Targeted Therapy Drives Improves Outcomes Throughout Lung Cancer Subtypes

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The availability of targeted agents for patients with advanced non–small cell lung cancer who harbor mutations in EGFR, RET, MET, and KRAS has not only led to improved outcomes, but provided greater flexibility for treatment-naïve and pretreated populations, with the possibility of enhanced intracranial activity.

Pradnya Patil, MD, FACP

Pradnya Patil, MD, FACP

The availability of targeted agents for patients with advanced non–small cell lung cancer (NSCLC) who harbor mutations in EGFR, RET, MET, and KRAS has not only led to improved outcomes, but provided greater flexibility for treatment-naïve and pretreated populations, with the possibility of enhanced intracranial activity, explained Pradnya Patil, MD, FACP, who added that such treatments, along with immunotherapy, are now making their way into the adjuvant setting.

“Targeted therapy in lung cancer has truly been one of those revolutionizing advancements that has changed how long our patients are living and their quality of life [QOL], as well,” Patil, a hematology and oncology fellow at the Taussig Cancer Institute of Cleveland Clinic, said in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on lung cancer.

“Over the past couple of decades, as we went from treating [patients with] NSCLC as a uniform disease, with 1 cytotoxic therapy, to understanding that this is a heterogeneous disease and using histology to assign treatments, followed by using genomic data to assign targeted therapies, we’ve seen consistent improvements in outcomes for our patients.”

In the interview, Patil, who chaired the event, provided key takeaways from the virtual meeting, which covered targeted therapy approaches for EGFR-, RET-, MET-, and KRAS-mutant advanced NSCLC, as well as frontline and second-line treatment of patients with small cell lung cancer (SCLC).

OncLive®: What has become the focus of research with targeted therapy in NSCLC?

Patil: Lung cancer is truly the poster child of targeted therapies in medical oncology. As time goes by, we find that we are now able to target more and more difficult targets and that we’re now finding newer and newer targeted therapy options in the refractory setting post progression, which is an exciting development in lung cancer.

In your presentation during the webinar, you highlighted developments in RET-, MET-, and KRAS­-mutant NSCLC. What have been the most significant updates in terms of drug development in these subsets?

We have known about KRAS-mutated lung cancer for a couple of decades, but the RAS pathway has truly been a very difficult pathway to target with targeted therapies, and decades of research has gone into it. We hadn’t had success until very recently, where we now have 2 very promising drugs, one of which is FDA approved in the refractory setting: sotorasib [Lumakras]. These are not our typical targeted therapies in that these are not TKIs, but rather inhibitors of KRAS G12C and therefore are allele specific. Perhaps that’s why when we’re looking at response rates for these agents, they are perhaps not quite as high as we see with other TKIs. But these are a novel class of drugs that have truly changed how we treat [patients with] a very difficult-to-manage subpopulation of lung cancer.

Although not seen very often, patients with RET fusions typically don’t do as well with our traditional treatments. Therefore, the discovery of newer agents that have very promising efficacy, very high response rates and are fairly tolerable has been a huge development for our patients.

Over the past year, we have seen 2 approvals for the management of advanced RET fusion–positive NSCLC. Both datasets from the pivotal trials are quite comparable. The first is from the LIBRETTO-001 trial [NCT03157128], which looked at selpercatinib [Retevmo]. Patients that were enrolled in the previously treated arm were fairly heavily treated. Most of the patients had received platinum-based chemotherapy with a PD-1/PD-L1 inhibitor, and 48% of patients had received a multikinase inhibitor prior to being treated with selpercatinib. Response rates in this previously treated population were as high as 64%. In patients who were treatment naïve, response rates by independent review were as high as 85%. The waterfall plot for both cohorts of patients was also quite impressive. It’s what we often see when we have a good, targeted therapy for a truly oncogene-driven lung cancer. These are very exciting data, and [the agent is], overall, fairly well tolerated.

