The coronavirus pandemic prompted a number of changes in patient care in medical oncology. “One of the things that we have learned and I hope we will continue to take forward even when the pandemic is under control is that doing virtual visits is an effective way of helping to care for our cancer patients”, says Dr Schenk.  This works particularly well for those that are doing well on long-term tyrosine kinase inhibitor (TKI) therapy ….. and for surveillance visits “where we are updating scans and making sure things are OK”, she comments.

For patients, virtual visits they eliminate the stresses of having to drive to the hospital, find parking space, and find their way through the academic institution. Virtual visits allow doctors to see patients in other areas of the country without patients having to travel long distances.  “I think that’s one of the major points of change that we will carry forward even after the pandemic”, emphasises Dr Schenk.

Early in the pandemic  there was much concern about having enough personal protective equipment (PPE) and also about how to do things safely in the face of many unknown risks.  “I think our understanding really crystallised as we got more information about the virus as well as tried to continue practising and that is – cancer does not wait – when people are eligible for curative intent therapy we should do everything we can to provide curative intent therapy as per the normal standard outside of the pandemic”, says Dr Schenk.  An article in a medical journal had examined the costs and outcomes as a result of delays in cancer therapy.

“They were able to look at a number of different cancers and what they saw was that even a four-week delay could reduce the chances of patients being cured. I think that has played out in our clinical practice. Patients, unfortunately, are coming to us with more advanced disease; we are seeing early stage cancer patients less [often]”, she says. In part this was probably because services were initially reduced to “the bare essentials” and also because patients were afraid to come into a large medical centre where there were sick people.

Other ways that the hospital worked around the pandemic involved organisational changes such as reducing the number of visitors permitted able to accompany patients to appointments or for infusion therapy.

Dr Schenk now has a number of patients under her care who receive pembrolizumab alone and whose lung cancer is probably not going to recur.  “They have no evidence of disease and they’ve been on it for several years. It’s really incredible – that is not how it was [in the past]”, she says.

Dr Schenk identified two sets of trial results to be presented at the World Conference on Lung Cancer (January 2021). Again, they reinforce the importance of biomarkers in this field.

The CODEBREAK 100 trial involves the KRAS inhibitor, sotorasib. KRAS has been recognised as an oncogenic driver in lung cancer for more than 40 years and there have been ongoing attempts to find a drug to inhibit KRAS.  KRAS is found in 12-13% of patients with adenocarcinoma of the lungs. A number of KRAS inhibitors are being used in clinical trials at present. “This is exciting because it appears that we are starting to get signals of efficacy from this drug even in the phase 1 trials”, says Dr Schenk. At WCLC, presentation of the phase 2 data for sotorasib is expected. “This will give us a better idea of response rate and duration of response as well as some of the side effects and adverse events”, she adds.

The Lung Cancer Mutation Consortium (LCMC)3 trial of neoadjuvant atezolizumab represents a new approach. In this trial atezolizumab – a PD-L1 inhibitor – was given to patients before they underwent resection of their lung cancers. The hypothesis was that giving immunotherapy before surgically resecting lung tumours would help to drive better outcomes.

“The hope is that the immune system can be activated to start eliminating some of the cancer cells. I am really excited about this because I think that neo-adjuvant (before the surgery) immunotherapy either alone or in combination with chemotherapy is going the be the next breakthrough for our patients with lung cancer and I am hopeful that this will result in more cures of patients up front so that we have fewer patients with metastatic disease”, explained Dr Schenk. LCMC3 is expected to report its primary analysis of outcomes and safety.

The use of neo-adjuvant therapy is likely to increase in future. Dr Schenk says,

“It is exciting to see all these therapies that were new to all of us not that long ago really making these leaps further into curative intent therapy.  Right now in the US we use durvalumab. If patients have unresectable stage 3 lung cancer they get concurrent chemotherapy and radiotherapy and then we give them a PD-L1 inhibitor, durvalumab, for a year and that has significantly increased cure rates for that population of patients. So, hopefully, moving it to an even earlier stage, where patients are able to have their cancer resected, this will result in even better outcomes.”

The other trial that has really come to the forefront in discussions in academic oncology practice in the United States is the ADAURA trial. This trial randomised patients with completely-resected, EGFR-positive, non-small-cell lung cancer (NSCLC) to receive either standard of care (SoC) treatment or SoC plus osimertinib. This trial again illustrates the importance of biomarkers.

“This is one of the trials where these biomarkers that we often use in metastatic disease may also become important in patients with early stage disease where we treat them with curative intent”, says Dr Schenk.

The ADAURA trial recruited patients with NSCLC with the EGFR mutation – a feature that in the metastatic setting is often sensitive to tyrosine kinase inhibitors (TKIs) that prevent certain mutations from being active and causing cancer cells to grow. Patients in the osimertinib group received the drug for a period of three years.

