Enhanced Grasp of Oncogenic Drivers Leads to Expanded Treatment Options in NSCLC

Lyudmila A. Bazhenova, MD

An increased understanding of the biology of non–small cell lung cancer (NSCLC) has led to a significant increase in therapeutic options for patients, according to Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at the Moores Cancer Center at the UC San Diego Health in California.

“The number of [known] oncogenic drivers is increasing every year,” Bazhenova said in an interview with OncLive^®. “It’s important not to under [assess patients for drivers]—or to skip genotyping altogether—because the medications have fairly significant efficacy and it’s important not to miss an opportunity to provide these treatments to patients.”

Ahead of her presentation, Bazhenova highlighted the active areas of investigation for patients with NSCLC where advances have resulted in several new targeted agents that may improve personalized medicine for these patients.

KRAS

KRAS mutations are observed in approximately 30% of patients with NSCLC, and KRAS G12C alterations are seen in 13% of patients with lung adenocarcinoma. Because of the high affinity of KRAS for GTP, the discovery of targeted therapies has previously proved to be challenging.¹

Investigators have demonstrated promise with 2 novel small-molecule inhibitors, both targeting KRAS G12C: sotorasib (Lumakras), which received accelerated approval from the FDA in May, and adagrasib, which received a breakthrough therapy designation from the FDA in June.^2,3

Sotorasib, a KRAS G12C inhibitor, was evaluated in the phase 1/2 CodeBreaK 100 trial (NCT03600883).⁴

Investigators enrolled 126 patients with NSCLC harboring a KRAS G12C mutation to the single-arm trial, and patients received oral sotorasib 960 mg once daily until disease progression.⁴

As of the March 15, 2021, data cutoff, the objective response rate (ORR) was 37.1% (95% CI, 28.6%-46.2%) among the 124 efficacy-evaluable patients, including 4 complete responses (CRs). At a median follow-up of 15.3 months, the median duration of response (DOR) was 11 months (95% CI, 6.9-not estimable [NE]) and the median progression-free survival (PFS) was 6.8 months (95% CI, 5.1-8.2). The median overall survival (OS) was 12.5 months (95% CI, 10.0-NE).⁴

In terms of safety, no fatal treatment-related adverse events (TRAEs) occurred. The most common TRAEs of any grade included diarrhea (31.7%), nausea (19.0%), and increased alanine aminotransferase (15.1%). TRAEs leading to dose modifications occurred in 22.2% of patients, and TRAEs that led to treatment discontinuation occurred in 7.1% of patients.⁴

The confirmatory phase 3 CodeBreak 200 trial (NCT04303780) evaluating sotorasib vs docetaxel in patients with pretreated KRAS G12C–mutant NSCLC is ongoing. Adagrasib (MRTX 849), a potent, covalent inhibitor of KRAS G12C, demonstrated clinical activity for this patient population in results from the phase 1/2 KRYSTAL-1 trial (NCT03785249). A total of 79 patients with pretreated NSCLC harboring a KRAS G12C mutation received adagrasib 600 mg twice daily.

Among 51 efficacy-evaluable patients, the ORR was 45% as of the August 30, 2020, data cutoff. Stable disease was reported in 26 patients. The median duration of treatment was 8.2 months.⁵

TRAEs of any grade were reported in 85% of patients. The most commonly reported TRAEs of any grade were nausea (54%), diarrhea (51%), and vomiting (35%). Grade 3/4 TRAEs occurred in 30% of patients, and 2% of patients experienced a grade 5 TRAE.⁵

The phase 3 KRYSTAL-12 trial (NCT04685135) will evaluate the efficacy of adagrasib 600 mg vs docetaxel in patients with advanced NSCLC harboring a KRAS G12C mutation who have progressed during or after treatment with a platinum-based regimen and an immune checkpoint inhibitor. The study will enroll approximately 450 patients and is currently enrolling in the United States, Europe, and Asia.⁶

“The efficacy for patients with KRAS-mutant NSCLC is not as good as the efficacy for other oncogenic drivers,” Bazhenova noted. “[However], we are very excited about [these agents] because they’re the first drugs that we can use for these patients. But, certainly, we need to work on increasing the response rate mostly by utilizing combination treatments.”

