Starting with the evolution of therapy in lung cancer. Traditionally a couple decades ago, lung cancer was treated as one, then we subtype it based on histology, whether it is non-small cell or small cell. Then subsequently, we had a histologic breakdown between non-squamous and squamous large cell adenocarcinoma over the last decade or so.

We have gotten really good at molecular pathology, really trying to subtype the lung cancer, not just based on either the pathology or histology, which is non-small cell, small cell, or squamous non-squamous, but also molecular, as well as PD-L1 expression. With the molecular pathology, we have different actionable alterations that we are looking for, and the PD-L1 expression we have different categories of PD-L1 expression that are important in terms of treatment decision making.

[00:10:29]

Targeted Therapy for NSCLC: Timeline of Milestone Events

Here is the landscape of targeted therapy and timeline of milestone events. Obviously, this slide is just meant to be expressing the amount of progress we have made over the last few decades, starting from 1970s up until recently, you can see the number of treatments that have been approved across the time in terms of all the different actionable alterations that we have in terms of targeted therapy.

[00:10:57]

2024 IASLC Survey on Biomarker Testing in Lung Cancer

We have also the results from the 2024 IASLC Global Survey on Biomarker Testing in lung cancer, where about 98% believe that biomarker testing impacts significantly outcomes as well as 91% really understood who should receive testing, and more testing is advised as well as done for late stage compared to early stage, and this ranked highly important to perform biomarker testing based on the late stage.

Again, this is something that has not just changed the treatment landscape and testing landscape within the US, but globally, and some of the results from this survey conducted by the IASLC, which is the International Study for lung cancer, really outlines the importance of biomarker testing.

Then more than one half of the patients receive biomarker testing in 67% when the survey was done in 2024, compared to 39% when it was done in 2018. That obviously, with time, we continue to realize the importance of biomarker testing. Then 40% of the times people still have to treat patients prior to obtaining biomarker testing results, but really, the best practices are if you can and if patient is asymptomatic, and there is no high burden of disease, then really what is recommended is to wait for biomarker testing before starting treatment.

[00:12:30]

Barriers to Precision Oncology

In terms of barriers to precision oncology, again, from the same study in 2018 was cost, lack of quality and standards, access awareness, and long turnaround times in 2024. These perceived testing rates improved from 2018, as I discussed below. However, the barriers continue to persist, and they are similar across tumor stages, with cost being the most common barrier to adoption of biomarker testing as is outlined in the figure here, then time, sample quality, access, and awareness being at 8%.

[00:13:07]

NSCLC Biomarker Testing - Tricky Timing

The biomarker testing, there is obviously a lot of different ways that we need to test for biomarkers. Specifically talking about advanced non-small cell lung cancer, which can be tricky in terms of also the timing and the time it takes for us to get the results back. When you think about immunohistochemistry, usually we would use PD-L1, IHC, or immunohistochemistry, again, as I mentioned, for treatment recommendations.

That typically is back within a couple of days depending on where you send it out or is it done in-house, but then the next generation sequencing, which usually will take weeks, at least two to three weeks tissue sequencing taking longer time than liquid biopsy or blood based next generation sequencing, which will typically take about one to two weeks, and then most external vendors when we send NGS takes about, I think two to four weeks, I would say, depending on the situation. There is a lot of testing that we do, and all of this testing is coming back, the reports are coming back at a different time point. It becomes very important for us to assess in terms of also like following up the patients when we see them first in order to start treatment and make treatment decisions.

[00:14:25]

Tissue vs Liquid Biopsy for Molecular Profiling of Advanced NSCLC

As I mentioned, there is also the tissue biopsy vs the liquid biopsy, so both of them are recommended. In fact, there is IASLC guidelines recommending concomitant testing, both with blood-based liquid biopsy, which is also known as circulating tumor DNA, as well as tissue biopsy. There is obviously unique advantages and disadvantages to doing each of these.

Tissue biopsy continues to be the gold standard in terms of molecular profiling because it will give you not just the information in terms of the next generation sequencing, but also pathology information helps with the assessment of PD-L1. Unfortunately, it takes longer turnaround time, as I mentioned. Then a lot of the times we face the issue that we have limited tissue quantities, which again can be an impediment in terms of doing tissue biopsy and getting results.

It is also not always feasible to do tissue biopsies at progression. Most of our patients, when they progress, they are doing fairly poorly, and it becomes very difficult for us to get biopsies at that point in time. Tissue biopsies are also limited by heterogeneity of the tissue, and depending on where you obtain the tissue from. Some of these disadvantages are actually countered by doing liquid biopsy or circulating tumor DNA, which basically will have a rapid turnaround time.

It is minimally invasive. It can be repeated over time, even at progression, without much invasive procedures required, and it better captures tumor heterogeneity. However, the disadvantage being that it is the only thing that we can test is just the actionable genomic alterations.

