Dr. Charles Rudin discusses key highlights from ASCO 2022

Dr. Upal Basu Roy and Margery Jacobson

The American Society of Clinical Oncology (ASCO) Annual Meeting was held in Chicago June 3-7, 2022. Dr. Upal Basu Roy, Executive Director of Research at LUNGevity Foundation, sat down with Dr. Charles Rudin to discuss key highlights from ASCO 2022 and what they mean for the lung cancer community.

Dr. Rudin is the chair of the LUNGevity Scientific Advisory Board. He is a board-certified medical oncologist specializing in the care of patients with lung cancer. In addition to serving as chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, he is the co-chair of the Eastern Cooperative Oncology Group Thoracic Committee and is a member of the National Cancer Institute Thoracic Malignancies Steering Committee.

Can you share your three key findings with the community and what they mean for patients?

Certainly!

  1. At the top of my list is a trial of adagrasib. This is a KRAS G12C-mutant inhibitor. It's actually the second drug in the class of KRAS-specific inhibitors, following up the already FDA-approved sotorasib. We saw updated data on adagrasib showing that this drug is effective in shrinking tumors that have a KRAS G12C mutation. These drugs look quite strong and are really changing our approach to a major subset of non-small cell lung cancer.
  2. Another area of progress discussed at the meeting is EGFR exon 20, a subset of EGFR-mutant lung cancer that has historically been difficult to treat. While there were a few updated trials presented. I will highlight the CLN-081 study here. CLN-081 is a drug with quite specific activity within this subset of patients whose tumors have an EGFR exon 20 mutation. Because the more typical EGFR inhibitors are less active for EGFR exon 20, finding specific drugs for these patients has been gratifying to see. There are now multiple drugs for EGFR exon 20.
  3. A third key finding are the results of the NADIM-02 trial for early-stage disease. These results  build on and complement recent progress that we've seen in other trials demonstrating a benefit with chemoimmunotherapy as induction therapy for patients with surgically resectable lung cancer. Specifically, It shows the dramatic efficacy of the combination of induction chemo and immune checkpoint inhibitors prior to surgical resection for patients with lung cancer. This is an approach that's transforming how we think about treating patients with lung cancer.

Last year, we saw two approvals in early-stage disease in the adjuvant setting, one with a tyrosine kinase inhibitor (osimertinib for EGFR-positive NSCLC) and one with an immunotherapy (atezolizumab). And this year, we saw a neoadjuvant approval using the immunotherapy nivolumab. And you just talked about the NADIM trial. In your perspective as a medical oncologist, what should be the goals of adjuvant therapy, and what should be the goals of neoadjuvant therapy?

To me, the goal is the same. The goal is cure. And for early-stage disease, we are treating in an intent-to-cure approach. Unfortunately, even early-stage disease remains challenging and frequently lethal. But we are curing more people, and I think these approaches are leading the way. As you point out, some trials have looked at adjuvant treatment, meaning post-surgical treatment—treatment after intervention to actually remove the primary tumor. Other trials are looking at neoadjuvant, meaning prior to surgery. The truth is we don't know which of these two approaches is best, but they both are showing quite nice efficacy in recent trial results.

What would be your advice to patients, those who been diagnosed with early-stage disease, when they're having that discussion with their surgical oncologist and their medical oncologist? Is it neoadjuvant or adjuvant therapy that’s preferable?

There isn’t one approach. At Memorial Sloan Kettering, we are currently committed and actually have been for decades to neoadjuvant approaches— presurgical therapy—as a paradigm approach. We don't know that it's better necessarily than adjuvant, but I think it is a space where we can make advances pretty quickly in trials and demonstrate efficacy.

There are pretty clear data that a good surgery matters. There were actually data presented at the meeting on intraoperative quality metrics that ought to be followed, and data from the Veterans Affairs, a VA series, a large VA series presented by Brendan Heiden on the importance of good surgery. For a patient with early-stage disease, again, the goal is cure. I think having an experienced thoracic surgeon who has performed a lot of these operations and is familiar with the approach is really important. Getting a good surgical resection is probably the most important single determinant of outcome, whether you get your systemic therapy neoadjuvantly or adjuvantly.

One topic we haven't talked about is locally advanced non-small cell lung cancer with a group of patients who are not amenable or who are not good candidates for surgery. Right now, these patients are treated with concurrent chemoradiation with immunotherapy. However, at this ASCO, we saw one or two small radiation trials that were looking at just radiation and immunotherapy, a chemo-sparing regimen, for lack of better words, for this patient community. What are your thoughts about that?