BRAF

BRAF is altered in 4.5% of patients with NSCLC, 96% of these alterations being mutations. The most common BRAF mutations include BRAF activating (38%), BRAF V600E (37%), and BRAF inactivating (18%). Rearrangements account for 4% of BRAF alterations. Several agents have demonstrated significant efficacy for those with BRAF V600E, which occur at a rate comparable to the frequency of ALK, ROS1, or RET.⁷

The antitumor activity and safety of dabrafenib (Tafinlar), a potent and selective inhibitor of BRAF kinase activity, plus trametinib (Mekinist) were examined in a phase 2 trial (NCT01336634) that enrolled 57 adult patients with pretreated metastatic BRAF V600E–mutant NSCLC. Patients received oral dabrafenib 150 mg twice daily plus oral trametinib 2 mg once daily. The median age of the study population was 64 years (range, 41-88) and most patients had previously undergone 1 prior systemic regimen for metastatic disease (67%).⁸

At a median follow-up of 11.6 months (interquartile range [IQR], 8.8-15.2), the ORR was 63.2% (95% CI, 49.3%-75.6%) and 3.5% of patients achieved a CR. The median PFS was 9.7 months (95% CI, 6.9-19.6) and the median DOR was 9.0 months (95% CI, 5.8-17.6). The disease control rate (DCR) was 78.9% (95% CI, 66.1%-88.6%) and the median duration of treatment for both dabrafenib and trametinib was 10.6 months (IQR, 4.2-12.2).⁸

In terms of safety, serious AEs were reported in 56% of patients. AEs leading to treatment discontinuation occurred in 12% of patients, and AEs leading to dose reduction were seen at a rate of 35%. Common AEs of any grade included pyrexia (46%), nausea (40%), and vomiting (35%).⁸

Investigators evaluated the efficacy of a vemurafenib (Zelboraf), a BRAF inhibitor, in patients with metastatic or unresectable locally advanced malignancies harboring BRAF genomic alterations in the phase 2 AcSé trial (NCT02304809). The study population included 118 patients in the NSCLC cohort; 101 of these patients presented with a BRAF V600E mutation. Vemurafenib was administered at 960 mg twice daily.

Most patients in both the BRAF V600E cohort and the BRAF cohort had previously received chemotherapy (79.3% vs 82.4%, respectively).⁹

After a median follow-up of 23.9 months (95% CI 19.8-25.0), among 100 efficacy-evaluable patients with BRAF V600E mutations, the ORR was 44.8%. The median DOR was 6.4 months (95% CI, 5.1-7.3), the median PFS was 5.2 months (95% CI, 3.8-6.8), and the median OS was 10 months (95% CI, 6.8-15.7).⁹

The median PFS in the in the efficacy-evaluable BRAF cohort (n = 15) was 1.8 months (95% CI, 1.4-2.1) and the median OS was 5.2 months (95% CI, 2.8-18.7). No objective response was observed in the cohort and enrollment was subsequently stopped.⁹

In the BRAF V600E cohort, the most common TRAEs of any grade were asthenia (56%), decreased appetite (46%), acneiform dermatitis (37%), and nausea and diarrhea (35% each). Treatment was discontinued because of toxicity for 24 patients in the BRAF V600E cohort and 3 patients in the BRAF cohort. Grade 5 toxicities were reported in 3 patients, due individually to dehydration, pneumonia, and neutropenic sepsis.⁹

MET

MET amplifications are reported in 3% to 7% of patients with NSCLC. Rare but actionable mutations within MET include MET exon 14 skipping mutations, which occur at a rate of approximately 3% in NSCLC. Two agents—capmatinib (Tabrecta) and tepotinib (Tepmetko)—have received accelerated FDA approval in the past 2 years.^10,11

Capmatinib, a selective MET inhibitor, was evaluated in adult patients with EGFR wild-type, advanced NSCLC in the phase 2 Geometry Mono-1 study (NCT02414139). Patients received oral capmatinib 400 mg twice daily. The study included 97 patients with NSCLC with a MET exon 14 skipping mutation and 210 patients with NSCLC with a MET amplification.¹²

Previously treated patients with NSCLC harboring a MET exon 14 skipping mutation (n = 69) had an ORR of 41% (95% CI, 29%-53%) and a median DOR of 9.7 months (95% CI, 5.6-13.0). Treatment-naïve patients with NSCLC harboring a MET exon 14 skipping mutation (n = 28) achieved an ORR of 68% (95% CI, 48%-84%) and a median DOR of 12.6 months (95% CI, 5.6-NE).¹²

The phase 2 VISION trial (NCT02864992) evaluated the efficacy of the highly selective MET inhibitor tepotinib in adult patients with advanced NSCLC with MET exon 14 skipping alterations or MET amplification. Tepotinib was administered at a dose of 500 mg, twice daily. The median age of patients in the efficacy population (n = 99) was 74 (range, 41-94).¹³

