USC Norris

Heinz-Josef Lenz, MD, FACP, professor of medicine, J. Terrance Lanni Chair in Gastrointestinal Cancer Research, and co-director, University of Southern California (USC) Center for Molecular Pathway and Drug Discovery, at the USC Norris Comprehensive Cancer Center, discusses updated results from the phase II CheckMate-142 trial in metastatic colorectal cancer (mCRC).

The trial examined frontline nivolumab (Opdivo) plus low-dose ipilimumab (Yervoy) in treatment-naïve patients with microsatellite instability-high/mismatch repair deficient mCRC.

At a median follow-up of 25.4 months, the objective response rate was 58%. Moreover, progression-free survival (PFS) was not yet reached with the combination.

These data suggest that the combination can provide patients with durable benefit,says Lenz.

Videos


Heinz-Josef Lenz, MD, FACP, discusses updated results from the phase II CheckMate-142 trial in metastatic colorectal cancer.
 

Dr. Lenz on Updated Results of the CheckMate-142 Trial in mCRC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses research on biomarkers in hepatocellular carcinoma (HCC). 

An important area of research in HCC is on biomarkers, says El-Khoueiry. Given that patients with advanced HCC have access to multiple therapies, it would be beneficial to know which patients are going to respond to which agents. To that end, some preliminary research regarding biomarkers for anti—PD-1 agents have emerged, adds El-Khoueiry.

For example, in the phase I/II CheckMate-040 trial, which evaluated the safety and efficacy of nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) in advanced HCC, investigators showed that PD-L1 expression was associated with a higher objective response rate. However, PD-L1 was not shown to be a definitive biomarker as there were responders in the PD-L1—negative group of the trial as well. Right now, it is an evolving area of research. As such, biomarkers should not be used to select patients for treatments in current practice, concludes El-Khoueiry.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses research on biomarkers in hepatocellular carcinoma (HCC).

Dr. El-Khoueiry Discusses Research on Biomarkers in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses immunotherapy combination in hepatocellular carcinoma (HCC).

There are several combinations of immuno-oncology (IO) agents plus other IO agents under investigation. One of the most promising combinations is PD-1/L1 inhibition with CTLA-4 inhibition. Additionally, there is the phase III HIMALAYA trial, which is combining durvalumab (Imfinzi) and tremelimumab versus durvalumab alone versus sorafenib (Sutent) in the frontline setting. Furthermore, data from a phase II cohort of nivolumab (Opdivo) plus ipilimumab (Yervoy) are anticipated.

There is also rationale to combine PD-1 inhibitors with anti-VEGF targeted therapies, says El-Khoueiry. For example, the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima), which has shown a promising early signal. There are also combinations of nivolumab and sorafenib as well as nivolumab and lenvatinib in ongoing trials. The combination of atezolizumab (Tecentriq) with bevacizumab (Avastin) is also worth mentioning, adds El-Khoueiry, as this combination has shown an objective response rate (ORR) of approximately 30%. Investigators are still working to determine whether the toxicity of these combinations is tolerable and whether the improvement in ORR will translate to improved overall survival.

Dr. El-Khoueiry on Immunotherapy Combinations in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses choosing between immunotherapy agents and TKIs in hepatocellular carcinoma (HCC).

According to data from phase I/II studies, nivolumab (Opdivo) and pembrolizumab (Keytruda) can be used in the second-line setting as well as in the third-line setting. The trial eligibility did not limit the number of prior lines of therapy; however, patients must have had prior exposure to sorafenib (Nexavar), says El-Khoueiry. It can be difficult to decide between a TKI and a PD-1 inhibitor in the second-line setting as there are no head-to-head trials that have compared these agents directly. Therefore, a lot of the decision comes down to patient characteristics.

PD-1 inhibitors may induce a long-lasting response. However, not all patients will reach third- or fourth-line treatment. In those cases, giving these agents as second-line therapy may be the patient’s best chance of deriving benefit from them. For patients who are progressing rapidly or have high-risk disease, giving them immunotherapy may also be preferable in the second-line setting as opposed to a TKI. However, the TKIs are FDA approved based on phase III data and level 1 evidence. For example, data regarding the sequence of frontline sorafenib and second-line regorafenib (Stivarga) indicate a median overall survival of 26 months.

Dr. El-Khoueiry on Choosing Between Immunotherapy Agents and TKIs in HCC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses the role of ramucirumab (Cyramza) in advanced hepatocellular carcinoma (HCC).