We cannot look at pathology, we cannot look at PD-L1 and other IHC tests, and obviously, it can increase cost to use it concurrently with tissue testing. In my practice, for any newly diagnosed non-small cell lung cancer patient that I am seeing, I order concomitant concurrent testing of tissue biopsy as well as a blood based liquid biopsy, because again, there are instances where tissue biopsy either comes back as insufficient or misses something, and you may be able to find something on a liquid biopsy that may be relevant currently or even in the future in terms of getting patients on clinical trials.

[00:16:49]

Real-World Biomarker Testing Patterns Among Patients With mNSCLC in the United States

Real world biomarker testing patients among patients with non-small cell - patterns among patients with non-small cell lung cancer in the United States. This is a study that was published last year and really showing the percentage of patients receiving biomarker testing year over year. Thankfully, we can see that there is a slow but definite increase in terms of the testing across the number of years on percentage of patients as well as biomarker-informed therapy use per year.

We can see that there is an increase in some, but not all, where some of them, for example, ALK is quite flat over the last decade or so. Again, use of biomarker-informed therapies were more prominent in patients, but comparison of approval years for biomarker-informed therapies with year of testing indicated that some patients received biomarker-informed therapies years after initially testing positive. That is really the gap that we have to fill.

[00:17:51]

Disparities in Biomarker Testing Rates

There is also disparities in biomarker testing. If we talk about patient characteristics, testing rates are generally higher in younger patients in females, and those that are commercially insured. The higher testing rates were observed in Asian patients, followed by Hispanic and then white, and then, unfortunately, lowest rates among African American or Black patients. Biomarker testing rates remain suboptimal in specific racial, ethnic as well as insurance subgroups, indicating that further work is needed to bridge these gaps and ensure that we do biomarker testing for all patients that come through the door with non-small cell lung cancer.

[00:18:28]

Molecular and PD-L1 Testing at Initial Diagnosis to Guide NSCLC Treatment

In terms of as I mentioned, initial diagnosis of non-small cell lung cancer biomarker testing is a very important aspect in terms of treatment decision making. It used to be that it was very valuable just for advance. Now, it is also very valuable for early-stage disease. When we talk about neoadjuvant and adjuvant setting, I think at least we need a PD-L1 IHC as well as EGFR and ALK testing.

While in the advanced stage disease, we need broad NGS testing along with PD-L1, IHC at diagnosis, and then broad molecular testing for all cases of non-squamous non-small cell, and there is a list, a whole bunch of mutations that we want to test for. That is why a broad NGS testing is preferred, which is EGFR, ALK, ROS1, BRAF, NTRK, NRG1, MET, RET, MET exon 14, skipping KRAS, G12C, and HER2. If your head is not spinning by me reading that, I think that should suffice in terms of just explaining why broad-based next-generation sequencing is much better than trying to do single-gene testing in advanced non-small cell lung cancer.

For squamous non-small cell lung cancer, it is generally recommended to consider testing if a patient is young never or light smoker or in female patients, but honestly, in our practice, we test all our patients, whether it is squamous or non-squamous because there are rare instances where you can identify these targets even in squamous patients.

We do not want to miss a patient with squamous who may be able to get on targeted therapy, although rare, could be very beneficial, especially in some of the emerging therapies like FGFR and others, where that is very common in squamous and again, very important for screening for clinical trials. Ideally, biomarker results should be obtained before starting checkpoint inhibitor therapy.

[00:20:30]

Polling Question 7

That leads us into question number seven. What frequency of PD-L1 testing do you perform for your patients with newly diagnosed advanced non-small cell lung cancer? The options are on the screen

A. Less than 1%;

B. 1% to 24%;

C. 25% to 49%;

D. 50% to 74%;

E. 75% to 99%; or

F. More than 99%.

Speaker 2: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We have a smattering, mostly all about 25%, all the way up to 99%.

[00:21:21]

Polling Question 8

Then how often do you initiate treatment before you receive molecular testing results for a patient who is not in a critical scenario? That being a key identifying factor, that patient is not in a critical scenario. The options are

A. Less than one;

B. 1% to 25%;

C. 25% to 49%;

D. 50% to 74%

E. 75% to 99%; and

F. More than 99%.

Speaker 2: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: Again, we see quite a good distribution. Most common answer being 25% to 49%, but really, like a normal distribution curve, we see all the ends of the spectrum here as well.

[00:22:21]

Polling Question 9

The next question is about typing in your experience, the greatest barriers to biomarker testing for your practice. You can type the answer in the chat, which will really help us figure out what are some of the real-world barriers that we are continuing to face today.

Speaker 2: As Dr. Desai said, you can type your answer in the chat, or we do have a polling box open. You can use either function. We will leave the polling box open. Dr. Desai, you can move forward.