I think those studies are really quite interesting. There are a lot of data suggesting the potential for combinatory synergy between radiation and immunotherapy, that radiation to a tumor can induce the release of tumor antigens to prime the immune system. Radiation may not have quite the immunosuppressive effect of chemotherapy. There are theoretical data to suggest that there should be combinatorial efficacy for that approach. I think the more dramatic finding that we saw for patients with unresectable lung cancer was the KEYNOTE-799 Phase 2 study, which was presented by Martin Reck at the meeting. The standard of care in this space has been chemoradiotherapy followed by immunotherapy, and that was really defined by the PACIFIC trial that introduced durvalumab as maintenance therapy after chemoimmunotherapy or after chemoradiotherapy. This trial pushed the immunotherapy up earlier to give combinatorial chemo-immunotherapy with radiation to these patients, and it really showed a very nice response and durability of response in that patient population. What that study suggests is that we should be giving the immunotherapy earlier in combination with chemoradiotherapy for these patients instead of waiting to give it after chemo-radiation. We should be more interested in trying to maximize the initial response in these patients, and I do think these induction chemo-immuno regimens from very early-stage disease and then chemo-immuno-radiotherapy approaches for more locally advanced disease may be a way forward for us.

We will now pivot to small cell lung cancer. This year, we saw a couple of interesting studies in small cell lung cancer, and I have two specific questions about them. The first study that I would like to hear a little bit more about, Dr. Rudin, is a phase 3 study using an antibody called serplulimab in combination with chemotherapy for the treatment of extensive-stage small cell lung cancer. Can you talk a little bit about this trial and how this trial fits with the two other trials, the CASPIAN trial and the IMpower133 trial?

Those two trials that you just mentioned were practice-changing trials that looked at chemotherapy doublets with or without the addition of a PD-L1 checkpoint inhibitor in immunotherapy. The trial that was presented this year at ASCO introduced a PD-1 inhibitor, a similar strategy, but targeting the receptor rather than the ligand with the immunotherapy. This antibody is similar to previous PD-1 antibodies like pembrolizumab or nivolumab. The trial was a pretty definitively large phase 3 trial led out of China. It, like the previous trials, compared chemotherapy alone versus chemotherapy with immunotherapy. There was demonstration of improved overall survival in that trial, moving the bar from about 11 months to about 15 months. Similar to the other two trials that have been published and have led to FDA approvals, there are some oddities in this new trial. Twenty percent of the patients were never-smokers, and we don't typically see anywhere near that number of never-smokers in our patient populations with small cell lung cancer. Ninety-eight percent of patients with small cell lung cancer are typically former or current smokers. We're seeing multiple trials out of China with very high numbers of never-smokers with small cell lung cancer. There's a little bit of a difference in disease there, maybe, with more patients who have an initial tumor with adenocarcinoma that is actually transformed to small cell lung cancer. We don't totally understand the reason for seeing multiple trials in small cell lung cancer in China that do have this higher rate of never-smoker small cell lung cancer patients. It's an interesting patient population and one that requires further study. Bottom line, though, this trial reinforced the results of the prior chemoimmunotherapy trials in small cell lung cancer, really establishing chemoimmunotherapy as a standard of care for patients with extensive-stage small cell lung cancer.

How do we raise the bar for extensive-stage small cell lung cancer? I'm happy to see the CASPIAN  IMpower133 trials, and now this trial. It's great to see three phase 3 trials confirming that chemo-immuno combinations as upfront therapy are great, but it's still not enough. What do we need to do to push the bar even higher?

We have a lot of strategies that we think may push that bar higher. The tail on the survival curve for patients in small cell lung cancer with extensive-stage disease, unfortunately, is thinner than it is for non-small cell lung cancer and other diseases, like melanoma. That is, there are fewer durable responses and fewer long-term survivors. We do have long-term survivors, though, and that is a real change. The advent of immunotherapy has led to that potential for patients to be in that cohort that has long-term survival even with metastatic small cell lung cancer. That's important, but how do we push the bar higher? There are a number of strategies. One of the real problems with small cell lung cancer is that it tends to be immune-cold because it just doesn't present antigens to the immune system. It lacks the key molecules that are needed to present mutant antigens to the immune system. That absence of presentation to the immune system is actually not mutational. It's what we call epigenetic, which means that it's silenced, but it can be reactivated. We have a number of strategies that might be able to effectively reactivate that presentation of the tumor to the immune system, leading to better outcomes. Our lab and others are working on that. Over the next several years, you're going to see some of these strategies coming forward to the clinic to try to increase antigen presentation to the immune system to get these tumors to respond. We're hopeful that these can raise that tail on the curve and lead to more patients experiencing the transformative benefit of immunotherapy.

