The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved rapidly over the past several years, with the availability of targeted therapies that offer the potential for improved patient outcomes.

Drugs that inhibit CD20—such as obinutuzumab (Gazyva)&mdash;have entered the space, as has the BCL-2 inhibitor venetoclax (Venclexta). Interest in the feasibility of using combination regimens is high, but therapeutic selection for these approaches remains challenging.

The FDA approved this combination for the frontline treatment of patients with CLL or small lymphocytic lymphoma in May 2019. The approval is based on data from the phase III CLL14 trial, in which venetoclax/obinutuzumab reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; 

Complex karyotype (CKT), which is defined as the presence of ≥3 chromosomal aberrations, is frequently observed in older, treatment-naïve patients with CLL, and is associated with a particularly poor prognosis. Results of a prospective analysis of the CLL14 trial, which were presented at the 2019 European Hematology Association (EHA) Congress, showed that the combination of venetoclax and obinutuzumab was able to overcome adverse risks associated with CLL who have CKT.

The findings suggest the significance of chromosomal analysis prior to physicians choosing frontline therapy for their patients with CLL, should they harbor CKT.

 during the 2019 EHA Congress, lead study author Othman Al-Sawaf, MD, University Hospital, Cologne, Germany, discussed these findings from the CLL14 trial, the rationale for exploring this proposed combination, and shared his thoughts on the emerging treatment paradigms in CLL.

: Could you discuss the rationale for exploring the combination of venetoclax and obinutuzumab in patients with CLL who have CKT?

: Venetoclax with obinutuzumab is a chemotherapy-free regimen that has been developed now for several years, originally in phase Ib and in phase II trials, and now, for the first time, in a randomized phase III trial. The idea behind that is to target BCL-2 in CLL, and to combine BCL-2 inhibition with a CD20-directed antibody as another target in CLL.

We showed in the CLL14 trial that the combination of both of these compounds is superior to standard chemoimmunotherapy in patients with previously untreated CLL. That was the rational to have a deeper look now at patients with the CKT.

Please provide an overview of the phase III CLL14 study.

CLL14 is a randomized, phase III trial. It was performed globally and in a broad range of countries—Europe, the United States, and South America. In this study, 432 patients were randomized to either receive 12 cycles of venetoclax and obinutuzumab or 12 cycles of chlorambucil and obinutuzumab. Each regimen was separated into 6 cycles of combination and 6 cycles of monotherapy with either venetoclax or chlorambucil.

The ultimate aim was to check whether there was a difference in progression-free survival (PFS) in these patients. This was the primary endpoint. The primary endpoint was met [in 2018], and venetoclax and obinutuzumab was superior to chlorambucil and obinutuzumab.

What is the likelihood of relapse for patients with CKT, and what is a typical prognosis for them? 

[CKT] is a phenomenon that we see in lots of hematological malignancies. Many hematologists know it from acute myeloid leukemia or myelodysplastic syndrome. We also make treatment decisions based on its presence.

In CLL, similarly, we’ve seen several trials—mostly of a retrospective nature&mdash;that CKT is associated with a very poor prognosis, similar to 

. And, in some analyses, it is even worse than TP53 aberrations.

The issue with CKT is that, in the past, it wasn’t as easy to detect during the diagnostic workup of CLL, because you need stimulated karyotyping for that. This is, in some cases, more challenging, but nowadays, the procedure has been widely standardized, and it’s relatively easy to do that in routine diagnostics.

We’ve seen that the prognosis of patients with CKT is poor when treated with chemoimmunotherapy, but interestingly, it is also very poor when treated with targeted agents. This has been shown in retrospective analyses of patients treated with ibrutinib (Imbruvica), where CKT was even worse than 

 mutations or aberrations. In small datasets, it was also observed that venetoclax monotherapy was not efficient in patients with CKT.

What were the findings of this analysis, and what are your next steps for research into this combination in CLL for patients with CKT?

In our analysis, we showed that, in this prospective setting of CLL14, we had a look at all patients randomized, and in 93% of patients, we had a CKT analysis done before we started treatment. [This way], we were able to evaluate how patients with and without CKT performed throughout the study and during follow-up.

What we’ve now observed is that, on the one hand, patients with CKT have a shorter PFS as well overall survival (OS) when treated with chemoimmunotherapy. In contrast to that, patients treated with venetoclax/obinutuzumab, irrespective of the presence of CKT, had a similarly high efficacy. This is the first time that a treatment regimen has shown, in a prospective manner, that it is similarly efficacious in patients with CKT.

For us, this means that, on the one hand, we should definitely check for CKT prior to initiating first-line therapy, because now we know that it even has a survival impact depending on the treatment regimen we choose, and to guide our treatment. Therefore, for a patient with CKT, the combination of venetoclax/obinutuzumab seems to be a good option.

When should a chromosome analysis be done in patients with CLL?