Ramucirumab, a VEGFR-2 antibody, is one of several agents that has been tested in the second-line setting for patients who have previously been treated with sorafenib (Nexavar). The drug was first evaluated in the phase III REACH study, which was negative. However, a subgroup analysis indicated that patients with an alpha-fetoprotein (AFP) ≥400 benefitted from ramucirumab. Therefore, the phase III REACH-2 study was launched, homing in on this specific patient population.

REACH-2 was a positive study showing an improvement in overall survival (OS) with ramucirumab versus placebo in patients with AFP ≥400. The median OS of 8 months was a little bit less than what has been seen with the VEGF TKIs in this space, but cross-trial comparisons have caveats, El-Khoueiry says. In a joint analysis of REACH and REACH-2, it was determined that there was a 3-month improvement in OS with ramucirumab in this select population.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, discusses the role of ramucirumab in advanced hepatocellular carcinoma.

Dr. El-Khoueiry on the Role of Ramucirumab in Advanced HCC

Heinz-Josef Lenz, MD, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, discusses next steps with immunotherapy in metastatic colorectal cancer (mCRC).

Initial data in the relapsed/refractory setting indicate have shown that immunotherapy can induce an overall response rate of over 50% in patients who are microsatellite instability—high and DNA mismatch repair deficient. The question moving forward is if physicians can avoid giving cytotoxic chemotherapy to these patients and treat with immunotherapy alone, says Lenz.

Studies are now evaluating the efficacy of PD-1 inhibition alone or in combination with anti—CTLA-4 therapy in the frontline setting. Other studies are looking at checkpoint inhibition combined with targeted therapy or chemotherapy to see if benefit can be further extended.

Heinz-Josef Lenz, MD, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, discusses next steps with immunotherapy in metastatic colorectal cancer.

Dr. Lenz on Next Steps With Immunotherapy in mCRC

With the armamentarium for advanced hepatocellular carcinoma (HCC) significantly expanding over the past few years, the next questions lie in the utility of biomarkers to determine which therapies are best for which patient, as well as the future role of combination therapies, said Anthony B. El-Khoueiry, MD.

“Our treatment has improved quite a bit because we have gone from having just one drug for about 10 years—sorafenib (Nexavar)&mdash;to now having a multitude of options,” said El-Khoueiry, an associate professor of clinical medicine at University of Southern California Keck School of Medicine, and the director of clinical translation at the Southern California Clinical and Translational Science Institute.

In addition to the plethora of available TKIs, more mature data could increase the prominence of PD-1 inhibitors, such as nivolumab (Opdivo) and pembrolizumab (Keytruda). The VEGFR2-inhibitor ramucirumab (Cyramza) is also now available for patients with alpha-fetoprotein (AFP) ≥400 ng/mL following treatment with sorafenib, added El-Khoueiry.

 State of the Science Summit™ on Gastrointestinal Malignancies, El-Khoueiry provided insight on the rapidly evolving treatment options in HCC.

: How has treatment of patients for advanced HCC changed over the past few years?

: Let me define “advanced HCC” for a minute. The classic definition of advanced HCC is what we call Barcelona clinic liver cancer (BCLC)-stage C, which includes patients with portal venous invasion or metastases outside the liver. The other group that's included in advanced HCC systemic therapy trials is the patient population with multifocal disease limited to the liver, who have progressed on locoregional therapy or who are not candidates for locoregional therapy.

I'll take a moment to emphasize that this is a subgroup of patients with BCLC-stage B disease, meaning liver-limited disease, but they have large lesions diffused throughout the liver. These patients would not be served well with locoregional therapy so they go right to systemic therapy. This is the patient population that we typically include in trials for systemic therapy.

Starting in the frontline setting, we had a noninferiority study comparing lenvatinib (Lenvima) with sorafenib, and it was a positive study. It showed us that lenvatinib was noninferior to sorafenib as far as overall survival (OS). We are also awaiting the results of CheckMate-459, which is a study comparing nivolumab with sorafenib. These results are pending.

Then, we go to the second-line setting. The first positive study in this setting was the RESORCE trial comparing regorafenib (Stivarga) with placebo. This was a 2:1 randomization, and it was a positive study showing an improvement in OS compared with placebo. The secondary endpoints of progression-free survival (PFS) and overall response rate (ORR) were also superior to placebo. This population was unique; it comprised patients who tolerated sorafenib at 400 mg daily for the last 28 days, which was a very select group. Nonetheless, regorafenib is now an FDA-approved option following sorafenib.