[00:22:58]

Frontline ICIs in Advanced NSCLC

Dr. Desai: All right. Then that leads us into our discussion for frontline immune checkpoint inhibitors, or ICIs, in advanced non-small cell lung cancer. There is a lot of data. Essentially, I am going to go through some of these studies, and by the end of it, a lot of the times when I am discussing this with fellows, they are like, do we have so many options and how do I make sense of it? Hopefully, as we go along, I will try to highlight some of the key things that are important, and hopefully some of that sticks with you after the talk.

Ideally, as I mentioned, we are really thinking about immune checkpoint inhibitors in three different buckets, which is the regimens in three different buckets based on the PD-L1 status. That is really your decision-making factor. If it is more than 1%, but less than 50%, or 1% to 49%, and then more than 50%.

When we talk about PD-L1, more than 50%, essentially all the regimens that you see here are single-agent immune checkpoint inhibitors. Now, obviously, there are different immune checkpoint inhibitors here, pembrolizumab, atezolizumab, cemiplimab, but just a big picture for PD-L1 greater than 50%, you could use a single IO or single ICI regimen with these. Then we will go through each of the studies for all these agents. Again, like I said, I want you to go out with a big picture understanding of single immune checkpoint inhibitors for PD-L1 more than 50%.

[00:24:36]

Frontline ICI Monotherapy Trials

The frontline trials we start with KEYNOTE-024, which is the pembrolizumab trial. Again, most of these trials, again had enrolled all these patients with PD-L1, TPS greater than 50%. Then the randomization was to an immunotherapy like pembrolizumab vs platinum doublet chemotherapy. Here is the EMPOWER-Lung 1, which is the cemiplimab trial.

Again, you can see very similar immunotherapy vs chemotherapy investigator's choice. Then IMpower110, which is the atezolizumab trial again atezolizumab vs chemotherapy platinum doublet, but that is defined per histology, and along with maintenance pemetrexed and best supportive care.

[00:25:20]

FDA-Approved ICI Monotherapies for PD-L1-High Advanced or Metastatic NSCLC

Going one by one through these results, so in terms of the KEYNOTE-024, which is the pembrolizumab trial, looking at the overall survival curves, you can see the median overall survival 26.3 vs 13.4 hazard ratio of 0.62. Similarly, Empower-lung one, median overall survival 26.1 vs 13.3, hazard ratio 0.57. Then Atezolizumab 20.2 vs 14.7 hazard ratio of 0.76. You can see in all of these three very comparable in terms of median overall survival in excess of 20 months with the immunotherapy and less than 20 months, really 13 to 14 months with the chemotherapy. Then the hazard ratios again being quite significant with significant p values 0.62. Somewhere around 0.6. Really, having good benefit in terms of overall survival compared to chemotherapy.

[00:26:25]

Frontline ICIs in Advanced NSCLC

When you look at the PD-L1 less than 50%, that is where we start getting more options outside of just using single-agent immunotherapies. There is the CheckMate 227, which is approved with dual immune checkpoint inhibitors without chemotherapy, that is nivolumab plus ipilimumab. Then in most of the cases, there is a smattering of different trials where there is an immunotherapy agent in combination with chemotherapy.

Now, here we have single-agent immunotherapy plus chemotherapy approved. We also have dual agent immunotherapy plus chemotherapy approved. You can see on the bottom of the screen here these two trials had two different immunotherapies. One being PD-L1 inhibitor and the other being an anti-CTLA-4 and along with chemotherapy. Then there is also the single-agent immunotherapy and chemotherapy that is also approved.

There is one regimen where we have a bevacizumab, which is a VEGF inhibitor that is approved only for non-squamous population, but most of the cases you would see the utilization of single-agent or dual agent immunotherapy with chemotherapy. Essentially, the idea is if the PD-L1 is not more than 50%, you need to give the patient some chemotherapy based regimen.

[00:27:49]

First-line Pembrolizumab + Chemotherapy in Advanced NSCLC

Going through the trials, so we will first talk about the use of pembrolizumab plus chemotherapy regimen. There were two different studies one in the non-squamous histology, which was the KEYNOTE-189 and then one in the squamous histology, which was the KEYNOTE-407. Again, overall survival curves, the idea was doing the single agent immunotherapy with pembrolizumab plus chemo vs placebo plus chemo. You can see median overall survival 19.4 vs 11.3 in the non-squamous population, 18.4 vs 9.7 in the squamous population. A hazard ratio of 0.6 here, 0.7. Again, definite improvement in overall survival, hence the FDA approval and the use of pembrolizumab plus chemotherapy in first line setting.

[00:28:40]

First-line Atezolizumab + Chemotherapy in Nonsquamous Advanced NSCLC

Similar study for atezolizumab plus chemotherapy in the non-squamous advanced non-small cell lung cancer setting. There were two trials one with atezo and chemotherapy vs chemotherapy. Then there is another trial, which is the IMpower150, where atezolizumab plus chemotherapy plus bevacizumab was used. Hence, in that table, you see plus or minus bevacizumab. Again, you can see here the hazard ratio the overall survival curves showing quite a benefit, 0.79, 0.80, so with the atezolizumab-based regimens.