Patients should be checked for CKT before initiating therapy. From my perspective, we don’t have any data that indicates—at the moment at least&mdash;that we should start treatment when patients are asymptomatic. For patients with CLL, with a first diagnosis of CLL who don’t have any symptoms or complaints, they don’t need therapy&mdash;particularly if they have a normal blood count. This is also defined in CLL guidelines: no treatment [is needed] for these patients&mdash;just a watch-and-wait strategy. No treatment has shown any survival benefit for those patients when they are treated, irrespective of their symptoms.

We would suggest that patients, when they require treatment, should be checked for CKT, because then there are direct therapeutic implications. One should do that with the whole diagnostic workup:

 status, and CKT. This should be done before we start treatment, and it can guide us to choose the treatment.

Another timepoint as well, although we don’t have sufficient data for it at this stage, is to check once the patient relapses. If they’ve completed treatment and the patient relapses, and they require treatment for their relapse because they have symptoms and the blood count has moved, we should again check for it in case the patients didn’t have it before.

How is the treatment paradigm for CLL taking shape?

What is important now is that we have, due to this broad battery of trials we have seen in the last 2 or 3 years on CLL, we surprisingly have 2 treatment paradigms that have appeared: we’ve seen that the treatment with ibrutinib as continuous monotherapy is highly effective in patients. Although only a very small fraction of these patients achieve minimal residual disease (MRD) activity, we still see that these patients continue to be in remission in a very relevant proportion of these patients.

In contrast, we have also now seen that chemotherapy-free regimens like venetoclax and obinutuzumab can be given over a fixed duration—for example, 12 cycles over a year&mdash;and patients can stop treatment and still continue to be in MRD.

These are basically 2 new treatment paradigms: continuous therapy without MRD negativity, but still highly effective, and short-duration therapy with MRD negativity, where we can stop treatment and—at the moment, with short follow-up&mdash;see that patients continue to be in remission.

Each of those had advantages and disadvantages. For ibrutinib or continuous BTK inhibition, we see that, in most patients, it seems to be tolerable, but we also see that there are adverse events that may come up as you treat for a long period of time. The patient has to stay on medication, so there is a question of compliance; sometimes patients do not want to take any further medication. We know that once you stop ibrutinib, CLL usually pops up quite quickly, so this is a disadvantage. Also, of course, [there is] the question of costs. When patients take it for 5, 6, or 7, years, it is also, of course, a financial burden.

This would be an advantage of fixed-duration therapy: to give it just for 12 cycles, the patient knows that, like in conventional chemotherapy, they have 12 cycles and then they are finished and should remain in remission. On the other hand, it can, for some patients, be a disadvantage because they need to get infusions, or they have to be in treatment for 12 cycles—that might be a challenge for them.

We need to see, in the future, in randomized trials, whether we can compare these 2 treatment paradigms and see whether we see differences in efficacy. If we don’t see differences in efficacy, this would also be an interesting result. Then we can see, what the patient’s preference is. What has more complications? Are there any survival implications? All of that has to be seen in a randomized trial, so this will be the next step to do.

FDA Prescribing Information for Venetoclax. https://www.rxabbvie.com/pdf/venclexta.pdf. Accessed May 15, 2019.

Al-Sawaf O, Lillenweiss E, Bahlo J, et al. High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype (CKT) and chronic lymphocytic leukemia (CLL): a prospective analysis from the CLL14 trial. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract S106.

2019 European Hematology Association Congress

Articles

Othman Al-Sawaf, MD, discusses findings from the CLL14 trial, the rationale for exploring this proposed combination, and shares his thoughts on the emerging treatment paradigms in chronic lymphocytic leukemia.

Frontline Venetoclax/Obinutuzumab Combo Emerges as Treatment Option for CLL With CKT

-mutated relapsed/refractory acute myeloid leukemia (AML) represents one of the most challenging hematological malignancies to treat and carries a poor prognosis. A novel small molecule FLT3 inhibitor, quizartinib, has been the subject of high hopes among clinicians who treat patients with this disease as it targets AML with 

-internal tandem duplication (IDT) mutations, one of the most common molecular aberrations identified in the malignancy.

However, in May 2019, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8-3 against approving quizartinib for adult patients with relapsed/refractory 

-ITD—positive AML. Nevertheless, clinicians remain optimistic on the novel agent and the significant impact it could have on patient outcomes. 

 during the 2019 European Hematology Association Congress, Naval G. Daver, MD, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, discussed the data that support quizartinib thus far, ongoing investigations with this drug in the frontline setting, and the potential for the agent to be approved by the FDA.

: Could you discuss the data that is available on the QuANTUM-R trial?

: The QuANTUM-R study is a randomized, phase III study in people who have 

-mutated relapsed/refractory AML. This is a very high-risk population. Patients who have 

-mutated AML, and especially those who have 

-ITD—mutated AML, have a very poor prognosis, both in the newly diagnosed setting, as well as in the relapsed/refractory setting.