Another agent that has been tested in the second- and third-line settings is cabozantinib (Cabometyx), another multikinase TKI. This drug targets VEGF, AXL, and MET, among others. This study did not select patients based on MET expression, [but it was] unique because about one-third of patients were being treated in the third-line setting. This was another positive study, and we again saw a median OS in the range of 10 to 11 months.

Ramucirumab is another agent that has been evaluated following treatment with sorafenib. This drug is an antibody against VEGF2. Ramucirumab was first evaluated in the REACH study, and this was a negative study. However, in a subgroup analysis, it appeared that in patients with an AFP ≥400 benefitted from ramucirumab. Therefore, the REACH-2 study [was started], which included patients with this characteristic, and all patients also needed prior exposure to sorafenib.

This was a positive study with ramucirumab showing an improvement in OS compared with placebo in this select population. A median OS of 8 months was a little bit less than what we were used to seeing, but cross-trial comparisons are a little bit unfair. There was a joint analysis of all the patients from REACH and REACH-2 with an AFP >400, and when these 2 trials are put together, we see approximately a 3-month improvement in OS with ramucirumab.

We also have immunotherapy agents. The PD-1 antibodies nivolumab and pembrolizumab both [received accelerated approvals [for use] following sorafenib. Nivolumab has an approval based on the CheckMate-040 trial; this was a phase II study with over 200 patients. The ORR with nivolumab was 20% when putting all of the cohorts together. When focusing on the post-sorafenib cohort, which is where the agent received accelerated approval, the ORR was close to 15%. What is important about these responses is that they were quite durable, with a median duration of response (DOR) reaching as long as 18 months. Looking at just that population, the median DOR was 10 months or longer.

Pembrolizumab was studied in a phase II trial with slightly more than 100 patients. We saw similar ORR of around 17% and the durability was comparable; toxicity profiles were also comparable. As I mentioned, we are waiting for results from CheckMate-459, which is the phase III trial evaluating nivolumab versus sorafenib.

How do you distinguish between lenvatinib and sorafenib?

REFLECT was a noninferiority study, so if we want to analyze the data from a purist's perspective, it's just another option; the OS was comparable. It's also interesting that the lenvatinib study excluded patients with >50% tumor burden in the liver, or with main portal vein invasion. When we look at secondary endpoints, the PFS and ORR were significantly higher with lenvatinib versus sorafenib; the ORR was in the low 20% range.

I am frequently asked, "When would you use lenvatinib?" It's hard to answer that question based on secondary endpoints. Nonetheless, this is quite a potent agent and the targets of lenvatinib are beyond just the VEGF receptor. Lenvatinib also targets FGFR, and this may offer unique mechanism of action. The higher ORR and higher PFS [seen with] lenvatinib [may make it] an option for symptomatic patients who need an immediate response or who may not make it to subsequent lines of therapy.

With regard to safety profile, these 2 TKIs actually had overlapping toxicities, except for 2 categories. There was a higher risk of hypertension with lenvatinib and a higher risk of hand-foot syndrome with sorafenib. If that matters to the specific patient, that could be taken into consideration as well.

What is your approach for choosing between immunotherapy agents and TKIs?

To elaborate a little more on the role of immunotherapy, the current data are based on phase I and II trials. The field is still evolving. Based on the data we have from the phase I/II studies, we could use nivolumab or pembrolizumab in the second-line setting, and they could also be used in the third-line setting because the eligibility did not have a limit on prior lines of therapy. Patients must have received sorafenib. It’s hard to know how to choose between a TKI and a PD-1 inhibitor in the second-line setting. There has not been a randomized phase III study comparing these agents in the second-line setting. A lot of this will be based on clinical judgement based on patient characteristics.

Let's look at the data and see how they may guide us. We know that with the PD-1 inhibitors, we give patients a chance for a long-lasting response. For those who may not be able to get to third- or fourth-line treatment, we may not want them to miss the opportunity to receive anti—PD-1 therapy. Maybe these patients are progressing rapidly or have high-risk disease, so we would give them immunotherapy in the second-line setting rather than a TKI. To be fair, the TKIs are FDA approved based on phase III data and level 1 evidence. We know that, with the sorafenib-regorafenib sequence in that select patient population, there are data that tell us if we look at the survival, this sequence had a median OS of 26 months. It's intriguing that sequencing these agents can give us survival beyond 2 years.