[00:29:16]

EMPOWER-Lung 3: First-line Cemiplimab + Platinum CT vs Placebo + CT in Advanced NSCLC of Any Histology

Then we have the cemiplimab-based regimen, which is cemiplimab plus platinum chemotherapy. There is only one trial with cemiplimab where they included any histology, so both non-squamous and squamous were included in this. You can see that cemiplimab plus chemotherapy vs placebo plus chemotherapy median overall survival 21.9 vs 13.0. Again, showing this overall survival curves, patients doing really well, and there are quite a number of patients even over after two years that are free from - do not have any events in terms of death or progression.

[00:29:57]

CheckMate 227: First-line Nivolumab + Ipilimumab vs Chemotherapy for Advanced NSCLC

Then we talk about the only dual immune checkpoint regimen that is approved as without chemotherapy in this population for advanced non-small cell lung cancer, which is the nivo plus EP vs chemotherapy trial, which is the CheckMate 227, five-year overall survival in those with PD-L1, more than 1% is a hazard ratio of 0.77. Nivolumab plus ipilimumab, you see 17.1 vs 14.9. Then, in the less than 1% population, you see 17.4 vs 12.2. Off note, this is not an FDA-approved indication for PD-L1 less than 1%. It is only approved for PD-L1 greater than 1%, where you could use the nivolumab plus ipilimumab dual immune checkpoint.

[00:30:48]

CheckMate 9LA: Nivolumab + Ipilimumab + CT vs CT in Advanced NSCLC

Then there is the CheckMate-9LA, which is nivo plus IPI plus chemotherapy vs chemotherapy. This is that dual immune checkpoint plus chemotherapy. One of those regimens that I was talking about. You can see overall survival here again, 15.8 vs 11. Hazard ratio of 0.74. Then in the PD-L1, less than 1% patients measured by IHC, you can see that 17.7 vs 9.8 hazard ratio here actually more significant with 0.66, and chemotherapy doing poorly here with the less than 1%. This is a poor prognostic subgroup. Just to add, in terms of in my practice, I do use dual immune checkpoint plus chemotherapy regimen, specifically in patients with PD-L1 less than 1%, for this very reason that they actually do quite poorly with chemotherapy. They do much better with the dual immune checkpoint plus chemotherapy, based on the CheckMate-9LA.

[00:31:50]

POSEIDON: IL Durvalumab Tremelimumab + Platinum Chemotherapy in Stage IV NSCLC

There is also another dual immune checkpoint plus chemo trial, which is the POSEIDON data, where you have durvalumab plus tremelimumab with platinum chemotherapy. Again, this was a trial with three different arms, but really comparing durva, treme plus chemotherapy vs chemotherapy. That is really the arm or the comparison or the regimen that is approved. You could see here 14 vs 11.6 months. You have the landmark overall survival results here. Then again, this is overall survival showing benefit with the dual immunotherapy plus chemotherapy in really all comer population.

[00:32:34]

Genomic Biomarkers for Immunotherapy Response

Talking about genomic biomarkers for immunotherapy response. We talked about a bunch of different immunotherapy regimens that we use.

[00:32:44]

Immunotherapy + Chemotherapy in EGFR-Mutated NSCLC After Progression on TKIs

In terms of if we talk about why we want to test these people, advanced non-small cell lung cancer patients for biomarkers, is when we do find a biomarker, let us say for example here, EGFR mutation. Then in most cases, you want to start them on a targeted therapy with EGFR tyrosine kinase inhibitor.

Now, the role of immunotherapy in this subset of population is debated essentially because we have had a slew of different trials with very muddy data in terms of the true value of immunotherapy in this population. We did we did start with the IMpower150, which was that atezolizumab plus chemotherapy trial that I showed you.

They had about 124 patients with EGFR-positive advanced non-small cell lung cancer. You could see here the hazard ratio was 0.90. Crossing 95% confidence interval that was being used for I would say a small bit of time based on this study, especially when we did not have other options like amivantamab and dato-DXd that we have today, but then there were quite a few trials, which were dedicated specifically to EGFR mutated TKI resistant population.

For example, the CheckMate 227, which looked at nivo plus chemo vs chemo, as well as KEYNOTE-789, which looked at pembro plus chemo vs chemo. Across the board, you can see that there is really no overall survival difference here. You can see again, hazard ratio crossing one. Similarly, here you can see hazard ratio 0.82 but with a 95% confidence interval crossing one.

Again, these are two negative trials that we see in the EGFR-mutated progressed on EGFR TKI population. We have a similar trial with sintilimab where we do not see again benefit despite adding bevacizumab in here. Then we have the IMpower150 one, which is the ABCP vs the BCP regimen. Again, we are not seeing any benefit with the immunotherapy compared to just using bev plus chemotherapy.