This has been a major area of research to try to develop targeted therapies. There are multiple FLT3 inhibitors that have been in clinical trials. The only one that was approved by the FDA until recently was a drug called midostaurin (Rydapt), which is a first-generation FLT3 inhibitor. It has reasonable activity, but it’s not as potent at the second-generation inhibitors that we have.

[Data] did show that when midostaurin was added to induction chemotherapy, it improved the overall survival as compared with patients who got induction chemotherapy alone. However, a number of these patients still do relapse.

QuANTUM-R was the first large, phase III randomized study that tried to look at the outcomes in these patients. A total of 450 patients were randomized to receive either quizartinib, which is the targeted therapy, or to receive [either] induction chemotherapy or low-intensity therapy. The comparator arm was basically the investigator’s choice. The primary endpoint was improvement in overall survival (OS), and secondary endpoints included improvement in response rates, including complete response (CR) and CR with incomplete hematologic recovery (CRi), overall response rates, as well as the number of patients who could go on to allogenic stem cell transplant.

The study showed that the primary endpoint of OS had been met; OS was significantly improved with the use of quizartinib as opposed to the investigator’s choice of therapy. What was more impressive and striking was that, if you look at the response rates of CR and CR, which have been the traditional way to look at 

-mutated relapsed AML, these were almost doubled with the quizartinib, at around 48% to 50% compared to 25% to 27% with traditional chemotherapy.

This is very good on its own, but it’s even more impressive when we realize that traditional chemotherapy was usually a cocktail of 3 drugs, so we were talking about high-intensity, intravenous 3-drug therapy as compared to oral, single-agent, targeted outpatient therapy.

Even if these would’ve been equal, I think most oncologists and experts would’ve been very excited; they were not equal, and the oral single-agent therapy was in fact showing double response rates with improvement in OS. About 32% of the patients could make it to transplant, as compared to 10% to 12% with traditional chemotherapy.

The study showed 2 things: it showed that in relapsed/refractory 

-AML, using traditional cytotoxic or low-intensity therapy is almost futile. You’re looking at OR rates of 20%, CR rates were 1% to 5%, and only 10% to 12% can make it to transplant, which is the only curative hope. If you use a single-agent targeted therapy, you could at least get about 30% to 35% to transplant with a much higher response rate.

Based on this, it is hoped that the quizartinib will actually be approved in the United States, in Europe, in Japan, and in other regions. We think this is just the beginning. Eventually, we hope that development will look at combinations, which we’re already doing at The University of Texas MD Anderson Cancer Center, and seeing if we significantly further improve the efficacy that you get with the single-agent, quizartinib.

Can you also discuss the QuANTUM-First study, and whether it has been impacted by the recent ODAC vote?

The QuANTUM-First study is a study that is looking at frontline, newly diagnosed, 

-AML. This study is trying to see whether the addition of quizartinib to standard induction therapy, which was selected to be 3 plus 7, improves the OS, event-free survival (EFS), and hopefully remission rates.

This is a large, multinational study that is open at about 100-plus centers across the world. We plan to look at about 500 patients who will be randomized in a blind fashion to receive standard induction therapy of 3 plus 7, or induction with quizartinib added on.

In general, QuANTUM-First is enrolling very, very well. There was concern about a year ago that the enrollment [would slow] because of the approval of midostaurin in the frontline 

 space. Enrollment has not only kept pace with what was anticipated, but is also about 10% to 20% ahead of schedule. At this time, almost 90% of the enrollment is complete.

We do not think there’s going to be any direct impact of the ODAC vote at this time; QuANTUM-First is moving ahead of schedule, and we hope that that data will also become available next year. That’s a very important data set, because it’s the first time we’re using a second-generation FLT3 inhibitor in combination with induction chemotherapy and have those results.

Can you discuss the efficacy and the potency of quizartinib?

Among the FLT3 inhibitors, the way we think of them are as first-generation drugs which were the ones that entered clinical development about 15 years ago. These included drugs like lestaurtinib, midostaurin, sorafenib (Nexavar), sunitinib (Sutent)—a lot of these are what we call repurposed FLT3 inhibitors. These were not developed as FLT3 inhibitors. They were developed to target other pathways, and later, it was found that they are multikinase inhibitors, and the kinases they inhibit include FLT3. They were tried in 

Then, there was a second generation of FLT3 inhibitors. These include quizartinib, which was the first among the second generation, gilteritinib (Xospata), and crenolanib. Gilteritinib and quizartinib were specifically designed to be FLT3 inhibitors. So these were not repurposed drugs; they did have other targets, but the main key is they were developed to be very potent inhibitors FLT3.

When you look at the single-agent studies of the first-generation FLT3 inhibitors like sorafenib or midostaurin, you see the response rate is about 5% to 10% as a single agent in relapsed/refractory AML. Very modest or negligible response. The only way these drugs work is if you combine them, either with azacitidine or induction [therapy].

But when you look at the second generation, both quizartinib and gilteritinib, you see that the marrow remission rates are almost 50%. This is 10 times higher than you would get with sorafenib or midostaurin. These are very potent as single agents in clearing out the marrow, killing the leukemiablasts, and giving patients an opportunity to go to transplant.