For those who may not make it beyond the second-line setting, we may want to preferentially use a PD-1 inhibitor. Some patients also may not tolerate TKIs, especially with the overlapping toxicities. Another angle to take here is the Child-Pugh class B patients, a population we always struggle with. Most of the data we have in clinical trials are from the Child-Pugh class A subgroup. We now have a cohort of 50 patients with Child-Pugh class B scores of 7 or 8 who were treated with nivolumab and the toxicity appeared comparable with the Child-Pugh class A population. The ORR was about 12%—so in the same range. This was a single-arm, small study, but it gives us some perspective.

What is some of the work being done with combinations in this space?

There are immunotherapy combinations of immuno-oncology (IO) agents plus other IO agents. The most obvious one in clinical trials right now is combining anti—PD-1/L1 with anti–CTLA-4. There is the phase III HIMALAYA trial combining durvalumab (Imfinzi) and tremelimumab versus durvalumab alone versus sorafenib in the frontline setting. We are awaiting data from a phase II cohort of nivolumab plus ipilimumab.

There is also rationale to combine PD-1 inhibitors with targeted agents against VEGF. For example, we can look at a pembrolizumab/lenvatinib combination, which has shown a promising early signal. We are also seeing nivolumab/sorafenib or nivolumab/lenvatinib in ongoing trials. We could go on and on. The question will be whether the toxicity is tolerable and whether the improvement in ORR will translate to better OS. The combination of atezolizumab (Tecentriq) with bevacizumab (Avastin) is also worth mentioning. This combination has data from slightly more than 100 patients, with a promising ORR in the 30% range. We will see again how this translates into survival.

Another important area of research is on biomarkers. Obviously, when we have multiple treatment options, it would benefit us to know how to select patients for the best therapy. There have been data emerging for the anti—PD-1 agents in terms of biomarkers. For example, in CheckMate-040, we showed that at least the PD-L1 expression was associated with higher ORR. This was not all or nothing, though—we still saw responders in the PD-L1–negative group. This is an evolving area, and none of these are definitive. I would not use any emerging biomarkers to select patients in my current practice.

Articles

Anthony B. El-Khoueiry, MD, provides insight on the rapidly evolving treatment options in hepatocellular carcinoma.

Novel Combos, Predictive Biomarkers Slated as Future of HCC Treatment

Heinz-Josef Lenz, MD, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, discusses the frontline combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in metastatic colorectal cancer (mCRC).

In a phase II study, nivolumab combined with low-dose ipilimumab is being evaluated as a frontline regimen for patients with microsatellite instability—high (MSI–H), mismatch repair deficient mCRC. At the 2018 ESMO Congress, initial data with this combination were presented, showing that the overall response rate (ORR) was over 55% and that median progression-free survival (PFS), overall survival (OS) and duration of response were not reached. Updated data were presented at the 2019 ASCO Annual Meeting.

At a median follow-up of 20 months, ORR increased to 58%, and median PFS and OS were still not reached, indicating that this a highly effective frontline therapy, Lenz says. In the future, the question will arise if patients with MSI-H mCRC need to receive frontline chemotherapy or whether they can start on this immunotherapy combination. Notably, this is only a single-arm study with a small group of patients, so a larger phase III study is likely necessary to receive regulatory approval, Lenz concludes.

Heinz-Josef Lenz, MD, associate director for Adult Oncology and co-leader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, discusses frontline nivolumab plus ipilimumab in metastatic colorectal cancer.

Dr. Lenz Discusses Frontline Nivolumab Plus Ipilimumab in mCRC

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, distinguishes between lenvatinib (Lenvima) and sorafenib (Nexavar) in the frontline treatment of advanced hepatocellular carcinoma (HCC).

Choosing between the 2 TKIs is challenging because the phase III REFLECT study, which led to the FDA approval of lenvatinib in the frontline setting, was a noninferiority study. Lenvatinib was successful in demonstrating noninferiority in terms of overall survival compared with sorafenib. The agent also demonstrated a superior progression-free survival (PFS) and overall response rate (ORR). However, PFS and ORR were secondary endpoints of the trial, and it’s difficult to make treatment decisions based on secondary endpoints, says El-Khoueiry.

Nevertheless, lenvatinib is a potent drug that targets VEGF and FGFR, creating a unique mechanism of action, El-Khoueiry says. The higher ORR and longer PFS may make lenvatinib an option for symptomatic patients who need an immediate response or who may not make it to subsequent lines of therapy.

