Key to Leveraging Emerging Approaches in Lung Cancer Lies in Balancing Benefit With Risk

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Partner | Cancer Centers | <b>Moffitt Cancer Center</b>

Novel immunotherapy combinations are gaining ground in the frontline treatment of patients with lung cancer, but the toxicities associated with these regimens must be weighed against the benefit they provide.

Novel immunotherapy combinations are gaining ground in the frontline treatment of patients with lung cancer, but the toxicities associated with these regimens must be weighed against the benefit they provide, according to Michael Shafique, MD. Emerging approaches, such as next-generation antibody-drug conjugates (ADCs), could potentially overcome tolerability challenges and provide an option to those who progress on immunotherapies.

“Ideally, we would like to have something that a patient is going to respond to for a long time, and the immunotherapy drugs do have that potential to be a very durable treatment option,” Shafique said. “However, it still stands that most patients are not going to have those kinds of responses, so we need something that we can use to treat those patients, achieve those responses, and establish disease control. [ADCs] may be the answer [for those patients].”

In an interview with OncLive®during an Institutional Perspective in Cancer webinar on lung cancer, Shafique, a medical oncologist in the Department of Thoracic Oncology at Moffitt Cancer Center, discussed the latest developments made across lung cancer treatment settings and highlighted ongoing efforts that are generating excitement.

OncLive®: Exciting developments have been made with immunotherapy in NSCLC and small cell lung cancer (SCLC). What are some of the efforts that are being made to build off of the success seen with the pivotal phase 3 PACIFIC trial (NCT02125461)?

Shafique: [That trial has] really given us peace of mind—at least in the thoracic oncology setting—that we can safely use immunotherapies around the time of radiation to the chest. We saw acceptable levels of pneumonitis, and [the incidence of] grade 3 pneumonitis did not [differ too much] between the placebo and durvalumab [Imfinzi] arms.

With that as a proof of concept, it has spawned multiple efforts in both NSCLC and SCLC to assess whether we could use a regimen with chemotherapy concurrent with radiation, but also with a checkpoint inhibitor. Some studies are looking at a protocol like that, but others are examining pembrolizumab [Keytruda], for example, in that setting. [Another area of interest] is stereotactic radiation with immunotherapy. Some studies are looking at stereotactic radiation followed by consolidative checkpoint inhibitors.

Even in the SCLC setting, [efforts are being made to bring] consolidative thoracic radiation back into the mix. Historically, we would give carboplatin plus etoposide. Then, in patients who had good responses and who had disease at the beginning that was intrathoracic, we would give some consolidative radiation. None of those techniques were allowed on CASPIAN or IMpower133, but we are kind of circling back to that.

[Those approaches have] demonstrated OS benefits prior to the advent of immunotherapies in SCLC. The idea is to bring that back now and ask whether we safely add that to a regimen that utilizes immunotherapy in the up-front induction setting, and then use some consolidative radiation, and then still use immunotherapy as more of a maintenance strategy in the long run. PACIFIC really paved the way for many interesting efforts on many fronts in lung cancer.

What are some of the most promising combination immunotherapy regimens under investigation in the frontline NSCLC setting? What are the toxicity challenges faced with these approaches?

We are getting more and more excellent data from the phase 3 KEYNOTE-189 study [NCT02578680]. The survival data [from the trial] were presented at the 2020 ASCO Virtual Scientific Program, and we just keep getting long-term survival [data for] these patients and they have been excellent for that combination. At least in my practice, I have looked at [this regimen] as the standard for my patients with nonsquamous NSCLC. Although [the approach] has been around for a while now, the constant updates are just further evidence of the benefit.

Some of the other combinations that have been interesting over the past year [were examined in] the phase 3 CheckMate-227 [NCT02477826] and CheckMate-9LA [NCT03215706] studies. [There is certainly a scientific rationale for the] combination of checkpoint inhibitors, [particularly] CTLA-4 and PD-1 [agents]. The issues we are going to run into with those [regimens] are going to be the discontinuation rates due to AEs.

Even though [discontinuation rates in some of these studies] were under 20%, [they] were still higher than [what has been seen] in those patients [who received] chemotherapy. In the long run, [we need to ask ourselves] whether the long-term benefit is worth some of those discontinuation events; that’s where the balance will lie with some of these up-front approaches.

What is your advice for choosing among these combination regimens?

In the long run, we will end up finding a rational way to choose between these regimens. It is going to take some experience with them, some additional long-term data, and maybe some cooperative group trials to really understand when we should be using them. For me, a lot of it comes down to the patients and talking through the options. There are certainly situations [for which I could see myself using] the combination of CTLA-4 and PD-1 agents, and there [are also] cases where chemotherapy plus immunotherapy is clearly the better option. The jury is still out in terms of how we can rationally choose between all these options, but it is exciting to have the options to choose from.