In the ARROW trial [NCT03037385], pralsetinib [Gavreto] was looked at in 2 very similar cohorts of patients [as in the LIBRETTO-001 trial]: a previously treated with platinum-based chemotherapy group and a treatment-naïve group. A fair number of the [previously treated] patients had, in addition, received immunotherapy and other multikinase inhibitors. The investigators noted overall response rates [ORRs] to the tune of 61% in those who were previously treated with platinum-based chemotherapy, and they noted an ORR of 70% in patients who were treatment naïve. The agent was also fairly well tolerated, and once again, we saw very impressive waterfall plots.

With both agents, there appears to be some intracranial efficacy as well, which is always a plus for our patients since we do see a fair number of patients with brain involvement at the time of diagnosis.

MET alterations in lung cancer can be seen in a variety of settings. In a minority of cancers, about 3% to 4% of cancers, MET alterations are the primary driver of the malignancy and these are often MET exon 14 alterations leading to exon 14 skipping or MET amplifications. We have noted MET alterations, in particular MET amplifications, that drive acquired resistance to other targeted therapies, such as osimertinib [Tagrisso]. What we saw in the Geometry Mono-1 trial [NCT02414139], which evaluated capmatinib [Tabrecta] was that, in the treatment-naïve arm, there was an ORR of 68%, with a median duration of response [DOR] of 12.6 months.

In patients who received capmatinib in the second- or third-line setting, the ORR was 41%, with a median DOR of 9.7 months. Although not FDA approved for this indication, responses were noted in patients who had MET amplification with higher gene copy numbers. More data will tell whether there are subpopulations of patients with MET amplification that might benefit from that therapy as well.

With the VISION trial [NCT02864992] that evaluated tepotinib [Tepmetko] in patients with MET exon alterations and advanced lung cancer, the investigators reported that, in the treatment-naïve group, the ORR with tepotinib was 43%, with a median DOR of 10.8 months. In the previously treated group, the ORR was 43%, with a median DOR of 11.1 months. One of the common adverse effects that has emerged with both medications is peripheral edema, which seems to be a class effect, rather than drug specific, and can be managed often with dose reductions.

Pivoting to the presentation that Khaled Hassan, MD, of Cleveland Clinic, gave on targeting EGFR, in which settings should the third-generation EGFR TKI, osimertinib (Tagrisso) be used?

In the past few years in the world of EGFR-mutated lung cancers, we’ve seen a couple of very exciting advancements. The first is the FLAURA trial [NCT02296125], where we saw that using osimertinib up front led to vast improvements in outcomes in patients with EGFR sensitizing mutations and advanced NSCLC. [Those data] have moved osimertinib to the frontline setting. Most of us now are using [osimertinib] in practice [in that setting]. I have known oncologists who have been in practice for a while that have moved their patients from older-generation TKIs to osimertinib due to intracranial activity without any evidence of disease progression. It is a fairly well-tolerated drug, and patients are able to maintain their QOL while on treatment, which is very important for our patients with advanced lung cancers.

We’re starting to learn more about mechanisms of resistance to osimertinib, which are quite varied, whether its the acquisition of a secondary EGFR mutation or other alterations in other pathways, including MET amplification, which can be seen in a fair number of patients. Some of our needs currently are to try to understand these mechanisms of resistance and to develop strategies to target them using this information.

Some of the other exciting data that have been recently reported in patients with EGFR-mutated lung cancer are those from the ADAURA trial [NCT02511106], where we now have evidence that there is improved disease-free survival [DFS] with the addition of osimertinib after the completion of adjuvant chemotherapy in patients with completely resected, EGFR-mutated, nonsquamous NSCLC.

Although the overall survival [OS] data are still yet to be seen, it’s very hard to argue against the use of osimertinib in this setting, given how impressive the hazard ratio for DFS was in this trial. More needs to be seen as to whether this is going to translate into OS improvement and how we balance out toxicities and emergence of resistance in a setting where patients might have asymptomatic micrometastatic disease. What does that leave in terms of options if patients do develop advanced disease at some point in time? However, these are practice-changing data and some of the biggest advancements that we have seen in resectable lung cancer in some time.

