Two oncologists give their expert take on KRAS- and EGFR-mutant non–small cell lung cancer.
Therapies targeted against oncogenic drivers have dramatically changed treatment options and outcomes for patients with non–small cell lung cancer, with new treatment options emerging.
“The number of [known] oncogenic drivers is increasing every year,” Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at the Moores Cancer Center at UC San Diego Health in La Jolla, California, said in an interview with Targeted Therapies in Oncology™ (FIGURE on page 311 ). “It’s important not to [underassess 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 at the 39th Annual Chemotherapy Foundation Symposium (CFS®), Bazhenova highlighted the active areas of investigation for patients with NSCLC where several new targeted agents may improve personalized medicine for these patients.
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.2 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 (MRTX 849), which received a breakthrough therapy designation from the FDA in June.3,4
Sotorasib, a KRAS G12C inhibitor, was evaluated in the phase 1/2 CodeBreaK 100 trial (NCT03600883).5
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.5
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).5
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.5
The confirmatory phase 3 CodeBreak 200 trial (NCT04303780) evaluating sotorasib vs docetaxel in patients with pretreated KRAS G12C–mutant NSCLC is ongoing.
Adagrasib, 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.6
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.6
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.7
“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.”
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; tepotinib was the most recent, receiving approval on February 3.8,9
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).10
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).10
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.10
Capmatinib, a selective MET inhibitor, was evaluated in adult patients with EGFR wildtype, 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.11
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).11
The antitumor activity and safety of crizotinib (Xalkori), a multikinase inhibitor with potent activity against, 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%).12
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).12
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.12
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).13
Among 61 efficacy-evaluable patients, the ORR was 49.2% (95% CI, 36.1%-62.3%) and the disease control rate 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).13
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.13
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).14
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.15
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).15
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.15
Based on prior results of the study, the FDA granted trastuzumab deruxtecan with a breakthrough designation for the treatment of patients HER2-mutant metastatic NSCLC who have progressed on or after treatment with a platinum-based chemotherapy regimen.16
“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 underway to optimize sequencing and combination strategies.
During the CFS meeting, Zofia Piotrowska, MD, MHS, continued the discussion of targeted therapies for NSCLC with a focus on EGFR-directed therapies.
“[EGFR exon 20 insertion mutations are the] new kid on the block and I know there’s a lot of interest in these mutations,” Piotrowska, an assistant professor of medicine at Harvard Medical School in Boston, commented during her CFS presentation.
Piotrowska noted that frontline therapy for patients with EGFR exon 20 insertion–mutant NSCLC remains platinum doublet chemotherapy with or without immunotherapy. In the second line, however, there are now targeted therapies available. Both amivantamab (Rybrevant) and mobocertinib (Exkivity) were approved after platinum-based chemotherapy.9
Amivantamab is an EGFR and MET–targeted bispecific antibody that showed an ORR of 40% (95% CI, 29%-51%) in patients with previously treated EGFR exon 20 insertion–positive NSCLC (n = 81) in the phase 1 CHRYSALIS trial (NCT02609776). Three patients achieved a CR, and the median DOR was 11.1 months (95% CI, 6.9–not reached). The median PFS was 8.3 months (95% CI, 6.5-10.9).17
Piotrowska noted that many of the toxicities with amivantamab are related to EGFR and MET. The most common TRAEs of any grade included rash (86%), infusion-related reaction (66%), paronychia (42%), stomatitis (18%), pruritus (17%), and hypoalbuminemia (15%). Infusion-related reaction typically presented on day 1 of cycle 1 of treatment and was improved with split dosing and treatment with steroids.17
Mobocertinib is an oral EGFR inhibitor that showed an ORR of 28% (95% CI, 20%-37%) in platinum-pretreated patients with EGFR exon 20 insertion–positive NSCLC (n = 114) in a phase 1/2 trial (NCT02716116). The median PFS was 7.3 months (95% CI, 5.5-9.2) and the median DOR was 17.5 months (95% CI, 7.4-20.3).18
Any grade AEs seen with mobocertinib treatment included diarrhea (91%), rash (45%), paronychia (38%), anorexia (35%), nausea (34%), dry skin (31%), vomiting (30%), creatinine increase (25%), and stomatitis (24%). Diarrhea was grade 3 in 21% of patients. Dose reduction was required in 25% of patients, and 17% discontinued treatment.18
Several agents are being explored for EGFR exon 20 insertion mutations, as well as study of a higher dose of osimertinib (Tagrisso). For now, further data are required to determine a sequence of events for these 2 agents.
1. Socinski MA, Pennel NA, Davies KD. MET exon 14 skipping mutations in non– small-cell lung cancer: an overview of biology, clinical outcomes, and testing considerations. JCO Precis Oncol. 2021;5:PO.20.00516. doi:10.1200/PO.20.00516
2. Addeo A, Banna GL, Friedlaender A. KRAS G12C mutations in NSCLC: from target to resistance. Cancers (Basel). 2021;13(11):2541. doi:10.3390/cancers13112541
3. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed October 29, 2021. bit. ly/2ZMCwY8
4. Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from U.S. Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics. June 24, 2021. Accessed October 29, 2021. prn.to/2SXZWqe
5. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/ JCO.2021.39.15_suppl.9003
6. Riley G, Ou SI, Rybkin I, et al. KRYSTAL-1: activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring KRASG12C mutation. J Thorac Oncol. 2021;16(suppl 4):S751-S752. doi:10.1016/S1556-0864(21)01941-9
7. Mok TSK, Lawler WE, Shum MK, et al. KRYSTAL-12: a randomized phase 3 study of adagrasib (MRTX849) versus docetaxel in patients (pts) with previously treated non-small-cell lung cancer (NSCLC) with KRASG12C mutation. J Clin Oncol. 2021;39(suppl 15):TPS9129. doi:10.1200/JCO.2021.39.15_suppl.TPS9129
8. Hong L, Zhang J, Heymach JV, Le X. Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer. Ther Adv Med Oncol. 2021;13:1758835921992976. doi:10.1177/1758835921992976
9. Oncology (cancer) / hematologic malignancies approval notifi cations. FDA. Updated October 29, 2021. Accessed October 29, 2021. bit.ly/2Y3yXMf
10. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931-943. doi:10.1056/NEJMoa2004407
11. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET exon 14–mutated or MET-amplifi ed non–small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787
12. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51. doi:10.1038/s41591-019-0716-8
13. Lu S, Fang J, Li X, et al. Phase II study of savolitinib in patients (pts) with pulmonary sarcomatoid carcinoma (PSC) and other types of non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping mutations (METex14+). J Clin Oncol. 2020;38(suppl 15):9519. doi:10.1200/JCO.2020.38.15_suppl.9519
14. Zhao J, Xia Y. Targeting HER2 alterations in non–small-cell lung cancer: a comprehensive review. JCO Precis Oncol. 2020;(4):411-425. doi:10.1200/PO.19.00333
15. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non–small-cell lung cancer. N Engl J Med. Published online September 18, 2021. doi:10.1056/ NEJMoa2112431
16. Enhertu granted Breakthrough Therapy Designation in the US for HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca and Daiichi Sankyo Company, Limited. May 18, 2020. Accessed November 19, 2021. https://bit.ly/3kPeRNR
17. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662
18. Zhou C, Ramalingam SS, Kim TM, et al. Treatment outcomes and safety of mobocertinib in platinum-pretreated patients with EGFR exon 20 insertion–positive metastatic non–small cell lung cancer: a phase 1/2 open-label nonrandomized clinical trial. Published online October 14, 2021. JAMA Oncol. doi:10.1001/jamaoncol.2021.4761