The reason that this trial has generated so much discussion and so many different opinions on what to do, is that it was an early report on the data and so we don’t have clear survival data [to show whether] adding osimertinib would help patients live longer. What we have is a measure called ‘disease-free survival’”, explains Dr Schenk.  This shows that patients, who received osimertinib for three years, had reduced chances of recurrence of their lung cancer compared to the control group. However, previous trials of a similar design have been carried out with early-generation EGFR inhibitors and the results showed that eventually the survival curves met, meaning that adding early-generation EGFR-TKIs did not help to cure more patients. Some clinicians argue that the degree of disease-free survival is so significant that patients need to be presented with the data and have an opportunity, with their physician, to make an educated choice about whether or not to take osimertinib.

“The way this trial has changed my clinical practice is that I have this type of discussion with patients with completely resected lung cancer who are EGFR-positive and we really talk about the pros and the cons because right now we simply don’t know whether this helps cure more patients with resectable lung cancer”, says Dr Schenk.

Surgical resection may not remove every trace of lung cancer.  “What we know about lung cancer is that it has a propensity to recur even with excellent surgeries – not only taking out the tumour but also taking out the lymph nodes in the middle of the chest. Unfortunately lung cancer has a high likelihood of recurring and so one of the main things that we talk about with patients is the use of adjuvant chemotherapy”, explains Dr Schenk.  Adjuvant chemotherapy is part of the SoC for larger lung cancers and those that involve lymph nodes in the chest. It has been shown to provide a survival benefit after surgery, presumably by helping to kill the very small number of residual tumour cells that remain after surgery. “The ADAURA trial is trying to add on to that because even with surgery and chemotherapy, even with no evidence of disease, unfortunately a large number of patients still have recurrence of their lung cancer”, says Dr Schenk. The ADAURA trial is trying to improve those numbers further by adding targeted therapy for a specific mutation.

It is possible for a tumour to ‘escape’ from the effects of a targeted agent. “Right now in the United States osimertinib is the first-line choice for patients newly-diagnosed with metastatic EGFR-positive adenocarcinoma. While the vast majority of patients have a response to therapy, meaning that the disease shrinks and is under control for some time, often years, eventually it does recur”, says Dr Schenk.  The cancer cells are able to develop mechanisms to evade the inhibitory effects of osimertinib. Some of these are known but others have yet to be described.  It is therefore possible that in the ‘curative intent’ setting patients could undergo the surgery, undergo chemotherapy if appropriate, and then take  osimertinib for three years and still experience a recurrence of the cancer.  In this situation “one of the concerns is that the lung cancer might no longer be responsive to osimertinib because the cancer was able to determine a way around that therapy”, she says.

Many oncogene-driven lung cancers, such as those with the EGFR mutation, have a propensity to develop brain metastases or they are present at the time of diagnosis. In the ADAURA trial “there were fewer CNS recurrences with the osimertinib and that would also be a result that is expected because osimertinib is able to get into the tissue of the brain, it’s able to penetrate the blood brain barrier (BBB) so that it is able to exert its anti-cancer effects in that area as well”, says Dr Schenk.

“Biomarkers are king! When patients are diagnosed with metastatic lung cancer, biomarkers are really important for helping people like me decide what therapies are best to treat my patient with”, explained Dr Schenk.

The first trial that she discussed was one that illustrated the importance of the programmed death ligand 1 (PD-L1) as a biomarker. PD-L1 is a marker on cancer cells that is used to decide whether or not patients should receive immunotherapy alone or whether they might receive immunotherapy plus chemotherapy.

Recently, a five-year update to KEYNOTE 024 was published. This was a large trial that randomised patients with metastatic non-small cell lung cancer (NSCLC) to receive either pembrolizumab alone or standard of care chemotherapy. The updated, five-year overall survival results were “remarkable”, said Dr Schenk.  Of the patients who received pembrolizumab alone, almost a third were still alive at five years. “Additionally, if patients happen to have a recurrence of their lung cancer, retreating with pembrolizumab at that time is also an effective way to get the cancer under control again”, she adds.

“This trial is one that firmly establishes the role of the PD-L1 biomarker for patients with lung cancer as well as the choice of using pembrolizumab as a first line option in patients with a high PD-L1 status”, says Dr Schenk.

The cut-off level for PD-L1 is set at 50%, so if more than 50% of cancer cells express PD-L1, it is considered to be ‘PD-L1 high’. “This cut point is one where you can have a discussion with patients about whether we use immunotherapy alone or whether we use immunotherapy plus chemotherapy”, explains Dr Schenk.