Whichever assay you do, if you look at just the potency of inhibiting FLT3, quizartinib is by far the most potent. Gilteritinib is probably the second most potent.

One of the things, though, with quizartinib is that although it works extremely well in the ITD mutation, it does not cover the D835 mutation, which is potentially one of the mechanisms of escape. That’s the difference: gilteritinib may not be as potent per se, but it does cover the D835.

In AML, I absolutely believe that the availability of 2 or 3 or 4 second-generation FLT3 inhibitors will be a great bonus to patients. If we can sequentially treat patients with second-generation FLT3 inhibitors, ideally in combination, we could then dramatically improve survival.

We still have a number of patients who are relapsed and refractory. At this time, we do have gilteritinib, which is a great improvement compared with chemotherapy, which has 10% to 20% response rates and very few true CRs.

If you look at the long-term outcome with gilteritinib, even if [patients] go to transplant or no transplant, at 2 years, only about 10% to 15% are still alive. We still have a huge unmet need, where 80% to 85% of patients will still need subsequent therapy.

As single agents, these drugs are good at achieving marrow remission, but durations are short, and the curative potential is low. We think a lot of these drugs will require combination. We feel there’s a lot of room for gilteritinib, quizartinib, potentially even drugs like crenolanib.

Can you discuss the recent ODAC vote on quizartinib and share your thoughts on getting this drug into the treatment paradigm?

The recent ODAC vote was based on the FDA’s review of the QuANTUM-R study. The study’s primary endpoint is OS, and this primary endpoint was met, with quizartinib showing an improvement in OS at 6.5 months versus 5 months with traditional chemotherapy. More importantly, key secondary endpoints, which were remission, CR, and CRi were also met, with quizartinib showing about a 50% CR/CRi compared with 27% with traditional chemotherapy.

When we saw this data, we were impressed that the phase II data that we saw with quizartinib were actually replicated in the phase III, which almost never happens. We almost always see that the phase II study is done in 8 or 9 major academic centers that usually have a better expertise of management, and response rates and outcomes are better, and you get a little bit of drop out when you go to 120 centers that may not be as proficient or see as much volume of [patients with] leukemia.

Here, actually, the response rate, the OS, the EFS in phase I, phase II, and phase III were almost exactly the same over 8 years of development. This is a very good, consistent signal.

In the ODAC vote, there was a lot of discussion about therapeutic equipoise and whether there was a clear signal of benefit. I think that, in most drugs in oncology, we rarely have that clear signal where we can absolutely say that a drug is superior, because we all know that when we [conduct] clinical trials, there are inherent biases and issues.

One of the key concerns in the ODAC vote was the number of patients who were randomized into the investigator therapy arm but did not get treatment. This is something that is impossible to control because of the pace of development.

For example, we [were aware] of many patients who were seen at smaller centers who were randomized, but once it was found out that they would be going on the standard chemotherapy arm, they asked their physician, “What would you do if you were a patient?” Most of the physicians said, “we would do a FLT3 inhibitor.” We actually got a lot of these referrals for patients who decided, after knowing that they would not get quizartinib, that they wanted to go off trial.

The other issue [cited] in the ODAC [review] was about the cardiac signal, QT/QTc. Luckily, both the ODAC cardiologist and the cardiologist from the sponsor found that there were no clinically significant cardiac concerns.

In general, when you look at the ODAC reading, we feel that a lot of the things that people were concerned about were actually found not to be major issues. I think it’s a bit of a surprise that we did not get a positive vote. The FDA still has time to deliberate on this, and a lot of the experts in the community are trying to analyze the data and find the subsets that have the best efficacy.

While QuANTUM-First is ongoing, one of the hopes is that, at least for these subsets where we have a very clear benefit and high impact, we’d be able to try and get [quizartinib] approved. More analysis and more data collection from QuANTUM-R and QuANTUM-First could further support this.

Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. 

. 2013;31(29):3681-3687. doi: 10.1200/JCO.2013.48.8783.

Naval G. Daver, MD, discusses the data that support quizartinib so far, ongoing investigations with this drug in the frontline setting, and the potential for the agent to be approved by the FDA.

Second-Generation FLT3 Inhibitors Are Future of Relapsed/Refractory FLT3-Mutant AML Treatment

 International Lung Cancer Summit took place in Geneva, Switzerland, on May 3, 2019, with an emphasis on creating an intimate and collaborative environment for attendees to be informed on the latest advances in lung cancer and to discuss pivotal remaining challenges.

The meeting, which was co-chaired by Alfredo Addeo, MD, a consultant medical oncologist at the University Hospital of Geneva, Switzerland, and Solange Peters, MD, PhD, professor and chair of medical oncology and the Thoracic Malignancies Program in the Department Oncology at the University Hospital of Lausanne, Switzerland, spanned a range of topics—from oligometastatic disease, to differentiating between immunotherapies, to which TKIs should be used in practice.