Again, all of these data to say that within the EGFR mutated non-small cell lung cancer population progressing on TKIs, the role of immunotherapy currently is limited. I would use the other targeted agents or targeted-like agents, like antibody drug conjugates that are currently approved and have good data in this particular setting.

[00:35:26]

Potential Toxicity With Sequential Use of Immunotherapy Followed by a TKI

The other reason is that there is also a potential toxicity with sequential use of immunotherapy followed by a TKI. This is really an example of when you start a patient on immunotherapy without biomarker testing results and you find that this patient in particular has an EGFR mutation, and then you switch them to a tyrosine kinase inhibitor targeted therapy, there is a potential for increased toxicity, which is the reason why we recommend not to start patients on immunotherapy, especially before the biomarker testing results are out.

Now, there are obviously cases where a patient has high burden of disease. They are quite symptomatic, and you need to do something. In those specific cases, my personal approach is to start them on chemotherapy and then plan to add immunotherapy only after the biomarker testing has resulted, typically by cycle two. Again, that is based on the fact that this retrospective review of patients, regardless of the sequence, whether you give ICI first and TKI later or TKI first and immunotherapy later. 

There were severe immune-related adverse events, specifically pneumonitis, that were observed in these patients, as you can see, as well as a couple of patients with colitis and hepatitis. There is some additive toxicity with immunotherapy TKI sequence, and hence this is avoided. Biomarker testing is of paramount importance to start with.

[00:36:59]

Practical Considerations for IO in Advanced NSCLC

Practical considerations for immunotherapy in advanced non-small cell lung cancer, as I mentioned, PD-L1 high disease, single-agent IO chemo IO combinations can increase response. Survival is similar to single-agent IO, and so that is the preferred approach. PD-L1 negative disease, mostly you are going to do IO plus chemo. You could do dual IO or single IO, and then PD-L1 1% to 49%.

Again, quite similar. Mostly, you are going to use IO, and usually you can use single IO or dual IO. There is a dual IO without chemo is an option, but I think it is not highly utilized in practice. Long-term survival is possible with this. It is realized only in a subset of patients. As we saw in all of those graphs, most of those graphs are two-year intervals. Yes, you have patients beyond two years and maybe even at five years. The percentage of patients really is about 10% to 20% that are the long term survivals, the tail of the curve, as we like to say.

[00:38:02]

Patient Considerations Informing Treatment

Patient considerations for informing treatment. Treatment goals, patient wishes need to be discussed. Obviously, discussing caregiver support transportation because these are usually every three-week infusions finances scheduled for administration, especially when patients are currently working and want to continue working.

A lot of our patients unfortunately, want to continue working through chemotherapy because of insurance issues or fear of losing insurance. Smoking history, autoimmune conditions, and use of immunosuppressant for those autoimmune conditions is important to know because again those autoimmune conditions may be exacerbated by using immunotherapies, then performance status as well as common comorbidities to be considered for treatment.

[00:38:50]

Case Intensive 1 Case Presentation

We will now dive into a case. This is a case of a 73-year-old man with COPD oxygen-dependent, presenting with newly diagnosed metastatic non-small cell lung cancer adenocarcinoma histology. Lives 90 minutes from the nearest clinic. Patient has a performance status of one. Imaging has showed a 4-centimeter left upper lobe mass, left hilar mediastinal adenopathy as well as bony metastases. PD-L1 is 30%, and you are still waiting for his NGS results after two weeks.

[00:39:22]

Case Poll 1

Would you recommend initiating treatment before his NGS results are available?

A. Yes; or

B. No; and

C. Unsure.

These are your options.

Speaker 2: Five more seconds. All right. Thank you. We will close the poll and share the results.

[00:39:54]

Case and Practice-Specific Discussion

Dr. Desai: We had 50% of cases saying yes. 33%, no. Recommending initiating treatment before NGS results are available. We have a bunch of considerations here, specifically to the case as well as the practice, one are the issues that you face that may delay NGS testing results, I just went to the chat. I saw in our previous poll someone said insurance as a barrier to NGS testing, which totally understandable.

That is, as mentioned, even in the study that was done, that could be a barrier, including cost. What is your algorithm when delays happen? What does your practice do for patients who do not want to wait for the results to initiate treatment, which can also be an issue because the patients really want to get started, usually by the time they see us?

There has been a lot of delays already in terms of diagnosis, biopsy results, and things like that. How long do you feel comfortable delaying therapy in different patient scenarios? If there is any one in the live environment or in the virtual environment wants to maybe talk about this, or we do have a few slides. Otherwise, I can keep going for the second case.

Speaker 2: I do not see anything being posted in a chat or Q&A, or nobody requesting their mic unmuted. I think we can move on to the next case.