Continuing with small cell lung cancer, there was another interesting trial that looked at a PARP inhibitor in combination with temozolomide. Temozolomide is unique;  it's an oral chemotherapy that's been approved for small cell patients. Can you talk a little bit about this trial and what it means for the community?

Sure. So, temozolomide isn't FDA-approved for small cell lung cancer. It was approved for glioblastoma. However, it is in the NCCN treatment guidelines, so it is available to us for use for small cell lung cancer. We've actually been very interested in temozolomide as a treatment for small cell lung  cancer, and there's a lot of interest in PARP inhibitors. This trial combined a very potent PARP inhibitor, talazoparib, with temozolomide in patients with extensive-stage small cell lung cancer, recurrent disease. As a phase 2  trial, it was fairly small, just 31 patients, but it did demonstrate a very nice response rate, I believe 39%. So it was quite a nice demonstration of initial efficacy. This is really a signal-finding phase 2 trial, but it does build on a backbone of prior trials that have suggested a benefit of PARP inhibitors in small cell cancer or at least within subsets of patients with small cell lung cancer. There's a prior trialout of MD Anderson that looked at a combination of temozolomide with a different PARP inhibitor, olaparib, that actually had quite promising results. Cathy Pietanza at Sloan Kettering had done a prior trial also with temozolomide and a PARP inhibitor, veliparib. Within that trial, together with MD Anderson, we were able to show that there are a group of patients who express a protein called Schlafen-11 that may be a marker for who responds to PARP inhibitors. Post hoc analysis suggested benefit within the group of patients whose tumors express high levels of Schlafen-11. The trial of talazoparib and temozolomide that was presented this year looks promising. It may be the most promising of these PARP inhibitor combination trials, and certainly warrants further investigation in the disease.

So, are you suggesting that small cell lung cancer treatment is also going to be biomarker-driven in the future?

Yes, I do think so. I think we need to define subsets of disease that are biologically distinct and that may have distinct vulnerabilities and direct our therapies to those patients who may be most responsive to different strategies. That's been our way forward in non-small cell lung cancer. It's also likely to be a way forward in small cell.

Dr. Rudin, I have some questions about non-small cell lung cancer. Let’s start with EGFR-positive NSCLC.  We have great first-line drugs for patients with EGFR-mutant lung cancer, but unfortunately, they don't last forever. Ultimately for most patients, though, the disease does progress, and we're looking for what the next regimen will be that can really be effective here. Can you discuss any ASCO 2022 findings in this area?

We did see some informative data at ASCO 2022. Cathy Shu at Columbia presented an update on the CHRYSALIS-2 study. This is a combination of a drug called amivantamab, an antibody, together with lazertinib, an oral tyrosine kinase inhibitor, specifically in the context of progression on osimertinib, or Tagrisso. This was an update on a previously reported population that demonstrated a pretty good response rate. And in particular, I was struck by what was admittedly anecdotal evidence presented in the activity in the CNS, in the brain. Brain relapse is a common site of progression for these patients and really an unmet need. The combination of the antibody with the TKI may be an effective strategy there.

There's also a drug called Teliso-V, which is an antibody drug conjugate, an anti-MET antibody. The MET gene frequently gets amplified in the context of EGFR resistance. This is an antibody directed against MET that also brings in a toxin to the cell, so the antibody is being used like a truck to bring in the troops, in a way. And the troops here are a molecule called MMAE, which is a commonly used cytotoxic on antibody agents. This trial is looking at combining Teliso-V with Tagrisso in this patient population to delay progression. Though a small trial with 25 patients, the response rate was about 58%. It's early days, certainly with that agent with that combination, but it does show some promise.

Let's turn now to those groups of patients whom we don't typically include in clinical trials, such as patients with brain mets, patients who have a performance status of greater than 2, and patients who are older than the age of 75. These are groups of patients who are traditionally excluded in clinical trials. And this year at ASCO, we heard about a couple of studies that addressed treatments for these unique populations. Can you discuss them?

