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Drugmakers Push to Improve Treatment in Key NSCLC Subgroups, Find Options Where There Are Few

CHICAGO – At the American Society of Clinical Oncology's annual meeting on Friday, drugmakers highlighted ongoing efforts to improve upon existing treatment options for advanced non-small cell lung cancer patients with molecularly defined tumors and explored a combination targeted therapeutic strategy in the hopes of overcoming resistance in patients who have exhausted other options.

One study looked at the activity of Cullinan Oncology's next-generation EGFR inhibitor CLN-081 in NSCLC patients with rare EGFR exon 20 insertions. A second study explored the activity of Janssen's EGFR and MET-targeting bispecific Rybrevant (amivantamab) in advanced NSCLC patients with MET exon 14 skipping mutations. A third study assessed whether EGFR-mutated advanced NSCLC patients would respond to Rybrevant plus a third-generation EGFR inhibitor, lazertinib, after they've stopped responding to all standard-of-care treatments including AstraZeneca's Tagrisso (osimertinib) and platinum chemo.

The molecularly defined treatment strategies in these three studies account for between 20 percent and 60 percent of the NSCLC population and speaks to their importance, said Daniel Tan, a senior clinical scientist at the Genome Institute of Singapore, reflecting on the three presentations at the meeting. "There's an ongoing quest to develop better kinase inhibitors," he said, noting that researchers are gaining a deeper understanding of the complex factors that impact response and drive resistance.

Going after EGFR exon 20 insertions

Cullinan Oncology's next-generation EGFR inhibitor CLN-081 shrunk tumors in more than a third of evaluated advanced NSCLC patients with rare EGFR exon 20 insertions in an early-phase study.

At the meeting, Helena Yu, a medical oncologist at Memorial Sloan Kettering, presented data from a Phase I/IIa dose escalation and expansion trial, in which CLN-081 led to confirmed partial responses in 38 percent of 73 patients. The median duration of response was 10 months. Responses were seen in patients who had previously received another EGFR inhibitor. Median progression-free survival across dose levels was 10 months.

In reviewing the data at the meeting, Tan pointed out that the 38 percent response rate seen with CLN-081 is comparable to the activity seen with other drugs approved for NSCLC patients with EGFR exon 20 insertions. In 2021, the US Food and Drug Administration approved two drugs specifically for advanced NSCLC patients with EGFR exon 20 insertions: Rybrevant and Takeda's Exkivity (mobocertinib).

Although cross-trial comparisons are not ideal, Tan pointed out for reference that Rybrevant has shown around a 40 percent response rate and median progression-free survival of 8.3 months in this setting, while Exkivity has a 28 percent response rate and a median progression-free survival of 7.3 months. "Numerically CLN-081 is hitting objective response rates and progression-free survival comparable to some of the current approved agents," he said.

Tan flagged some differences, noting that CLN-081 is an oral drug, whereas Rybrevant has to be given intravenously. He also pointed to the significantly longer duration of response for Exkivity, around 17.5 months, to suggest that there may be further subsets within the EGFR exon 20 insertion group who have differential responses to these targeted agents.

EGFR exon 20 insertions occur in 2 percent to 3 percent of NSCLC patients, representing a larger subset than the groups with RET, ROS1, and NTRK fusions. Patients with EGFR exon 20 insertions have poorer prognosis and shorter survival times than those with more common EGFR exon 19 deletions and exon 21 L858R point mutations. Additionally, patients with EGFR exon 20 insertions don't respond to drugs, such as AstraZeneca's Iressa (gefitinib) or Tagrisso (osimertinib) or Genentech's Tarceva (erlotinib), which have been approved for patients with the more common activating EGFR mutations.

CLN-081 is a novel, irreversible oral EGFR inhibitor that blocks a broad spectrum of EGFR mutations, including exon 20 insertions, and it was designed to avoid inhibiting wild-type EGFR. The drugmaker is hoping that this will allow CLN-081 to avoid the toxicities seen with other EGFR-targeted therapies on the market. "For some people, these drugs can be limited by toxicities," such as rash and diarrhea, said Yu, because they also inhibit wild-type EGFR.

As of the May 9 data cutoff, 33 percent of 73 patients were still receiving treatment, while two-thirds had discontinued. Thirty patients discontinued due to disease progression and a dozen due to toxicities. Yu noted that none of the patients had grade 3 or higher rash or diarrhea at doses below 150 mg and dose reductions or discontinuations were uncommon when CLN-081 was given at the 150 mg dose.