With regards to safety, the 2 TKIs appear to have overlapping toxicities. However, there was higher risk of hypertension with lenvatinib and higher risk of hand-foot syndrome with sorafenib in the REFLECT study. This could be another factor in determining the right TKI to use, El-Khoueiry concludes.

Anthony B. El-Khoueiry, MD, associate professor of clinical medicine, Keck School of Medicine, USC Norris Comprehensive Cancer Center, distinguishes between lenvatinib and sorafenib for the frontline treatment of advanced hepatocellular carcinoma.

Dr. El-Khoueiry on Choosing Between Lenvatinib and Sorafenib in HCC

Results of the phase III KEYNOTE-189 and IMpower150 trials showed a profound survival benefit in patients with advanced nonsquamous non—small cell lung cancer (NSCLC), when pembrolizumab (Keytruda) and atezolizumab (Tecentriq), respectively, were added to standard chemotherapeutic backbones. Now, selection between the 2 regimens must be based on individual risk factors and comorbidities, explained Bing Xia, MD.

In KEYNOTE-189, patients who received the combination of pembrolizumab, pemetrexed, and platinum-based chemotherapy experienced a 51% reduction in the risk of death compared with those who received chemotherapy alone.

 In IMpower150, the regimen of atezolizumab, carboplatin, paclitaxel, and bevacizumab (Avastin) led to a 22% reduction in the risk of death versus those who received chemotherapy and bevacizumab alone.

“Now we know that patients do better when we combine chemotherapy and immunotherapy,” said Xia. “If you have a healthy patient with no contraindications to immunotherapy, try the combination upfront.”

Given that patients will now be exposed to immunotherapy and chemotherapy in the frontline setting, treatment beyond progression has become a hot area of research, added Xia.

However, for patients with an actionable 

 mutation, sequential therapy is still very much a part of modern approaches given the number of ALK inhibitors available. Alectinib (Alecensa), for example, is approved as a first-line therapy for patients with 

-positive NSCLC, based on the robust median progression-free survival (PFS) of 34.8 months observed in the phase III ALEX trial.

 If patients are intolerant of or progress on the third-generation inhibitor, other options are available that they can switch over to, such as brigatinib (Alunbrig), ceritinib (Zykadia), or lorlatinib (Lorviqua).

 rearranged space is very exciting right now. We have very impressive therapies—not just 1 but multiple drugs,” said Xia. “I’m excited to see the updated data from the lorlatinib study, in terms of its efficacy in patients who have progressed on multiple ALK inhibitors.”

 State of the Science Summit™ on Non—Small Cell Lung Cancer, Xia, assistant professor of clinical medicine, Keck School of Medicine, University of Southern California, discussed the latest immunotherapy developments in nonsquamous NSCLC, as well as sequencing strategies for patients with 

: Could you discuss the KEYNOTE-189 and IMpower150 trials in advanced nonsquamous NSCLC?

: Both the KEYNOTE-189 and IMpower150 trials are practice changing. The regimens in both studies have National Comprehensive Cancer Network category 1 recommendations. As we saw in the KEYNOTE-189 study, the combination of pembrolizumab plus platinum-based chemotherapy and pemetrexed improved PFS and overall survival (OS) compared with [chemotherapy alone].

In the IMpower150 study, investigators looked at the combination of carboplatin, paclitaxel, bevacizumab, and atezolizumab versus chemotherapy plus bevacizumab alone. Similar improvements in PFS and OS were noted in that study.

Since they both have level 1 recommendations, how are you choosing which frontline regimen to give to patients?

It's patient-specific. I look at their risk factors to see whether they have other medical comorbidities, or other medical issues that would preclude their use of bevacizumab. If so, I would prefer to use the pembrolizumab regimen.

An area of additional research that needs to be done is in the patients with actionable mutations. [We need to know] what to do after they progress on initial TKI therapy. These are our 

-positive patients who, after receiving treatment with a TKI, have progression. What is the best treatment combination for them? Is it chemotherapy or chemotherapy plus immunotherapy? If so, which combination? In a subgroup analysis of the IMpower150 study, investigators looked at that and they showed that there was benefit with atezolizumab in that patient population.

Is there rationale to explore sequential use of pembrolizumab and atezolizumab?

Perhaps in a clinical trial. [Determining] what to do for patients who progress on initial chemotherapy and immunotherapy is a very big focus of research right now. Prior to the KEYNOTE-189 and IMpower150 studies, we were using mostly sequential [therapy]. Patients were receiving chemotherapy or chemotherapy/bevacizumab first, and then, upon progression, they would receive immunotherapy as second-line treatment. We're now using chemotherapy and immunotherapy altogether, so we're using all our equipment upfront.