The ATEZO-BRAIN trial discussed at ASCO 2022 showed that immunotherapy is effective in treating patients with brain metastasis. We know that immunotherapy can be effective in the brain. That study builds on prior data from Yale University. The Yale Lung Cancer Group had done a very nice study showing that for patients with brain metastases who are treated with immunotherapy, the rate of response in the brain is actually very similar to the rate of response elsewhere. So even though these immunotherapy drugs are antibodies, and we don't typically think of them as penetrating well into the brain, we do see CNS activity of the therapy. There are two thoughts there. One is that the drugs actually can get into the brain because of the breakdown of the blood-brain barrier in patients with lung cancer. The other is that they actually stimulate the immune system outside the brain and the lymphocytes get into the brain and have effect on brain metastases. So, it is definitely a strategy that we're interested in for brain metastases.

Let's talk about the other groups of patients, patients who are over the age of 75 or patients who have a performance status of 2 or greater. Patients whose cancers don't have any biomarkers, especially patients who have adenocarcinoma, get a chemo-immuno regimen or an immuno regimen based on the expression of the PD-L1 protein. In your opinion, especially for patients who are elderly or patients with performance status 2 or more, is a chemo-sparing regimen better than a regimen that includes chemotherapy?

That is a very individualized decision that needs to be made, and a lot of factors can go into that decision. Certainly, for the elderly, we think about biological age and not calendar age. We have many patients who are older but healthy, and those patients can tolerate therapy quite well, actually. And so, there are certainly elderly patients who get fairly complex multi-drug regimens and can tolerate them well. It really requires some local consideration and really careful evaluation by the clinician and the patient to determine what are the patient’s desires, and what is their risk-benefit threshold, and what are they willing to put up with for what benefit? That's a complicated decision. To me, dor patients with poor performance status (patients who maybe are spending more than 50% of their time resting and whose ability to conduct activities of daily living is substantially compromised), it depends a lot on what the basis of that poor performance status is. Are they limited because of their disease, or are they limited because of other comorbidities? I think that those patients whose limitations are because of disease problems that we hopefully can address can really improve their performance status substantially, and  should be offered the therapy. Patients who come with a lot of comorbidities and who are not going to tolerate therapy well, and even if therapy works, they're going to continue to have limitations are a very different group, and a group where we don't want to be overlyaggressive. So, the therapy we use depends on the basis of the poor performance status. And again, age alone is not, to me, a definitive criterion. I don't have an age limit, and I have patients in their nineties who continue to do well.

I have one last question for you, and this is really a philosophical question. This goes back to the trial that you presented this year at ASCO, the SKYSCRAPER-02 trial, which was looking at adding on a new immunotherapy molecule to the one currently used in IMpower133 regimen. The trial from a scientific perspective did not prove to be successful, but from a patient perspective, it's patient lives here and patients participate in a trial in good faith. What can we learn from these types of trials?

This was a large trial looking at patients with newly diagnosed extensive-stage small cell lung cancer randomized to chemoimmunotherapy (standard of care) versus the standard of care plus a new immunotherapy (an antibody targeting a molecule called TIGIT). As we were saying at the very opening, one of the goals is to broaden the number of patients who respond to immunotherapy and improve outcome in this patient population. That was certainly the goal of this trial. The trial was negative in that we saw essentially identical outcome on both arms of that trial. This is obviously disappointing, but I think there were some important take-home messages there. One, the outcome really reinforced our standard of care. That is, the curves for outcome were essentially identical to what we had previously seen, and I think really helped to reinforce the benefit that we do see with the triplet regimen of platinum, etoposide, and atezolizumab in this instance. Reinforcing that data is important. This trial included patients with previously untreated brain metastases. This is an important message—that patients with asymptomatic brain metastases can get chemoimmunotherapy and can do quite well. We make progress in lung cancer research by both defining new therapies and by excluding targets that aren't going to be the way forward. There are so many paths to success, and we need to call out the ones that are not going to work in order to focus on the ones that are. One of the real take-home messages from that trial to me is that this target, TIGIT, is not the path forward for small cell lung cancer. It allows us to focus on some of the other strategies and set this one aside.

However, I do think that TIGIT is an important target in cancer. We have a lot of data to that end, and it may have the potential for success in patients with non-small cell lung cancer. That is an ongoing trial for which the results are not mature and haven't been released. I would maintain hope for TIGIT as an immunotherapeutic target. There are multiple ongoing trials within that space, but I think we can take it off the list, honestly, for small cell lung cancer, and focus our efforts on other targets.

The patients who participated in this trial helped us make that determination. We don't get to make that determination without their active engagement. We really appreciate the patients on these trials who are our partners in research and help us define what targets are going to work and what targets are not going to work. There are still some 40 some patients on that trial, so there are patients who continue to benefit on both arms of the trial, and we will continue to provide those patients with the drugs that will be controlling their disease well as part of this initiative.

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