“What I’m enjoying about the summit is the very friendly environment,” said Addeo in an interview with 

. “We’re all colleagues and friends who have the same doubts when they see the patient. They want to share their views and they want room to do that. Perhaps we don’t have enough room at the moment to do this.”

Other updates in the paradigm that were discussed in detail included targeted agents for patients with biomarker-driven cancers, treatment options for nondriver patients with non—small cell lung cancer (NSCLC), small cell lung cancer, and much more.

 International Lung Cancer Summit, Addeo discussed the uniqueness of the 1-day conference and recent therapeutic advancements that have occurred in the lung cancer space.

: What were the goals of the 1st International Lung Cancer Summit. How did it come about?

: The goal of the meeting was to discuss a bit more thoroughly all of the evidence that we have seen coming out this year. Things have changed really rapidly, and they keep on changing. It’s very difficult sometimes to keep up with all of the evidence that we have, or to discuss it thoroughly.

The idea was: how about we set up a smaller meeting? We can all discuss a few topics, and really dig in and have a proper conversation that can be very interactive.

What sets this meeting apart from others that focus on lung cancer?

This meeting clearly has a different goal—a different aim. When you go to a meeting like the European Lung Cancer Congress, the ASCO Annual Meeting, or the ESMO Congress, [the meetings are often comprised of] trial results, new evidence, breakthrough evidence, or change-of-practice trials.

Here, it was more about a summit. Just a summary of all of the evidence we have seen so far and focusing on a few topics. But also, the advantage of a small meeting is that it is more interactive. It’s fine to go and have somebody lecturing you and giving you the data and presenting you with data, but now we’ve reached the level where we really want to ask questions and interact a lot more with the speaker(s). Even if we have a lot of evidence, there’s still a lot of gray area. It’s good to have time to go through these and discuss them in an open way.

What key topics were discussed in this year’s meeting?

At this meeting, we decided to focus on NSCLC primarily, and a bit of small cell lung cancer. We couldn’t really include mesothelioma, for instance, because we didn’t have enough time.

The topics are of course immunotherapy, which is a big, big topic at the moment, as well as targeted therapy. We decided to also add a few components, such as quality of life, which is very important and is an underestimated topic, frankly, which should be more relevant. We decided to give room to that.

The oligometastatic setting, is [an area] I would say, is its own entity. It often doesn’t get discussed too much, and it’s becoming more relevant with immunotherapy, radiotherapy, stereotactic radiotherapy. Having a session dedicated to oligometastatic disease makes a lot of sense.

What are the most exciting advancements that have recently occurred in the lung cancer space. What are some remaining challenges?

At the moment, we could say that things have improved quite remarkably. We have certainly improved some treatment for patients with driver mutations. That is one of the improvements we’ve had; however, for the vast majority, we have introduced immunotherapy. We have seen now, in the recent data, that there’s an increase in overall survival.

The limit is that we still lack a biomarker [for immunotherapy], so we’re not very good at all at selecting patients. Therefore, yes, there are patients who respond very well. They respond for a long time. However, we still have a big group of patients who don’t respond at all, and we still don’t understand why or how we can improve. There’s still room for improvement in the way we select the patient and improve the treatment we are giving. We need to improve our patient selection.

How could the Lung Cancer Summit evolve in 2020?

I would say I’m very much hoping to keep it as it is—being very informal, very open and friendly so that everybody can chip in with a question&mdash;and to keep it online. It’s essential to broadcast it; this kind of meeting needs to be broadcast.

We might change, perhaps, the topics. We might decide to perhaps focus a bit more on mesothelioma if something interesting comes out, like new treatment. We have been discussing cell therapy, for example.

The idea is to keep the format as it is; perhaps we might change topics, we might have mesothelioma onboard and perhaps take out something else, but the idea anyway is to keep it more or less as it is.

For me, what is really important is that it is not just the topic, but it’s really the friendly environment and the very relaxed attitude where we can all ask questions without having that kind of fear or a bit of embarrassment about asking a question—that is something I frankly don’t want.

What has been your experience chairing this summit?

During conferences, very often, there is a lot of data to present, and there’s no time for discussion. Therefore, when we’re at the bedside, or when we’re with a patient, we do wonder. If I have a question that I’d like to get off my chest, it’s a good opportunity at the summit to do that—to say, “Okay, we’ll discuss it. It’s not only your doubt, it’s my doubt, too.”

We can perhaps share our views and come up with some kind of decision that might be helpful for somebody. Or, [an attendee] might feel more comfortable now that they know I do exactly as they would do—I may back them up on something. That is what I think makes this summit special.

Alfredo Addeo, MD, discusses the uniqueness of the 1-day Lung Cancer Summit and recent therapeutic advancements that have occurred in the lung cancer space.

Lung Cancer Summit Co-Chair Advocates for Interactive, Evidence-Based Discussions in Evolving Field

Results from a final analysis of the phase III KEYNOTE-042 trial have confirmed the benefit of pembrolizumab (Keytruda) monotherapy in patients with non—small cell lung cancer (NSCLC), said Tony Mok, MD.