[00:41:36]

Case Poll 2

Dr. Desai: Okay. Case number two, the patient's NGS results eventually arrive show no actionable genomic alterations. Now the question is, what is the first-line treatment would you recommend for this patient? Just as a reminder, we had a PD-L1 of 30%. Here is the pole. Patient's NGS results are back and no actionable genomic alterations. First-line treatment, do you want to use nivolumab, ipilimumab plus chemotherapy? Pembrolizumab plus chemotherapy, pembrolizumab monotherapy, or you want to use atezo bev plus chemotherapy.

Speaker 2: Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We see most commonly pembrolizumab plus chemotherapy at 50% and 38% showing dual IO plus chemotherapy. Both valid options as we discussed. Pembrolizumab monotherapy would not be a valid option with a PD-L1 of 30%, so moving on to the next.

[00:42:53]

How to Equip Patients and Caregivers for Immunotherapy-Based Treatment

The next section of our discussion is how to equip patients and caregivers for immunotherapy-based treatments. This is something we encounter not just for non-small cell lung cancer, but obviously, I am sure as you treat other cancers as well, because immunotherapy is now becoming a backbone for quite a lot of different cancers.

[00:43:11]

Patient and Caregiver Education and Counseling

I think one is the just providing the overview of the mechanism of action and how it is different from chemotherapy. A lot of the times I end up discussing that this is boosting the immune system compared to what traditional chemotherapy is trying to do is cytotoxic killing cancer cells. There is obviously information booklet, wallet cards and as well as reviewing recommendations for non-live vaccinations, that is important part of practice and patient education.

Then it is very important for the patients to understand the adverse events associated with immunotherapy as well as chemotherapy during and after treatment. Obviously, with chemotherapy we know we talk to our patients about drop everything and see us urgently if you have a temperature, contact the office to report symptoms, but specifically with immunotherapy talking about what are the different symptoms that they can have.

Like for example, diarrhea with colitis or shortness of breath when they have pneumonitis concerns. Those are unique in terms of immunotherapy. It is important to talk about that because, again, catching the IRA early, there is a better chance that we can reverse it and restart them on the immunotherapy.

[00:44:24]

Underlying Mechanism of irAEs

The underlying mechanism of immune-related adverse events, or irAEs for short. The common conception is that it is directly drug-related, but it is actually T cell mediated. Then the alternative conception is more complicated, so consideration of distinct mechanism may drive more personalized or biologically direct management approach. There are obviously clinical factors.

There are factors like genomics that play a role in terms of who gets immune-related adverse events vs who does not. Then at a cellular preclinical level, there is also the ratio of Tregs B cells that are present in a particular patient that may also dictate the immune-related adverse events.

[00:45:10]

irAEs: Timing of Onset

Now, the timing of onset is also quite important and quite different across dual immune checkpoint inhibitors or single immune checkpoint inhibitors. When you talk about anti-PD-L1 antibodies on the left, you can see the toxicity grades, but also you can see the different colors, which are the different toxicities like pneumonitis and nephritis colitis.

You can see that all of these occur at different time points in terms of how far along patients are in treatment. Pneumonitis for example, typically occurring after six weeks. Similarly, on the earlier side, you see nephritis as well as colitis being more early compared to pneumonitis. Then also liver toxicity that can happen at any point in time. Vs if you look at dual immune checkpoint inhibitors like ipilimumab, which is CTLA-4 with an anti-PD-1 antibody.

In that case, you can see more of these lines in the graph that you can see are more shifted towards the left, meaning that there is an early onset of these toxicities because of the dual agent IO nature of the regimen. Then again, it can vary in terms of mostly still, you see that colitis and liver toxicity can occur earlier than pneumonitis. Again, these are very important to understand as how to manage them.

[00:46:31]

Shared Decision-making in the Clinic

Shared decision making in the clinic, so we have to work together to match the preferences for patients, address conflicts, solve problems, and so that the meaning - address the meaning of patient experience. There are strategies for facilitating that shared decision-making. We want to have a productive conversation in which the patient preferences are discussed.

We want that quality of time and space that we can protect with our patient and have them increase participation, also including caregivers as well as other members of the multidisciplinary team. Just going on to the discussion here, I would say, how does your multidisciplinary team interplay with the patient management, as well as most common or most difficult aspects or topics to discuss with your patients and caregivers? 

I think I saw something in the Q&A which was talking about what questions do patients ask most about immunotherapy. I think for me one of the most common questions that I have seen and most difficult, I would say, also to discuss with patients is to really differentiate what immunotherapy is compared to chemotherapy.

I think most patients have a very in intrinsic intuitive understanding of chemotherapy because maybe their family member has been through chemotherapy and have also some of them also have a very vivid unfortunately harsh memory of how chemotherapy is but I think immunotherapy and how different it is and how probably more tolerable it is, I think that is the conversation that is most challenging in terms of getting the patients to understand the differences between these regimens.

[00:48:08]

Guidelines for irAE Management and Real-world Application

Moving on in interest of time, so guidelines for immune-related adverse event management and real-world application.

