Chemoimmunotherapy Combos “Game-Changing” in Frontline Metastatic NSCLC

Nicholas Rohs, MD

Pivotal trials such as KEYNOTE-189 and IMpower150 evaluating novel chemoimmunotherapy combinations have shifted standards in the frontline treatment of patients with non–small cell lung cancer (NSCLC), according to Nicholas Rohs, MD, and emerging data indicate that these approaches could also be beneficial in those with actionable mutations, such as EGFR and ALK.

Results from the phase 3 KEYNOTE-189 showed a 12-month overall survival (OS) rate of 69.2% with the addition of pembrolizumab (Keytruda) to pemetrexed and either carboplatin or cisplatin versus 49.4% with placebo plus pemetrexed and either carboplatin or cisplatin (HR, 0.49; 95% CI, 0.38-0.64; P <.001).¹ An updated analysis from the trial presented during the 2020 ASCO Virtual Scientific Program showed continued survival benefit with the chemoimmunotherapy combination.²

The addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) was found to significantly improve survival compared with bevacizumab, carboplatin, and paclitaxel alone (BCP) in a similar patient population, according to data from the phase 3 IMpower150 trial.³ The median OS was 19.8 months with ABCP versus 14.9 months with BCP in the intent-to-treat population. Notably, ABCP was also found to have a survival benefit in patients with EGFR mutations (HR, 0.61) and those with sensitizing EGFR mutations (HR, 0.31).

Updated data presented during the 2020 ESMO Virtual Congress showed that with approximately 20 months of additional follow-up, ABCP continued to demonstrate an OS benefit compared with BCP in patients with sensitizing EGFR mutations, including patients who progressed on TKIs.⁴

These data underscore a need to perform a randomized prospective trial examining immunotherapies in these patient subsets to better understand the benefit of this approach, according to Rohs.

“In both the KEYNOTE-189 and IMpower150 trial, we think that there's probably some synergy between the chemotherapy causing cell death and releasing a immunogenic stimulus to help these immunotherapies do what they need to do,” said Rohs. “These were 2 pivotal trials that have been game-changing for frontline metastatic NSCLC.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Rohs, an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine, Mount Sinai, further discussed the progress made with chemoimmunotherapy combinations in frontline NSCLC, future research directions, and emerging approaches that seek to propel progress in this disease.

OncLive®: Chemoimmunotherapy combinations have become a key component of care in the first-line treatment of patients with NSCLC. Could you speak to how the data from the KEYNOTE-189 trial led to a new standard of care?

Rohs: KEYNOTE-189 is a critical study that was presented a couple of years ago and published in the New England Journal of Medicine. This [trial was done in] untreated patients with nonsquamous, stage IV NSCLC who do not have an EGFR or ALK sensitizing mutation. Patients had to have a good performance status and we had to be able to check their PD-L1 score, which is pretty critical to the evaluation of the trial.

Participants were randomized in a 2:1 fashion to receive pemetrexed and a platinum-based drug plus either pembrolizumab or placebo. Patients received this [regimen] every 3 weeks for 4 cycles and then they went on maintenance placebo or pembrolizumab if they had a response. We're looking at OS and PFS. These data, when they first came out, were really striking: They showed a really good OS benefit [with the pembrolizumab combination], with a really nice hazard ratio (HR) of 0.49.

This year, an update [was published] in the Journal of Clinical Oncology; these results continued to show positivity [with the chemoimmunotherapy]. The addition of the pembrolizumab to this up-front chemotherapy doublet really improved patient outcomes.

The PFS benefit was observed irrespective of PD-L1 status [with the pembrolizumab combination]. We do see, however, that you get decreasing returns with a lower PD-L1 score, so patients with a PD-L1 score of 50% or more did better. However, all patients with immune expression were able to benefit.

It's really nice because adding on the pembrolizumab to this regimen did not add a lot of toxicity. We did see an unexpected uptick in immune therapy–related changes, but overall, this was a well-tolerated regimen and it became one of the standards of care for this patient population. We will continue to see these data mature, but this is a treatment [approach] that's here to stay for a long time.

A similar patient population was enrolled to the IMpower150 trial. How did these data compare with what had been seen in KEYNOTE-189?

The IMpower150 trial [enrolled] a similar patient population: those with stage IV or recurrent metastatic nonsquamous NSCLC. [Data from IMpower150] was also published a couple of years ago in the New England Journal of Medicine. Patients were treatment naïve, similar to the previous study, but the interesting thing is that this trial actually permitted [patients with] EGFR and ALK mutations to enroll. In the 3-arm trial, investigators randomized patients to receive atezolizumab with carboplatin and paclitaxel or atezolizumab with carboplatin, paclitaxel, and bevacizumab. The third arm, the control arm, was given carboplatin, paclitaxel, and bevacizumab. [Patients were randomized in] a 1:1:1 fashion. Investigators looked OS as well as PFS, originally, in the wild-type population.

The first analysis was done in patients without EGFR or ALK translocations. Similar to the other trials, they showed a very nice survival and PFS benefit with the addition of the immune therapy, but it was maybe not as striking as the KEYNOYE-189 trial; that may have to do with the chemotherapy backbone.

