Targeted Agents, Immunotherapy Transforming Treatment Across NSCLC Spectrum

Mark G. Kris, MD

Not only has osimertinib (Tagrisso) become the frontline standard of care for patients with EGFR-mutant non—small cell lung cancer (NSCLC), but it is a potent and tolerable agent to examine in combination as a way to prevent acquired resistance, said Mark G. Kris, MD.

“It doesn’t do the patient or our field well to wait for acquired resistance,” said Kris, medical oncologist, William and Joy Ruane Chair in Thoracic Oncology, Memorial Sloan Kettering Cancer Center. “Recurrence is devastating, particularly when it occurs in the central nervous system or the bone. We want to prevent that.”

To that end, several combination strategies are under investigation, including osimertinib and dacomitinib (Vizimpro; NCT03810807) and osimertinib and ramucirumab (Cyramza; NCT03909334) in patients with EGFR-mutant NSCLC.

Moreover, in squamous cell NSCLC, immunotherapy has become a therapeutic staple, either alone or in combination with chemotherapy, as it has demonstrated an improvement in overall survival (OS) in both cases. For example, in a subgroup of patients with squamous NSCLC in the phase III KEYNOTE-024 trial, results showed an OS benefit with single-agent pembrolizumab (Keytruda) versus chemotherapy alone (HR, 0.78; 95% CI, 0.63-0.95).¹ Additionally, data from the phase III KEYNOTE-407 trial showed a 36% reduction in the risk of progression or death with the combination of pembrolizumab and chemotherapy versus chemotherapy alone, irrespective of PD-L1 expression (HR, 0.64; 95% CI, 0.49-0.85; P = .0008).²

“Now, every patient [with squamous cell NSCLC] is getting a checkpoint inhibitor, [regardless of PD-L1 expression],” added Kris. “The question is who to give chemotherapy to as well, and what chemotherapy backbone you should use.”

In an interview during the 2019  OncLive^®  State of the Science Summit™ on Non—Small Cell Lung Cancer, Kris discussed the impact of targeted therapy in patients with EGFR-mutant NSCLC and the encouraging activity that has been reported with checkpoint inhibitors in advanced squamous disease.

OncLive: Could you discuss how targeted therapy has evolved EGFR-mutant NSCLC treatment?

Kris: Almost 15 years ago, we discovered that there were a number of patients with lung cancer whose cancers were driven by mutations in the EGFR gene. That changed the face of lung cancer—adenocarcinoma in particular. We found that these patients’ tumors would shrink when they received drugs that targeted EGFR. That discovery opened up a new opportunity for those patients and led to the development of other targeted therapies. 

Could you discuss the data that have been reported with osimertinib?

We previously saw that osimertinib improved progression-free survival (PFS) in previously untreated patients with EGFR mutations. We expected that those numbers would be consistent with long-term follow-up, and that’s what the recent presentation at the 2019 ESMO Congress showed. There was a clear improvement [in overall survival] of approximately 7 months with osimertinib versus standard EGFR TKIs.

What distinguishes osimertinib from other available EGFR TKIs?

Osimertinib is more potent than other TKIs. The agent has activity against tumors that have developed a T790M mutation; it’s also more effective in preventing central nervous system metastases. [In addition to] its potency, it's also more tolerable [than standard EGFR TKIs]. Tolerability is becoming increasingly important as we discover that giving a TKI alone is not sufficient. We have to add other modalities to the TKI. Osimertinib, because of its enhanced tolerability, [allows us] to open that door.

How would you describe the utility of dacomitinib?

Dacomitinib is a second-generation TKI. In addition to blocking EGFR, the agent has more activity against wild-type EGFR; it also has activity against other members of the HER family, such as HER2. In that way, [dacomitinib is] different from osimertinib. When you look at [dacomitinib’s] use in patients with EGFR mutations, it clearly has more adverse events. Its pattern of resistance is similar to the first-generation TKIs or afatinib (Gilotrif) in that these patients develop T790M. It's ultimate risk-benefit ratio is not as good as osimertinib. Osimertinib is still the drug of choice [in the frontline setting]. Dacomitinib could have a role for patients who develop second-site EGFR mutations while on osimertinib, such as C797S.

Could you elaborate on what is known about mechanisms of resistance to EGFR TKIs?

The resistance patterns that we see with osimertinib are not the same as what have been observed with other TKIs. If you get a first-generation TKI, two-thirds of patients develop a second-site EGFR mutation in T790M. With osimertinib, only one-quarter of patients develop a second-site mutation in EGFR.

The other thing we have very commonly seen [with osimertinib] is that there is a transformation in the phenotype where patients go from adenocarcinoma to small cell or adenocarcinoma to squamous cell. That was seen with the first-generation TKIs, but not to the extent that we’re seeing it with osimertinib; it occurs in 15% to 20% of cases. Many physicians are looking for mutations with blood-based tests after progression on osimertinib. [Histologic transformations] are going to be missed completely [with blood-based assays].