The ORR in the efficacy population was 46% (95% CI, 36%-57%) and the median DOR was 11.1 months (95% CI, 7.2-NE). The median PFS was 8.5 months (95% CI, 6.7-11.0).¹³

In terms of safety, among the 152 patients in the safety population, 89% experienced an AE of any grade. The most common AEs of any grade were peripheral edema (63%), nausea (26%), and diarrhea (22%). Serious AEs related to tepotinib were reported in 15% of patients and led to permanent discontinuation of treatment in 11% of patients.¹³

The antitumor activity and safety of crizotinib (Xalkori), a multikinase inhibitor with potent activity against MET, was evaluated in 69 patients with advanced NSCLC harboring MET exon 14 alterations in an expansion cohort of the phase 1 PROFILE 1001 study (NCT00585195). Crizotinib was administered orally at a dose of 250 mg twice daily in continuous 28-day cycles. The median age of the study population was 72 (range, 34-91) and most patients had 1 prior treatment for advanced disease (42%).¹⁴

The ORR among the efficacy-evaluable patients (n = 65) was 32% (95% CI, 21%-45%); 5% achieved a CR. The median DOR was 9.1 months (95% CI, 6.4-12.7) and the median time to response was 7.6 weeks (range, 3.7-16.3).¹⁴

The most common TRAEs of any grade were edema (51%), vision disorder (45%), and nausea (41%). TRAEs associated with a dose reduction or permanent treatment discontinuation occurred in 38% and 7% of patients, respectively.¹⁴

Savolitinib, a highly selective MET tyrosine kinase inhibitor, was examined in patients with pulmonary sarcomatoid carcinoma and other types of NSCLC harboring MET exon 14 skipping mutations in a phase 2 study (NCT02897479). Oral savolitinib 600 mg for patients weighing at least 50 kg or 400 mg for patients weighing less than 50 kg was given once daily until disease progression or intolerable toxicity. The median age of treated patients (N = 70) was 68.7 (range, 51.7-85.0).¹⁵

Among 61 efficacy-evaluable patients, the ORR was 49.2% (95% CI, 36.1%-62.3%) and the DCR was 93.4% (95% CI, 84.1%-98.2%). The median DOR was 9.6 months (95% CI, 5.5-not reached). The median treatment duration was 6.8 months (range, 0.2-37.3).¹⁵

Most patients experienced an AE of any grade (98.6%) and 41.4% experienced an AE of grade 3 or higher. TRAEs that led to dose discontinuation were reported in 14.3% of patients.¹⁵

HER2

Investigators are also actively evaluating the role of targeting HER2 aberrations in patients with NSCLC. HER2 overexpression occurs in approximately 59% of patients with NSCLC. HER2 mutations are seen in 1% to 5% of patients with NSCLC and the most common mutations occurs in exon 20 (80%-90% of all HER2 mutations).¹⁶

Fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed antibody-drug conjugate (ADC) that has demonstrated efficacy in breast and gastric cancers, was evaluated in patients with HER2-mutant NSCLC in the phase 2 DESTINY- Lung01 trial (NCT03505710). The trial enrolled a total of 91 patients and the median age was 60 (range, 29-88). Trastuzumab deruxtecan was administered intravenously at a dose of 6.4 mg/kg.¹⁷

The ORR was 55% (95% CI, 44%-65%) and 1 patient achieved a CR. The median DOR was 9.3 months (95% CI, 5.7-14.7) and the median time to response was 1.5 months (range, 1.2-9.3). The median PFS was 8.2 months (95% CI, 6.0-11.9) and the median OS (95% CI, 13.8-22.1).¹⁷

In terms of safety, 97% of patients experienced an AE; the most common AEs of any grade were nausea (73%), fatigue (53%), and alopecia (46%). AEs leading to dose reduction occurred in 34% of patients and dose interruption occurred in 32% of patients. Adjudicated drug-related interstitial lung disease of any grade was reported in 26% of patients.¹⁷

“We still do not know a lot about resistance to ADCs,” Bazhenova said. “These are new medications for us in the thoracic oncology space. For HER2 exon 20 insertions, hopefully an ADC is approved at some point. The unmet need here is to understand what type of resistance patients develop, and to get a better understanding of how to prognosticate patients for interstitial lung disease.”

Bazhenova noted that understanding mechanisms of resistance extends beyond ADCs. “At this point, we don’t yet know what to do [in terms of] resistance to medications,” she said, adding that investigative efforts are under way to optimize sequencing and combination strategies.

References

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