Briefly touching on immunotherapy in the adjuvant setting, what are your thoughts on the results from the phase 3 IMpower010 trial (NCT02486718), which were presented during the 2021 ASCO Annual Meeting?

Most of us in thoracic oncology are quite excited by the IMpower010 data. Beyond chemotherapy, in patients who have non–EGFR-mutated, completely resected lung cancers, we haven’t really seen therapies that might improve outcomes. What was very exciting to see was that in patients with PD-L1 expression and had complete resection of their lung cancers, when they went on to receive about 1 year of atezolizumab [Tecentriq] following chemotherapy, there appears to be a significant DFS benefit.

Although it remains to be seen if this is going to be an approved therapy for the management of our patients with resected lung cancer, these are truly exciting data. We would love to see if this translates into an OS advantage, but truly in a population where despite complete resection and despite adjuvant chemotherapy, we are still seeing a fair bit of relapses. These are practice-changing data.

Pivoting to SCLC, James Stevenson, MD, of Cleveland Clinic, discussed frontline treatment. What have been the clinical implications of introducing immunotherapy into up-front treatment of patients with extensive-stage disease?

For decades in SCLC, while usually a platinum-sensitive disease, we have struggled with maintaining responses in these patients and outcomes have traditionally been very poor despite traditional chemotherapy. Therefore, it has always been an area of need in the field of thoracic oncology. It was exciting to see data from 2 clinical trials, which have truly changed the way we practice and the way we manage our patients with extensive stage SCLC [ES-SCLC].

Both trials––IMpower133 [NCT02763579] and CASPIAN [NCT03043872]––looked at the addition of a PD-L1 inhibitor to platinum-based chemotherapy for the management of ES-SCLC. Although we do not do cross-trial comparisons, the data are comparable. The median OS was a little over 1 year, which, although it doesn’t seem like a whole lot, is a vast improvement over what our traditional outcomes used to be, and a vast improvement over the control arm in both studies as well. The data truly have been practice changing. I have had patients who have had durable responses on immunotherapy, which is exciting to see. Hopefully, we’ll have more combinations or more novel agents that will continue to improve outcomes in this particularly difficult-to-treat population.

Marc Shapiro, MD, of Cleveland Clinic, highlighted the use of lurbinectedin (Zepzelca) in his presentation on second-line treatment in SCLC. Has that agent replaced the use of chemotherapy for patients who experience disease progression on frontline chemoimmunotherapy?

The caveat with lurbinectedin is that it has not been approved for use at our cancer center for a variety of reasons. There was a lot of discussion about it, and the decision was made not to proceed with updating it at our center. It’s a little challenging because we don’t use it as often.

The way we approach patients with refractory SCLC is to first determine if they have platinum-sensitive disease. Often, we use 6 months as a benchmark. If patients have relapsed within 6 months of therapy, we move on to another type of therapy. If they have relapsed after 6 months of receiving their initial platinum-based chemotherapy, then we often retreat with the initial platinum-based chemotherapy, which is often carboplatin and etoposide. In patients who have relapsed within a relatively short period of time after receiving their platinum-based chemotherapy, topotecan has traditionally been one of the alternative chemotherapy options for us.

We did see data for lurbinectedin, which is now approved for use in the refractory setting as well. This is an alkylating agent that is given every 3 weeks; it’s an intravenous drug, and in the study that looked at lurbinectedin, 105 patients were enrolled with SCLC who had progressed after platinum-based chemotherapy. The investigators noted that the ORR with lurbinectedin was about 33%. The median DOR was 5.1 months, and 25% of the patients had a DOR exceeding 6 months, which is impressive in this population.

Chemoresistance relapse was defined by a chemotherapy-free interval of less than 90 days; in this population, the ORR was 22%, and the median OS was about 5 months. In patients who had chemosensitive relapse, so patients who had recurred more than 90 days after their platinum-based chemotherapy, the response rate was 45%. The median OS was a little over 11 months. Both [chemotherapy and lurbinectedin] are approved options, and both are comparable until we get more data. The toxicity profile of both drugs can often help decide which [agent] may be more favorable to use for one population vs the other.

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