The FDA recently expanded the label for pembrolizumab monotherapy for the frontline treatment of patients with stage III NSCLC who are ineligible for surgery or definitive chemoradiation, as well as for patients with metastatic disease with a PD-L1 expression tumor proportion score (TPS) level of 1% or greater who do not harbor 

The regulatory decision was based on positive findings from the phase III KEYNOTE-042 study, in which investigators randomized 1274 patients with locally advanced or metastatic NSCLC to receive either pembrolizumab or chemotherapy.

Results from the trial showed that frontline pembrolizumab demonstrated a median overall survival (OS) of 16.7 months versus just 12.1 months with standard chemotherapy in those with advanced or metastatic disease and a TPS ≥1%.

 Further, data from an exploratory analysis, which examined all patients with PD-L1 TPS of 1% to 49%, showed a median OS was 13.4 months with pembrolizumab compared with 12.1 months with chemotherapy.

At the 2019 European Lung Cancer Congress, Mok, a professor in the department of clinical oncology at the Chinese University of Hong Kong, presented results from the final analysis of the trial, which showed that with an additional 6 months follow-up, pembrolizumab demonstrated continued OS benefit compared with chemotherapy.  

, Mok discussed the study and the implications of its findings, and shed light on the evolving role of immunotherapy in NSCLC.

: Could you discuss the findings from the final analysis of the phase III KEYNOTE-042 trial?

: KEYNOTE-042 is the sister study of KEYNOTE-024. KEYNOTE-024 study selected patients who had PD-L1 over 50% and randomized them to receive either pembrolizumab or standard chemotherapy, using progression-free survival (PFS) as the primary endpoint. KEYNOTE-042 selected patients [with PD-L1] over 1%, and then did the same randomization of pembrolizumab versus chemotherapy, but the primary endpoint was overall survival (OS), looking at the 1% cutoff, the 20% cutoff, and the 50% cutoff. That’s the distinction between the 2 trials. Obviously, OS is the primary endpoint and the sample size is larger in KEYNOTE-042.

Since our presentation at the 2018 ASCO Annual Meeting, we reported our final analysis at the European Lung Cancer Congress this year. At this time, we confirmed the improvement in OS of 20 months versus 13 months in the [PD-L1] over 50% subgroup. Similarly, in the 20% subgroup and the 1% subgroup, we also had an improvement in OS with a positive hazard ratio.

In the exploratory analysis, we also looked at the 1% to 49%, where we did not observe an improvement in OS. What does that mean? That a lot of the benefit is driven by the 50% subgroup. One caveat that we can take from this is that in the 50% subgroup, the standard treatment is single-agent [pembrolizumab]. However, in the 1% to 49% subgroup, the standard treatment should be chemotherapy or chemotherapy with pembrolizumab as per KEYNOTE-189.

On the other hand, for patients who cannot receive chemotherapy, then these data may support consideration of the use of single-agent pembrolizumab because it’s not actually inferior. Although this is not an inferiority analysis, the data suggest that it’s possible to consider this option.

What are the next steps for this research with pembrolizumab?

That’s an important question. Right now, on the standard indication, with the number of studies available, it’s use is pretty well-defined as either a single-agent or in combination with chemotherapy.

I think the next wave is, number 1, how do we manage resistance to single-agent pembrolizumab? There tends to be, potentially, continuation of the drug or combination with other drugs.

The second part of this is, do we use pembrolizumab as a frame—a so-called skeleton&mdash;and add on other immunotherapy agents? Obviously, it’s still very risky business because there are several negative data that have already come out, so we have to do this a lot smarter. If we see an advantage, we must make use of it.

The third part of it is, although I like PD-L1 expression, I still don’t think that it’s a perfect biomarker. We still have to work hard to understand the science a little bit more so that we can choose patients smarter. We’ve made it clinical, relevant, and applicable, but it’s still not the perfect one. Just like 

 mutation, before we found that mutation, we had used FISH. FISH was actually popular for a little while, but eventually we were able to find the 

 mutation. Hopefully we’ll find a more specific biomarker in the future.

What are some of the other key advances made with immunotherapy that are being presented during this congress? 

I think there are several discussions on tumor mutational burden (TMB), and the relevance of TMB was discussed on the basis of the MYSTIC data. That was cross-referenced with the TMB data from CheckMate-227.

How we’re going to apply that information is actually quite important, because there are other randomized studies, such as the B-FAST study, which will use TMB as a selective biomarker for patients to go on atezolizumab (Tecentriq). I think more work has to be done in this regard, number 1.

Number 2, there was another great talk about tumor heterogenicity, especially about the microenvironment and the immune reaction based on this heterogenicity. I think that was outstanding. In some ways, we treat lung cancer like a single disease, but inside this tumor, there are actually many inhabitants, and we have to recognize the behavior of these different inhabitants to determine how to deal with them.