We have clinical trials looking at multiple immunotherapy drugs, including CTLA-4 inhibitors, plus perhaps a PD-1/PD-L1 inhibitor, to see whether that combination has efficacy. Furthermore, [other trials are] looking at other treatment modalities that could include priming before immunotherapy to see whether that could improve patient outcomes. Right now, clinical trials are the best option available to patients [in the second-line setting].

How do the regimens compare in terms of tolerability?

Both are equally well tolerated. The adverse events (AEs) with both immunotherapies are very similar. In both trials, the AEs included thyroid issues with hypothyroidism and hyperthyroidism, risk of pneumonitis or colitis, and rash. However, the 2 regimens have both been equally well tolerated in my anecdotal use.

What unanswered questions would you like to see addressed in future research?

I'm very interested in [learning more about] what to do after patients develop resistance to chemotherapy plus immunotherapy and whether there is a preferred combination in terms of response rates and PFS. That question remains to be answered.

-positive NSCLC at the State of the Science Summit. What should clinicians be aware of in this space?

[In my presentation,] I focused on frontline treatments for patients with 

-positive lung cancers. Crizotinib (Xalkori) has historically been the ALK inhibitor that's been used in the frontline setting. However, we now have data supporting the use of alectinib, brigatinib, and ceritinib in the frontline setting. Brigatinib is not currently FDA approved for treatment-naïve patients who harbor an 

 rearrangement, but there are convincing data that show that brigatinib is effective in that setting. I went over the data and talked about potential off-label use of frontline brigatinib.

I also talked about lorlatinib, which is a newer ALK inhibitor. We have data showing that not only is this ALK inhibitor effective in the frontline setting, but it's FDA approved for use in patients who have received crizotinib and 1 other ALK inhibitor, or a second-generation ALK inhibitor. It does have a place in patients who have developed resistance to alectinib, brigatinib, or ceritinib.

What would lead you to choose a different agent over alectinib in the frontline setting?

In my personal practice, I do use alectinib in the frontline setting. If patients develop AEs from alectinib or they have an allergy to alectinib—and I have a patient who does&mdash;then I would switch to brigatinib or ceritinib. In my own personal practice, I've been switching to brigatinib in that setting for patients can't tolerate or have toxicities with alectinib.

What distinguishes the ALK inhibitors from each other?

These newer ALK inhibitors have greater efficacy. Their FDA approvals were based on a direct comparison with crizotinib, which is an older-generation ALK inhibitor. Specifically, alectinib and brigatinib were both compared directly with crizotinib and were shown to have better PFS compared with crizotinib.

Is it too early to comment on the activity of ensartinib and repotrectinib?

We have interesting data coming out for those agents. I’m very excited to see where or what happens at the 2019 ASCO Annual Meeting with studies and updates.

Are you able to sequence agents based on anticipated mechanisms of resistance?

In patients who experience progression on alectinib, the options become brigatinib, as there have been some data to support the use of this agent, or even lorlatinib, which has shown efficacy in this space.

These drugs are well tolerated overall. If patients are not able to tolerate alectinib, it's nice to have other ALK inhibitors to select from. Being able to switch to a different ALK inhibitor might provide patients with [similar] efficacy and better tolerated AEs.

Although these agents show impressive activity on their own, is there rationale to explore them in combination?

 data are very good. With alectinib, an update at the 2018 ASCO Annual Meeting showed updated PFS data from the ALEX trial of over 30 months, which is very impressive. Combinations could be explored in clinical trials; we just have to be mindful of the potential AEs or toxicities when they’re used in combination.

Are patients adherent to the administration of these agents?

These are pills, so patients who have an 

 rearrangement are very fortunate. Patients are able to essentially administer the therapies at home without having to come to us every 2 to 4 weeks for intravenous infusion. As such, patients are pretty compliant. In general, these patients are very motivated to treat their cancer, so when you tell them that this is a very effective therapy for their cancer, they become driven to take the pill every day. [Patient compliance] has been less of an issue for me [with this approach].

Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. 

. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.

Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.

Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. 

 2018;36(suppl 15, abstr 9043). doi: 10.1200/JCO.2018.36.15_suppl.9043.

Bing Xia, MD, discusses the latest immunotherapy developments in nonsquamous non–small cell lung cancer, as well as sequencing strategies for patients with ALK-positive disease.