In SCLC, the pivotal phase 3 CASPIAN trial (NCT03043872) showed that the regimen of durvalumab plus platinum-based chemotherapy and etoposide had benefit across all subgroups examined. Could you expand on the subgroup analysis and what the data mean for clinical practice?

The CASPIAN study was interesting [in that] it allowed patients to receive carboplatin or cisplatin. In general, the majority of patients in my clinical practice with extensive-stage SCLC are going to get carboplatin. Cisplatin is something I reserve mostly for [those with] limited-stage disease, so while it was allowed on the study, it is very rare that a patient with extensive-stage disease is going to get cisplatin. It is an interesting subgroup analysis, but with the toxicity that we see with cisplatin, carboplatin is still what we would use [in this population].

How do you feel the CASPIAN regimen measures up against the regimen used in the pivotal phase 3 IMpower133 trial (NCT02763579)?

When [trying to make] cross-trial comparisons, I mostly look to see whether [these trials] look congruent. Do they look like they have similar data [in terms of] response rates [and other factors that] are more hypothesis generating? [These trials] look almost identical in terms of response rates, overall survival [OS], adverse effects, etc. At the end of the day, either atezolizumab [Tecentriq] or durvalumab are appropriate up-front options.

To try to advocate for one over the other would be a tough task. I do have some patients who prefer the every-4-week infusion of durvalumab. Also, some of us are comfortable using durvalumab more frequently because we use it often in [our patients with] stage III NSCLC. [For those reasons,] some folks prefer durvalumab, but it is hard to [choose] between them.

Several advances have also been made with regard to targeted therapies in NSCLC. Could you speak to the excitement surrounding the phase 1/2 LIBRETTO-001 trial (NCT03157128) examining selpercatinib (Retevmo)?

When that [agent] came out, it was widely anticipated [for that] patient population. We had several patients with RET infusions who were candidates [to receive the drug], and so it was a welcome addition to what we already had. [Selpercatinib] has generally been very effective and well tolerated in the patients I have given it to.

The other thing to note is, before the introduction of selpercatinib, we had platinum chemotherapies and immunotherapies that we used up front in patients. The first patients I put on [this agent] were those who had been pretreated. [Now,] selpercatinib, and the other RET inhibitor pralsetinib [Gavreto], are options I would consider for up-front treatment of these patients. I would reserve the systemic chemotherapies and the chemoimmunotherapy [approaches] as [options] for the second-line setting.

How do you approach selecting between selpercatinib and pralsetinib in practice? What are some of the factors you consider?

It is hard to [weigh] the 2 [options]. The studies [examining their use] were relatively small, and [these agents have] not really been compared head-to-head. They are both options. In our practice, we see them as equivalent options, and they are both appropriate in the up-front setting for patients. We know they both have good response rates and can treat central nervous system disease. As such, in the absence of any real direct comparisons between the 2 agents, it is hard to tease out the differences.

That being said, some toxicity issues could come into play. The safety profiles look relatively similar, with hypertension, [for example, reported with both drugs]. QTc changes, however, is seen [a bit more often] with selpercatinib. As such, there may be some subtleties with regard to the toxicities that could [be the deciding factor] for some patients. In general, the efficacy data support either of these options as up-front [options].

What is some of the work that is being done with ADCs?

Due to the success of the phase 2 DESTINY-Lung01 study [NCT03505710], we have been opening additional ADC studies. Some of these confirmatory studies will help define the role that these [agents] will play [in the paradigm]. What strikes me the most is the response rates and the disease control rates that we have seen [with these agents]—even though these patients were heavily pretreated.

Even if they are not ultimately found to be the next frontline option, these drugs are excellent options to have, and are going to produce responses in the majority of our patients. [ADCs] are going to be an exciting addition [to the arsenal], particularly for patients who progress on immunotherapies.

What is on the horizon for some of these emerging agents?

We're going to start seeing more confirmatory studies. With many of these drugs, there's the risk of interstitial lung disease. As such, I think combinations with immunotherapies are probably not going to be the rational approach. The next generation of ADCs [may] work through some of the lung toxicity that we have seen, [which] could allow for some more rational combination approaches. However, the next step is to establish the long-term survival benefits with these drugs and really see where they fit in the current treatment paradigm.

Are you, or your institution, involved in any ongoing efforts that you wanted to highlight?

Quite a few frontline clinical trials [are being done] to see whether there are any rational additions to, for example, the KEYNOTE-189 and the KEYNOTE-407 [NCT02775435] studies. There's a study that we have that is looking at the sequencing of the agents involved in the KEYNOTE-189 study, so looking at different combinations and sequences of pembrolizumab with carboplatin and pemetrexed. [We are trying] to further define how to sort through all of these studies and determine a way to sort through everything. Andreas Saltos, MD, of Moffitt Cancer Center, is also taking the lead on many ADC studies; quite a few studies are examining emerging targets for these agents.