Navigating Frontline Therapy and Treatment Beyond Progression in NSCLC

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.

Bing Xia, MD

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.1 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.2

“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 ALK 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 ALK-positive NSCLC, based on the robust median progression-free survival (PFS) of 34.8 months observed in the phase III ALEX trial.3 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).

“The ALK 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.”

In an interview during the 2019 OncLive® 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 ALK-positive disease.

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

Xia: 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 EGFR- or ALK-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.

You also spoke on ALK-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 ALK-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 ALK 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—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?

Possibly. The ALK 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 ALK 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].


  1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.
  2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301. doi: 10.1056/NEJMoa1716948.
  3. 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. J Clin Oncol. 2018;36(suppl 15, abstr 9043). doi: 10.1200/JCO.2018.36.15_suppl.9043.