[00:48:16]

Spectrum of irAEs

This is our next section to discuss. As we mentioned, immunotherapy can have immune-related adverse events across different organs of the body. On that image on the right, you can see all these different organs can be affected. We looked at the onset, which can be usually two to three months after starting treatment, but can happen up to two years after treatment completion. We always have to maintain a high level of suspicion if and when new symptoms develop for our patients.

[00:48:44]

Frequency of irAEs With ICI Monotherapy

Again, looking at the frequency of immune-related adverse events, along with its grading, this is specifically for immunotherapy ICI monotherapy. We see that pneumonitis is more common in non-small cell lung cancer. This is frequency across different tumor types. You can clearly see that pneumonitis could be one of the most common for our patients with non-small cell lung cancer. Most of these irAEs are grade 1 to 2, but again, when you have the grade 3 to 5 irAEs specifically in these patients with CTLA-4 inhibitors, that can become quite challenging, specifically the colitis aspect of it.

[00:49:25]

General Recommendations for Treatment of irAEs

The general recommendations of treatment for irAEs is all based on the grading. Whether it is grade 1, 2, 3 or 4, which is mild, moderate, severe or very severe. Just these grades are all based on the common terminology criteria for adverse events or CTCAE from when they have been established during the clinical trials, but the early grade, grade 1 2, which is mild and moderate side effects obviously can be managed in outpatient or community setting, but as you move towards grade 2 to 3 and grade 4, you have to get steroids on board as well as perhaps hospital admission is usually required and maybe IV steroids in some of these cases.

For steroids, there is PO and IV, usually starting with about 1 mg per kg, the range is 0.5 to 2. Then, for some of the irAEs, we can even restart after resolution, like, for example, rash. Then, for endocrinopathies that they can be generally continued with management of, for example, in hypothyroidism, you can put the patient on levothyroxine and then continue immunotherapy during the course of that.

[00:50:43]

General Recommendations for Management of AEs With Chemoimmunotherapy

General recommendations for management of AEs with chemoimmunotherapy. Again, reporting all the symptoms to the provider is important. Then timing is critical, and so we need to be highly suspicious as well as figure out the cause of adverse events as early as we can. In terms of the subtle differences between chemotherapy toxicity vs ICI is that chemotherapy usually happens - the toxicities usually happens rapidly after administration, and it can be cyclical with an onset and then recovery in the three-week break period.

Generally, we hold dose we reduce dose. We can switch to a less toxic agent. For ICIs, it is usually after several cycles. It can worsen over time. There is obviously no dose reduction. There is no other less toxic agent switching. We need to hold them as needed. Then we may have to bring steroids on board and permanently discontinue if they are severe.

[00:51:45]

Differences in AEs Between Chemotherapy and ICIs

Again, this is another way of looking at chemotherapy and ICI adverse events. Most patients will experience chemotherapy adverse events, but only some with ICIs. Those are well described for chemotherapy, not very well described but well defined for ICIs. The time course is well established for chemotherapies. As we mentioned, the cyclical nature of toxicities in terms of immunotherapy it is quite variable. Then common toxicities are also quite different between chemotherapies as well as immunotherapies.

[00:52:18]

Case Intensive Case Presentation

Moving on to our case number two, same person in his mid-70s from case one initiates first-line anti-PD-1 plus chemotherapy two months later. Daughter informs the clinic that patient has persistent diarrhea despite taking an antidiarrheal. She reports that the patient is reluctant to bother the doctor with something he can manage himself.

[00:52:40]

Case Poll 1

How would you manage this patient's grade 2 diarrhea?

A. Is test for infection, start steroids if negative;

B. Is start steroids immediately;

C. Is increase antidiarrheals and continue IO.

Speaker 2: Portal is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We got 100%, and most have rightly answered test for infection and start steroids if negative, obviously with the patient being on chemo IO.

[00:53:32]

Case and Practice Specific Discussion

I am going to skip the case and practice specific discussion in interest of time.

[00:53:37]

Case Poll 2

Going on to the next question, considering the current scenario, how would you address the patient's reluctance to report the diarrhea?

A. Reassure comfort patient regarding the diarrhea;

B. Further educate them;

C. Educate the patient's caregiver;

D. Check in with the patient and caregivers regularly to survey diarrhea occurrence; or

E. Other.

Speaker 2: Poll is open. Please vote. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: Most people have rightly answered further, educating the patient about severity and risk associated with not reporting.

[00:54:24]

Practice-Specific Discussion

In terms of practice-specific discussion, we want to talk about what role do clinical trials play in your management of patient diseases, and what are the logistical constraints affecting treatment selection, and how do you employ and ensure quality of care for rural patients with non-small cell lung cancer? Do we have anyone who wants to speak up about this or anything in the chat?

Speaker 2: I do not see any incoming post, Dr. Desai, and I think in the interest of time, we will move on.