In balancing the safety with efficacy, patients' outcomes to CLN-081 were best when they received a 100 mg twice daily dose, with an objective response rate of 41 percent, median duration of response of more than 21 months, and a median progression-free survival of a year. The safety profile of CLN-081 is "amenable to long-term treatment at doses less than 150 mg twice a day," Yu said. Tan agreed that 100 mg twice daily could be the recommended dose of this agent based on the efficacy and safety profile.

Patients with EGFR-mutated NSCLC commonly experience disease metastases to the central nervous system. There were three patients in this Phase I/II trial with CNS metastasis, of which one patient had both an intracranial and systemic response on CLN-081; the second patient is still on treatment after a year with stable disease intracranially and systemically; but a third patient progressed.

Yu's team will begin enrolling the Phase IIb portion of this trial in the second half of this year. Based on early signs that the drug may have CNS activity, researchers are also studying the activity of this drug on CNS metastasis in a separate study.

The liabilities of Rybrevant, Exkivity, and CLN-081 "remain poorly characterized, and it would be key to collect such data pertaining to site of progression and patient preferences," Tan added.

Rybrevant's other talents

During the same session at the meeting, Matthew Krebs, a clinical senior lecturer in experimental cancer medicine at the Christie National Health Service Foundation Trust, reported results confirming that Janssen's Rybrevant has activity in advanced NSCLC patients with MET exon14 skipping mutations.

The EGFR-MET bispecific inhibitor is already FDA-approved to treat advanced NSCLC patients with EGFR exon 20 insertions who have progressed on platinum chemo. However, Krebs noted that the drug has an even higher affinity to bind to and block MET than it does EGFR and highlighted that the drug has already shown activity in patients who have EGFR mutations and MET amplifications but are resistant to tyrosine kinase inhibitors.

MET exon 14 skipping mutations occur in approximately 3 percent of NSCLC patients. There are two approved drugs for this subset of patients, Novartis' Tabrecta (capmatinib) and EMD Serono's Tepmetko (tepotinib), but patients eventually develop resistance by acquiring a secondary MET mutation or by activating bypass signaling.

In the multi-cohort CHRYSALIS study, the same trial that led to Rybrevant's approval for NSCLC patients with EGFR exon 20 insertions, researchers set out to explore the activity of the drug in the subset of patients with MET exon 14 skipping mutations. There was a mix of treatment-naïve patients, those who had prior treatment but not with a MET inhibitor, and those who specifically had other MET inhibitors. Patients in the study had their biomarker status established via next-generation sequencing or circulating tumor DNA analysis.

At the meeting, Krebs reported initial data on 45 evaluable patients. The objective response rate was 33 percent. Treatment-naïve patients fared best, with four out of seven patients, 57 percent, responding to Rybrevant; seven out of 15 patients, 47 percent, responded among those who were previously treated but had no prior MET inhibitor; and four out of 24, or 17 percent, responded if they had a prior MET inhibitor.

"Moreover, the responses are durable with amivantamab in this setting," he added, noting that the median duration of response hasn't been reached in the overall population, and 11 out of 15 responding patients are still benefiting on Rybrevant.

The median progression-free survival was 6.7 months in the overall cohort. Again, treatment-naïve NSCLC patients with MET exon 14 skipping mutations did best with Rybrevant, with the median progression-free survival not reached, but median progression-free survival was 8.3 months in previously treated patients and 4.2 months in those who had received a prior MET inhibitor.

These preliminary results, Krebs said, shows that single-agent Rybrevant has activity similar to other MET inhibitors. "The observed activity in MET exon 14 skipping NSCLC confirm the independent targeting action of each arm of the bispecific amivantamab," he added, noting that researchers will continue to enroll patients in this cohort until they've reached their goal of 100 participants.

Meanwhile, "toxicities remain a concern," Tan said in reviewing this data, noting that across trials of Rybrevant, patients have experienced infusion reactions, pneumonitis, as well as peripheral edema and rash common to EGFR and MET inhibitors. The infusion reactions may be a "logistics barrier," he cautioned, "depending on the capacity of your outpatient treatment facility."

Krebs noted that in the entire CHRYSALIS study, 21 percent of patients needed treatment modifications, 12 percent needed dose reductions, and 5 percent discontinued due to Rybrevant's toxicities. Most patients experience rash-related adverse events.

Still, with the safety and efficacy data taken together, Krebs concluded that his team had "demonstrated [Rybrevant's] monotherapy activity in exon 20 insertion mutated NSCLC patients and now [in] MET-driven NSCLC patients" in CHRYSALIS.

