [immunotherapy], we can take out the blanket and make the immune system work,” Dr Babu elaborates.
Newer sub-types of lung cancer are getting identified as genomic information helps to reclassify tumours. “There are many [subsets in lung carcinoma], more than we can count,” says Dr Kurt A Schalper, Assistant Professor of Pathology and Medicine (Medical Oncology), Yale School of Medicine, USA. Even as sub-typing helps re-group tumours more specifically, the deluge of information can also complicate the diagnosis process at times.
“It is better because now oncologists can understand the biology and treat the patients accordingly. But, it is also bad because it gets the diagnosis complicated, requiring many different approaches and resources,” says Schalper.
What makes immunotherapy a better option for lung cancer are certain features characteristic of this carcinoma. Tumours in the lung tissue, as in case of melanoma, are very good at invading immunity. Therefore, the stimulation and the restoration of the body’s immunity generates a lot of anti-tumour effects. Conventional treatments, when combined with immunostimulatory agents, have been shown to be more effective than either used alone. For example, advanced carcinoma of the lung, which used to be treated with standard platinum-based chemotherapy, now depends on the expression of PD-1 marker. This can improve the outcome.
Immunotherapy is very a dynamic field and it has a very well-established role in lung cancer. Investigations are going on to see the effect of PD-1/PD-L1 blockers in earlier stages as well as in second and third-degree lesions, informs Dr Schalper.
In personalised medicine, oncologists can select drugs which works best for the individual by assessing the genetic makeup of a particular tumour. This concept of personalised medicine has greater relevance to the treatment of lung cancer. Earlier, chemotherapy used to be the only option to kill cancer cells. Then came targeted therapy where the tumour tissue is first sequenced and then specifically targeted by drugs. Now, immunotherapy shows that it is possible to enhance immunity with the help of some medications so that the body itself can attack the cancer cells. Here, all one has to do is to check for relevant biomarkers. “For lung cancers, biomarkers like PD-1 are currently available. If it is strongly positive, we can avoid chemo and go ahead with immune therapy,” comments Dr Rejiv Rajendranath, Consultant Oncologist, Apollo Specialty Hospital, Chennai, India.
The identification of the right kind of treatment is better than exposing patients to tedious chemo regimens without being sure of their efficacy.
Oncologists, according to Dr Rajendranath, are trying to lessen the use of chemo and radiation in case of lung cancer and stratify the patients to check the feasibility of various therapeutic regimes like targeted therapy, immunotherapy or chemotherapy. “Only if all the targets fail, will we go back to chemotherapy, unlike earlier days where we treated everybody with chemo,” he says, explaining how targeted and immunotherapies have brought about a shift in treatment approaches.
Clearly, NSCLC has a lot of druggable targets. But SCLC is a different story altogether. SCLC has, largely, been an orphan disease. Cisplatin chemotherapy for lung carcinoma is now almost 20-30 years old. Hardly any trials are taking place in this direction. Most recently, some breakthrough studies have come up with data showing that if we add an immunetherapy agent along with chemo in advanced stage SCLC, the survival of the patient can be improved. Survival rates are still modest. But such an advancement is really practice-changing, because clinicians now have one more drug to use on patients left with no option after all available drugs failed, contends Dr Rejindranath.
Several oncologists in India, however, prefer a wait-and-watch approach to immunotherapy. They believe that the concept is still in its infancy. Moreover, immunotherapy it is not curative. “We always tell patients that immunotherapy is not curative. But it is a better option for elderly patients, who cannot stand chemo,” says Dr Arun Warrier, Consultant Oncologist at Aster Medcity, Kochi, Kerala. Overall, immunotherapy benefits only 10%-15% of the patients with lung cancer, although it is easier on the patients. The survival benefits are also not quite significant vis-a-vis the cost, he adds.
Immunotherapy, as a breakthrough treatment modality, comes with a hefty price tag. Most Indian patients consider it unaffordable. Now, the effort is to combine the benefits of different therapies with checkpoint drugs. “But all these come at a financial cost that we like to call financial toxicity,” comments Dr Govind Babu.
Cost is an issue but it might also come down over time, believes Dr Rejindranath. But the survival rate in lung cancer, which otherwise has the poorest prognosis among malignancies, has changed dramatically with the targeted therapies. Survival benefits, for certain subsets of lung cancer, are ten times higher than those of decades past. Most of the time, patients with lung carcinoma come for diagnosis at very late stages of their disease. “Here we can only prolong their survival and give a meaningful quality of life; instead of 5-6 months to 24-28-40 months, slowly but steadily,” opines Dr Rejindranath. Surely, it does make a difference, all the more.