[00:55:03]

Posttest Question 3

Dr. Desai: Now we go back to our original questions for post-test, and this is the last five minutes, so please bear with me. How confident are you now in educating patients and caregivers? Here are your choices on the screen.

Speaker 2: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: Most people now have a D, which is confident at 86%. C modest confidence at 14%.

[00:55:47]

Posttest Question 4

Question number four. Patient receiving I o therapy develops grade 3 pneumonitis confirmed by imaging and clinical symptoms. What is the most appropriate management strategy?

A. Administer antibiotics and resume IO;

B. Continue IO therapy and monitor symptoms closely;

C. Withhold IO therapy and initiate high-dose corticosteroids;

D. Reduce IO therapy dose and add inhaled corticosteroids; or

E. Discontinue IO therapy and administer best supportive care.

Speaker 2: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We have 100% answer. Withhold IO therapy, initiate high-dose corticosteroids, which is correct.

The rationale being that grade 3 pneumonitis can be life-threatening. That is the reason why we want to withhold IO and start high-dose corticosteroids.

[00:57:07]

Question 5: Case Presentation

Moving on to the next. 62-year-old patient presenting with newly diagnosed stage 4 non-squamous PD-L1 of 65%. No actionable genomic alterations. Non-squamous histology. ECOG performance status of one.

[00:57:21]

Question 5

What is the most appropriate treatment regimen?

A. Dual immune checkpoint inhibitors;

B. Single immune checkpoint inhibitors;

C. Chemo plus dual immune checkpoint inhibitors;

D. Chemo plus single immune checkpoint inhibitors;

E. Chemo plus VEGF plus immune checkpoint inhibitors; or F. Chemo plus or minus VEGF inhibitor.

Speaker 2: Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We have 75% at single-agent immune checkpoint inhibitor therapy. 25% at dual immune checkpoint inhibitors.

Correct answer being here, single-agent immune checkpoint inhibitor therapy. Again, PD-L1 greater than 50%. No actionable genomic alterations based on the KEYNOTE-024 EMPOWER-Lung 1 and atezolizumab IMpower110 that we discussed.

[00:58:34]

Question 6: Case Presentation

Then another case, a 72-year-old patient hypertension, CKD, newly diagnosed stage 4 squamous. PD-L1 of 20%, no actionable genomic alterations, ECOG of one.

[00:58:47]

Question 6

Then with the same options. What is the most appropriate treatment for this patient?

Speaker 2: Poll is open. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: We have about 83% saying platinum doublet, chemo plus immune checkpoint inhibitors. Some saying platinum doublet, chemo plus dual checkpoint inhibitors. I would say both of them are good options.

Based on at least the program here, we have the platinum doublet chemo plus immune checkpoint inhibitors. Again, with the PD-L1 low squamous population, that is the preferred strategy based on KEYNOTE-407.

[00:59:43]

Polling Question 10

Then, do you plan to make any changes in your clinical practice based on what you learn in today's program? Please answer

A. Yes; or

B. No; or

C. Uncertain.

Speaker 2: Poll is open. Please vote. Five more seconds. All right. Thank you. We will close the poll and share the results.

Dr. Desai: 86% saying yes.

Polling Question 11

Then here is my follow-up question. Please take a moment to enter one key change you plan to make in your clinical practice based on this education.

Speaker 2: Once again, you are welcome to type any comments and questions in the chat or Q&A. Also, we have a polling box open for you so you can respond to this poll. Dr. Desai, we will leave that open for a few more seconds. All right. We will close the poll, and we can move on.

[01:01:05]

Final Q&A

Dr. Desai: Then final Q&A. That was the final question. Now, thank you for attending our program. Please scan this QR code to access online evaluation and claim your credit. Then there are additional program resources that you can scan the QR code on the right. Thank you so much for your time attending our program today.

Speaker 2: All right. Thank you, Dr. Desai.

Andy: Thank you so much. I apologize, I am a little late jumping over. Just want to point out the QR codes on the screen. The QR codes will take you to the program [inaudible] for you to complete it. As well as the additional resources from the program that you can see at your leisure. I also put this information in the chat, so you will be able to grab those links that way. Just a reminder, you do need to be logged in to or create and log into your account at deceraclinical.com/education. You will see that on the bottom of the slide here. Then, Dr. Desai, it looks like I did see one final question that was in Q&A from online. I am not sure if you can see that on your side.

Dr. Desai: Yeah, I think I saw that, and we addressed the PD-L1 more than 50%. The factors that most influence monotherapy vs chemo IO is really the burden of disease and the symptoms. If there is a high burden of disease, patient has symptoms, and you think that you want a quicker response so that we can actually help the patient from a symptomatic standpoint or the burden of disease standpoint, that those are usually the patients where I would choose chemo IO in the high PD-L1 more than 50%. Otherwise, usually monotherapy is treatment of choice.