Mok TSK, Wu Y-L, Kowalski DM, et al. Final analysis of the phase III KEYNOTE-042 study: pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for patients (pts) with PD-L1—positive locally advanced/metastatic NSCLC. 

. 2019;30(suppl 2; abstr 1020). doi: 10.1093/annonc/mdz063.

Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. 

. 2018;36(suppl 18; abstr LBA4). doi: 10.1200/JCO.2018.36.18_suppl.LBA4.

Tony Mok, MD, discusses the KEYNOTE-042 trial and the implications of its findings, and sheds light on the evolving role of immunotherapy in non–small cell lung cancer.

Mok Provides Pembrolizumab Update, Next Steps With Immunotherapy in NSCLC

The encouraging activity with osimertinib (Tagrisso) for patients with 

-mutant non—small cell lung cancer (NSCLC) continues to be highlighted in the form of prolonged progression-free survival (PFS); however, next steps are focusing on understanding the primary and acquired resistance mechanisms to the third-generation EGFR inhibitor.

Regarding its benefit, frontline osimertinib continued to show extended PFS in patients with advanced 

-mutant NSCLC, according to final efficacy and safety results from phase I expansion cohorts of the AURA trial that were presented at the 2019 European Lung Cancer Congress (ELCC).

At a median follow-up of 19.1 months, the median PFS in patients who received the third-generation EGFR inhibitor at 80 mg was 22.1 months (95% CI, 12.3-30.2) and was 19.3 months (95% CI, 11.1-26.0) for those who received it at 160 mg, leading to an overall median PFS of 20.5 months (95% CI, 13.7-26.1).

The FDA approved osimertinib as a first-line treatment for patients with NSCLC whose tumors harbor 

 mutations (exon 19 deletions or exon 21 L858R substitution mutations) in April 2018.

However, studies have emerged exploring primary and acquired resistance mechanisms to osimertinib. A Chinese study presented at the meeting evaluated targeted next-generation sequencing of patients with stage IIIb-IV 

-mutant T790M NSCLC to detect molecular marker status.

Findings showed that of the 117 patients who received osimertinib, 82.91% developed acquired resistance, and 7.69% had primary resistance.

 From the baseline samples, it was determined that there were 3 (33.33%) patients with 

 mutation, and 2 (22.22%) patients with unknown status. The data suggest that the mechanisms of this resistance could be highly heterogeneous.

“Acquired resistance to EGFR TKIs, or any other TKI for that matter, is matter of fact: it happens,” said Suresh S. Ramalingam, MD. “What we’re beginning to learn is what the resistance mechanisms to osimertinib are.”

 during the 2019 ELCC, Ramalingam, professor of hematology and medical oncology at the Emory University School of Medicine, described these findings with osimertinib, and discussed the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

: Could you discuss the data we have with frontline osimertinib in EGFR-mutant NSCLC?

: The FLAURA study demonstrated that osimertinib was superior in terms of PFS compared with either erlotinib (Tarceva) or gefitinib (Iressa). This has resulted in FDA approval of osimertinib in the United States and many other countries in the world. The study itself was a randomized, phase III trial in 556 patients who were randomized 1:1. Osimertinib was given at 80 mg per day in the experimental arm, and patients received standard doses of either erlotinib or gefitinib.

The primary endpoint was PFS, and we had independent assessment of radiographic images. Patients in the control group could cross over if they had progression and developed a T790M mechanism of resistance, and then receive osimertinib.

It was a very well-designed, phase III clinical trial that we reported, and it showed that the median PFS with osimertinib was 18.9 months, and the median PFS in the control group was 10.2 months. This represented a 54% reduction in the risk of disease progression or death for patients treated with osimertinib.

We also saw a very favorable toxicity profile for osimertinib. Since it’s a mutation-specific inhibitor, it has less of an effect on the wild-type receptor. Finally, the overall survival (OS) data suggested that there was a favorable outcome, though, from a statistical standpoint, the results are still very immature. We found a positive hazard ratio of 0.63, which did not quite meet the statistical significance at that level of low maturity, but it was still very promising regardless. Therefore, from all standpoints, we found that osimertinib came out ahead.

One problem that we see in lung cancer—specifically in 

-mutated patients—is brain metastases. Therefore, any agent we choose, we want to be effective against brain metastases. We saw that in the FLAURA study with osimertinib; we saw intracranial responses. For about 20% of the patients who came into the study with brain metastases, their PFS hazard ratio was similar to the overall patient population. We also saw less disease progression in the brain for patients with osimertinib. Therefore, another key piece of information that came out from the FLAURA study is that osimertinib has activity in the brain.

Another study being presented at the 2019 ELCC focuses on real-world data on long-term survival in patients with stage IV NSCLC who harbor T790M and were treated with osimertinib. Why is this study notable?

What we’re now beginning to see, now that osimertinib has been around for almost 4 years in clinical practice, is more outcome data from a real-world setting. In the second-line setting, that was the first indication for osimertinib in clinical practice for patients with T790M acquired resistance to a first- or second-generation TKI. This is the setting where the AURA3 trial had demonstrated superiority for osimertinib over platinum-based chemotherapy.