Investigators conducted an analysis on patients who harbored EGFR and ALK aberrations, as well. Could you speak to the importance of this component of the trial? What was learned?

[This is arguably the] most exciting thing that many people are talking about with regard to this trial, the prespecified analysis that looked at the subset of patients with EGFR and ALK mutations. Investigators actually saw some interesting activity in that population, which is great, because we haven't seen a lot of benefit with the addition of immune therapies [in these] patients who have these actionable mutations.

As such, this generated a lot of interest in the lung cancer community. Investigators went back again and looked at this prespecified subset analysis. There are a couple of caveats to this. This was a small patient population and it was not a prospective randomized evaluation. However, when they looked at patients with EGFR or ALK aberrations, as well as those with liver metastases, another challenging group, they saw a benefit to adding atezolizumab to the triplet therapy in both groups.

A lot of questions were generated out of this trial and I think it really highlighted the need for us to do a randomized prospective trial in these populations with immunotherapies to really understand [more about this approach in this subset]. There’s a lot of discussion about what was doing the heavy lifting in this trial. Was the bevacizumab a game-changer or was it the immunotherapy? There’s probably some sort of interaction. Maybe the bevacizumab primed the tumor to be a little bit more response to immunotherapy.

What were some of the updated data that read out at the 2020 ESMO Virtual Congress?

At the meeting, Martin Reck, MD, PhD, of Lung Clinic Grosshansdorf, had a poster presentation that updated some of the IMpower150 data in the subset of patients with EGFR and ALK mutations. Patients with EGFR mutations continue to see an OS benefit [with this approach]. Particularly patients with an EGFR sensitizing mutation saw an improved HR of 0.60 versus 0.91 with any EGFR mutation.

The exciting thing about this is that it’s still applicable to patients who received a prior TKI; they still had a good HR of 0.74 if they had been previously treated. That's often where these patients would be getting this kind of a regimen; they would receive it after a targeted therapy. As such, to know the patients who have had TKI exposure still may respond to this is really where I think that this regimen is best used right now.

Given these results, do you believe the combination should be evaluated in patients with other sensitizing mutations, as well, beyond EGFR and ALK?

Potentially. We always talk about [patients with] EGFR and ALK alterations, but you'd be putting on blinders if you didn't see the amazing progress we're making in other areas. [We need] to include these patient populations in chemotherapy and immunotherapy trials, as is appropriate. We know that sometimes immunotherapies do not mix with patients [who are treated] with targeted therapies but some of these preliminary data [have been encouraging]. Everyone would like to see some more prospective data and in larger patient populations.

Looking to other novel approaches that are generating excitement in the space, what are your thoughts on the novel anti-TIGIT therapy, tiragolumab?

[The anti-TIGIT antibody was examined in] CITYSCAPE, a randomized phase 2 trial that was done in [patients with] stage IV NSCLC who have no EGFR or ALK mutations. Patients were randomized in a 1:1 fashion to receive either atezolizumab with placebo versus atezolizumab with tiragolumab, which is a very interesting, exciting new compound. Tiragolumab is 1 of the novel checkpoints; instead of direct PD-1/PD-L1 kind of binding that we talk about a lot, this is more on the T cells and natural killer cells.

We’ve seen some synergy in early-stage trials and preclinical data [with this approach], and we saw in this trial that adding tiragolumab to atezolizumab improved overall response rates and PFS. The last update was at a 10.9-month median follow-up, so I'm really excited to see these data mature further.

This has given us the impetus to go further with this compound in combination with immunotherapies because it does seem to improve response rates and PFS with good toxicity. All 3 of the trials we've talked about so far have, with the addition of these immunotherapies, had modest upticks in adverse effects (AEs), with the exception of the new immunotherapy-related AEs; however, most of [these effects] are very [manageable].

The more that we can maximize the benefit of these immunotherapies, [the better]. We have really shifted the entire paradigm of lung cancer care with the addition of immunotherapy. The further we can push this, the better we can do for our patients. I'm really excited to see what the next couple of years bring with regard to this.

What are the next steps for this TIGIT therapy? Where are efforts focused right now?

Tiragolumab is [being examined in so many] different trials right now. [We are] really excited about this compound. At Mount Sinai, we have a couple of trials that we're doing in small cell lung cancer and NSCLC across different groups of populations to see whether we can improve that immune therapy response. I really don't believe this compound is going anywhere, anytime soon. We're going to continue to examine it in different combinations. As we build up the data, and if it continues to be reaffirming in advanced stage [disease], we will eventually introduce this into earlier stage. They're already doing some of those trials right now.

References

1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Eng J Med. 2018;378:2078-2092. doi:10.1056/NEJMoa1801005

2. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic non–small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517. doi:10.1200/JCO.19.03136

3. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non–small–cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med. 2019;7(5):387-401. doi:10.1016/S2213-2600(19)30084-0

4. Reck M, Mok T, Socinski MA, et al. IMpower150: Updated efficacy analysis in patients with EGFR mutations. Presented at 2020 ESMO Congress; September 19-September 21, 2020; Virtual. Abstract 1293P.