The third thing we are seeing is that patients are getting mutations in novel pathways, particularly fusion genes and in KRAS, which we really didn't see with the first- and second-generation TKIs.

Could the combination of erlotinib (Tarceva) and ramucirumab play a role in this space?

The regimen probably won’t play a role in patients who have progressed on osimertinib. Patients could develop rare, on-target EGFR mutations that would be sensitive to erlotinib. In that case, the combination could be reasonable. However, that is in a minority of cases. I don't believe people are going to recommend erlotinib and ramucirumab as frontline therapy because the effects of erlotinib are not strong enough to warrant [its] use over osimertinib. What I can see is ultimately combining osimertinib with ramucirumab, and trials have shown that this can be done safely.

What else is on the horizon in this paradigm?

In the past, we would give these drugs, patients would recur, and then we would have to deal with resistance. Now, we’re trying to prevent resistance. We want to give therapies that will increase the time the disease is controlled. The [latest investigational] approaches that have come to the forefront [involve] chemotherapy. Multiple trials have reported marked improvements in PFS with combinations of chemotherapy and TKIs in the frontline setting. We are also going to see combinations osimertinib with antiangiogenic agents, such as bevacizumab (Avastin) and ramucirumab, to prevent or delay acquired resistance.

Other strategies are also under evaluation. One mechanism of acquired resistance to osimertinib is MET amplification, so you could consider combining a drug that targets MET with osimertinib. The other strategy that my colleague Helena A. Yu, MD, of Memorial Sloan Kettering Cancer Center, is pursuing is the combination of dacomitinib and osimertinib. We know that one of the resistance mechanisms to osimertinib is a second-site EGFR mutation like C797S, which is sensitive to dacomitinib or afatinib. Conversely, [patients who receive] dacomitinib or afatinib develop T790M. If a patient receives [those agents] with osimertinib, that won't happen. As such, that's another logical combination.

The other aspect that’s changing is the use of local therapy. Instead of using this approach at the time of progression, we might consider using it at the time of maximum response [in patients with] oligometastases. We know that when patients with EGFR-mutant lung cancer recur, they recur in the same sites of disease they had at presentation. It would make a lot of sense to intensify therapy for those disease sites that were present upfront. Many people are exploring that further. 

At the State of the Science Summit™, you also spoke about the management of advanced squamous NSCLC. Could you discuss the therapies that have emerged in this space?

Squamous cell lung cancers represent about 20% of lung cancers. We’ve seen the way targeted therapy can help patients with adenocarcinoma. We haven't found a target in squamous cell cancers. However, the one thing that has emerged is checkpoint inhibitors. Data have shown the benefit of giving checkpoint inhibitors [alone] and in combination with chemotherapy based on PD-L1 status.

What have been the pivotal trials in squamous NSCLC?

Checkpoint inhibitors can lead to durable and meaningful responses in patients with squamous cell cancers. These agents are most effective in patients with high PD-L1 expression. There is still some controversy about their efficacy in patients with high tumor mutational burden (TMB). The majority of the data we have suggest that TMB is another biomarker of response to PD-1/PD-L1 inhibitors. We have also seen that chemotherapy in combination with PD1/PD-L1 inhibitors can enhance effectiveness; you see that most clearly for patients with low PD-L1 expression. Even in patients with high degrees of PD-L1 expression, you see higher rates of response when you combine chemotherapy with checkpoint inhibitors.

The general rule of thumb is the closer to 0% PD-L1 expression the patient has, the more likely they're going to receive chemotherapy. Conversely, the closer the patient is to 100% PD-L1 expression, the less likely [they’re going to chemotherapy and will receive single-agent immunotherapy]. Also, the more symptomatic the patient is, regardless of PD-L1 expression, the more likely they are to get chemotherapy. We're encouraged that we now have something more to offer our patients with squamous cell NSCLC.

Could you provide insight into biomarkers that predict response to immunotherapy?

In lung cancer, we have been led to believe we can find these potent markers. If a patient has an ALK rearrangement, we can essentially guarantee that they will benefit from a drug like alectinib (Alecensa) or brigatinib (Alunbrig).

Unfortunately, we don't have that in the checkpoint inhibitor space. We have characteristics that are associated with response, but it's nowhere near the predictive value that we have with [actionable alterations]. The two available markers that have been the most studied are PD-L1 and TMB. Microsatellite instability—high [is another marker], although it’s not common in lung cancer. Researchers are looking for other markers, but we don't have anything beyond [PD-L1 and TMB right now].

What can we anticipate in squamous cell NSCLC?

We’re going to continue to learn more about squamous cell cancer. We’re going to continue to study the biology of the disease, but as of yet, we don't have a squamous-specific treatment we can point to. That said, chemotherapy works and checkpoint inhibitors work. We just haven't found a targeted therapy yet that works. 

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non—small-cell lung cancer.  N Eng J Med. 2016;375(19):1823-1833.doi: 10.1056/NEJMoa1606774.   
2. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small cell lung cancer.  N Eng J Med. 2018;379(21):2040-2051. doi: 10.1056/NEJMoa1810865.