It’s encouraging to see these long-term survival data come up. We will soon hear the survival data from the AURA3 trial sometime maybe this year or early next year, and what this all tells us is that patients with 

-mutated NSCLC are living longer because of better treatment options.

Another study being presented addresses potential resistance mechanisms in patients with EGFR-mutant NSCLC who develop T790M. What is important to note about this trial?

We have to think about it in two different ways. What are the resistance mechanisms when osimertinib is used in the frontline setting for 

-mutated disease? What are the resistance mechanisms when it’s used in the second-line setting after someone has T790M?

In the frontline setting, when we looked at the plasma samples from patients on the FLAURA study, there was not a single case of T790-mediated acquired resistance, which, mechanistically, speaks to how effective osimertinib is at blocking both the EGFR exon 19 and 21 mutations, and also T790M.

 mutations, in the form of C797S, and we saw 

 pathway amplification; approximately 20% to 25% of the patients have 1 of these mechanisms of resistance. We’re still too early in the era of frontline osimertinib to know the full spectrum of resistance mechanisms.

When you think about second-line osimertinib use, we see a slightly higher prevalence of the C797S mutation. We continue to see 

 amplification, which is an important resistance mechanism in that situation. What does all this mean? Well, we have to now develop combination approaches based on the mechanisms of acquired resistance, so we can either overcome it or prevent it.

We already saw some exciting data at the 2019 AACR Annual Meeting just 2 weeks ago: combination therapy with osimertinib and savolitinib with acquired resistance seem to have a promising response rate of about 35%. When a MET inhibitor was used with osimertinib for patients with 

 amplification, the response rates and duration of response were quite promising. We’re already beginning to see movement in that direction.

What do we know about frontline osimertinib treatment and mechanisms of acquired resistance?

When osimertinib is used in the frontline setting, we see a response rate of about 80%, and the median PFS is 19 months. The key question now is, “Does it result in an improvement in OS?” For that, we are waiting for the full maturation of the FLAURA study data, which we’ll have either later this year or in early 2020.

Also, when somebody develops acquired resistance, how do we overcome that? Now we go to chemotherapy after patients progress on osimertinib, but we’re already learning about 

 pathway amplification, mutations of the renin—angiotensin system, mitogen-activated protein kinase pathway, and secondary 

 mutations. All of these can have potential targeted approaches to overcome that resistance.

We’re also learning to use liquid biopsies to understand resistance mechanisms, and perhaps there’s a possibility down the road to prognosticate patients early on during the course of treatment and be in a position to adapt therapies even before they acquire resistance mechanisms. That is another key area of interest.

The good news is osimertinib is a very well-tolerated drug compared with the previous generations of EGFR inhibitors. That allows us to develop combinations based on osimertinib and have them come at a safe tolerability profile for patients, and that provides new opportunities to understand and develop strategies against resistance mechanisms.

What is next in the clinical management of patients who progress on first-line osimertinib?

The key question is, “Can we go from osimertinib to another TKI based on resistance mechanisms rather than going to chemotherapy?” Early evidence of that came from the TATTON trial that was reported, which recently showed that combining a MET or a MEK inhibitor could be a potential way to delay acquired resistance, or use it to treat acquired resistance mediated by those pathways. That’s clearly the next level of investigation about what is the best way to salvage patients who develop resistance to osimertinib.

I look at it even at a broader setting. Can osimertinib be used in earlier stages of lung cancer to cure patients? A phase III study in patients with locally advanced, surgically unresectable disease has just been launched a few months ago, the LAURA trial, where patients get chemoradiation and are then randomized to osimertinib or no TKI.

The other key study in this space is in the adjuvant therapy setting for patients who’ve had surgical resection. This study, called ADAURA, has already completed accrual, where patients either received osimertinib or not after surgery and adjuvant chemotherapy.

In the United States, we’re pursuing the ALCHEMIST study, which is also asking a similar question of EGFR inhibition versus no EGFR inhibition in patients undergoing surgery. The goal there is now to leverage the exciting results from metastatic disease to improve cure rates for patients with earlier stages of lung cancer.

Yang J, Ramalingam S, Lee C, et al. Osimertinib as first-line (1L) treatment for epidermal growth factor receptor (EGFR) mutation-positive advanced non-small cell lung cancer (NSCLC): Final efficacy and safety results from two phase I expansion cohorts. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 122P.

Xu C, Wang W, Zhu Y, et al. Potential resistance mechanisms using next generation sequencing from Chinese EGFR T790M+ non-small cell lung cancer patients with primary resistance to osimertinib: A multicenter study. Presented at: 2019 European Lung Cancer Congress; April 11-13, 2019; Geneva, Switzerland. Abstract 114O.

Suresh S. Ramalingam, MD, describes findings with osimertinib, and discusses the emerging body of data exploring primary and acquired resistance mechanisms to the third-generation agent.

Kelly Davio

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