After failing standard of care

Even though there are more treatment options for NSCLC patients who harbor the more common EGFR exon 19 deletions or exon 21 L858R point mutations, there is presently not much that can be done for those who have failed all standard of care. "This is a major unmet need at the moment," Tan reflected, adding that in his view, prior attempts to target dual pathways to overcome EGFR inhibitor resistance "has been fairly modest."

"More is not always better," he cautioned. In the TATTON trial, for example, the combination of Tagrisso and AstraZeneca's checkpoint inhibitor Imfinzi (durvalumab) caused a high incidence of interstitial lung disease.

However, earlier data on the combination of Rybrevant and lazertinib from a different cohort of the CHRYSALIS-2 trial, suggested this combination may have promise in a treatment-resistant population. At the European Society for Medical Oncology's annual meeting last year, investigators from this trial reported that 36 percent of 45 patients who had progressed on Tagrisso but were chemo-naïve had responded to this combo with a median duration of response of 9.6 months. At the time, 38 percent of this group were confirmed to have resistance mutations in EGFR and MET.

At the ASCO meeting, Catherine Shu, a thoracic oncologist at Columbia University's Irving Comprehensive Cancer Center, reported results from 160 such advanced, EGFR-mutated NSCLC patients in the CHRYSALIS-2 trial who were given Rybrevant and lazertinib after they had progressed on all standard therapies including Tagrisso and platinum-based chemotherapy.

While Rybrevant is an EGFR/MET bispecific inhibitor, lazertinib, a drug Janssen developed with South Korean firm Yuhan, has shown to work in tumors with activating EGFR mutations, T790m resistance mutations, as well as in central nervous system metastases. The drug is approved in South Korea but not in the US.

Among advanced, EGFR-mutated NSCLC patients in the CHRYSALIS-2 trial who had exhausted other standard options, the objective response rate by blinded independent central review in these patients was 33 percent with a 9.6-month median duration of response. Two patients had a complete response, 52 had a partial response, and 69 patients had stable disease, which amounted to a 57 percent clinical benefit rate.

Among 54 responders, 30 patients were still on trial as of the March 15 data cutoff and responding to treatment while 27 patients had been responding for more than six months. Meanwhile, 28 patients have progressed on the Rybrevant-lazertinib combo.

At a median follow-up of 10 months, median progression-free survival was 5.1 months and median overall survival was 14.8 months.

Considering all the combination targeted treatment and immunotherapy studies currently trying to overcome or circumvent resistance in EGFR-mutated treatment-resistant NSCLC patients, Tan said around a 30 percent or 40 percent response rate seems the average. The overall responses seen with the Rybrevant-lazertinib combination are in line with this estimate, but the results suggest the regimen may particularly benefit heavily pretreated patients who go on to receive Tagrisso and chemo.

In this subset of 56 patients, the blinded independent central review objective response rate was 39 percent. "While this may be due to the limited sample size, it is plausible that the resistance landscape in each of these treatment sequences might be different," Tan said, suggesting that perhaps the rate of EGFR resistance mutations and MET activation in patients, and their relative benefit to combination approaches, can partly be explained by the sequence of treatments patients are receiving.

In this cohort of CHRYSALIS-2, more than a quarter of the patients had more than four lines of prior treatment, including first- and second-generation tyrosine kinase inhibitors, Tagrisso, and platinum-based chemo. "This is a heavily pretreated and real-world population," Shu underscored, noting that there were consistent responses to Rybrevant-lazertinib even among heavily pretreated patients.

With combination treatments there are always toxicity concerns, and while there were no new safety issues raised in this cohort, dose interruptions, reductions, and discontinuations due to toxicities related to the combination were reported in 35 percent, 9 percent, and 7 percent of participants, respectively. Ten percent of patients had grade 3 or higher rash-related adverse events.

All the data taken together, Shu concluded that Rybrevant-lazertinib may be a chemotherapy-free option for patients who have blown through other standard treatments. The CHRYSALIS-2 trial will continue and researchers will report data on the underlying resistance mechanisms in patients in this study at a future meeting.

Shu also highlighted two ongoing randomized Phase III studies, which will further elucidate the activity of Rybrevant and lazertinib against the current standard of care. Since Tagrisso is the standard of care in first-line EGFR-mutated advanced NSCLC, that's the regimen Janssen wants to beat with the Rybrevant-lazertinib combo in the MARIPOSA trial. And in MARIPOSA2, Janssen is comparing Rybrevant, lazertinib, carboplatin, and pemetrexed versus carboplatin and pemetrexed in metastatic, EGFR-mutated NSCLC patients who have failed Tagrisso.