Targeting STK11 Mutations in Cancer

David R. Gandara, MD

STK11 mutation recently have become a biomarker and potential target of interest, especially for patients with lung cancer. Recent trials explore drugs like bemcentinib, everolimus, talazoparib, and others for potential approaches to targeting these mutations.

STK11: What’s Known

The serine/threonine kinase 11 (STK11) gene encodes the liver kinase B1 (LKB1) protein, an intracellular serine-threonine kinase with important roles in cellular metabolism, cell polarity, regulation of apoptosis, and the DNA damage response.¹ Alterations in STK11 have been found in 3.04% of all cancers, with lung adenocarcinoma most strongly represented (13%) followed by breast invasive ductal carcinoma, non–small cell lung cancer (NSCLC), colon adenocarcinoma, and adenocarcinoma of unknown primary.^1,2 Cancers such as cervical, gastrointestinal, and lung may also have STK11 alterations.¹

STK11 was first recognized as a tumor suppressor gene in the late 1990s, but the mechanisms of oncogenicity due to loss-of-function mutations in STK11 remain under investigation.²

Alterations in STK11 can lead to loss of mTOR and hypoxia-inducible factor-1α (HIF-1α) regulation mediated by adenosine monophosphate–activated protein kinase (AMPK).² Loss of LKB1 due to inactivating mutations in STK11 results in greater HIF-1α protein expression; this, in turn, shifts glucose metabolism to the glycolytic pathway to maintain energy supply.^3,4 Therefore, tumor cell proliferation can continue despite glucose depletion. Increases in genomic instability and cancer invasion and metastasis have also been associated with LKB1 inactivation, although the mechanism is not fully understood.^5,6

David R. Gandara, MD, director of the Thoracic Oncology Program and senior adviser to the director of the UC Davis Comprehensive Cancer Center in Sacramento, California, said in an interview with Targeted Therapies in Oncology™, “STK11 is of interest because it can be comutated in a variety of situations affecting drug outcomes.”

Recent Findings Concerning STK11

STK11 mutations are common comutations in KRAS-mutant lung cancers (FIGURE) and are more common than in KRAS wild-type tumors. Analysis of these comutations' effect on survival have led to mixed results though.^7,8

A retrospective study compared comutation subgroups and the impact of these mutations on overall survival (OS) and progression-free survival (PFS) in patients with NSCLC treated with ICI. A total of 100 patients with known KRAS status were included: 50 KRAS wild type and 50 KRAS mutated. Comutations in STK11 were found in 39% of the total patient population. STK11 or KEAP1 mutations were associated with a negative impact on survival when compared with wild type (median OS, 7.4 months vs 20.4 months, respectively; P = .001). In tumors with STK11 mutations but KEAP1 wild type, a better prognosis was observed for KRAS mutated vs KRAS wild type (median OS, 21.1 months vs 15.8 months, respectively; P = .15); however, there was no difference between KRAS-mutated and KRAS wild-type cases in STK11-mutated plus or minus KEAP1-mutated tumors (7.4 months for KRAS mutated vs 7.0 months for KRAS wild type).⁸

Additionally, the neutrophil to lymphocyte ratio (NLR) was significantly higher with STK11 comutations (P = .0012) but was not found to be impacted by KEAP1 mutations (P = .72) or KRAS mutations (P =.34). These findings suggest that STK11 and KEAP1 mutations are significant adverse predictors of ICI therapy benefits. STK11 has a greater impact on NLR than KEAP1, suggesting differences in resistance mechanisms for both mutations. KRAS mutations appear to be associated with improved survival in patients with NSCLC harboring STK11-mutated and KEAP1 wildtype tumors when treated with ICIs.⁸

Records of patients with metastatic NSCLC who initiated first-line immunotherapy (IO) or chemotherapy under routine care were analyzed for STK11 in a separate retrospective study. STK11 mutations were present in 13.6% of 2407 patients and worse OS outcomes were observed in patients with STK11 mutations in first-line IO (HR, 1.4; 95% CI, 0.9-2.3; P = .1), second-line IO (HR, 1.6; 95% CI, 1.3-2.0; P = .0002), or chemotherapy (HR, 1.4; 95% CI, 1.2-1.6; P < .0001). These real-world data further support the negative prognostic impact of STK11 mutations in patients with metastatic NSCLC when treated with ICI or chemotherapy.⁹

Another retrospective study from 2018 evaluated whether STK11 alterations predict a lack of response to PD-1/PD-L1 blockade independently of PD-L1 expression in patients with nonsquamous NSCLC. Out of 66 patients with nonsquamous NSCLC treated with PD-1/ PD-L1 inhibitors, STK11 alterations were associated with significantly lower objective response rates compared with tumors with intact STK11 status (0% vs 34.5%, respectively; P =.026). Significantly shorter PFS was also observed in STK11-mutant tumors (median PFS, 1.7 months vs 19.3 months; HR, 4.8; 95% CI, 2.0-11.1; log-rank P=.00012) along with shorter OS (median OS, 11.1 months vs 26.5 months; HR, 14.3; 95% CI, 3.4-66.7; log-rank P<.0001). These data suggest evaluation of STK11 genomic status may improve the predictive outcome for PD-1/PD-L1 inhibitor use.¹⁰

However, a larger retrospective study evaluating patients with lung adenocarcinoma differed regarding the predictive value of STK11 status. Somatic mutations in STK11 and KEAP1 are frequent in nonsquamous NSCLC and are associated with poor response to IO. The observational study of patients diagnosed with nonsquamous NSCLC from stage IIIB through IVB compared the predictive vs prognostic effect of STK11 or KEAP1 mutations. Mutations in STK11 or KEAP1 were associated with poor outcomes across multiple therapy classes but were not specifically associated with poor outcomes in ICI cohorts. Anti–PD-1/anti–PD-L1 treatment and STK11 mutations did not have an apparent interaction on real-world PFS (HR, 1.05; 95% CI, 0.76-1.44; P=.785) or OS (HR, 1.13; 95% CI, 0.76-1.67; P=.540). Similarly, no interaction between KEAP1 mutations and treatment was seen to have an effect on real-world PFS. These results suggest that STK11/KEAP1 mutations are prognostic, not predictive, biomarkers for anti–PD-1/anti–PD-L1 therapy.¹¹

Gandara commented on the discrepancy. “The data are mixed. With immunotherapy it’s been felt STK11 is a bad prognostic marker for efficacy of checkpoint inhibitors. The question is whether it’s prognostic independent of therapy or predictive, and we just don’t know yet.”

Potential Targeted Treatments for STK11-Mutant Cancers

Target 3 Cambridge, Massachusetts–based Tango Therapeutics is looking to develop an undisclosed target to reverse the immune evasion effects of STK11 loss-of-function mutations. TANGO has identified a novel drug target (Target 3) that reverses the cancer cell immunotherapy resistance when STK11 is deleted. The anticipated clinical development will be the first to combine genetically based patient selection and ICI therapy. Advancing a clinical candidate for this target and investigational new drug–enabling studies are expected in the second half of 2022 with an application filing in 2023.¹²

Bemcentinib

FDA fast track designation for BerGenBio’s bemcentinib (BGB324) for use in STK11-mutated advanced/metastatic NSCLC in combination with an anti–PD-(L)1 agent was announced on November 9, 2021.¹³ The same day, BerGenBio announced sensitivity to PD-1 blockade was evaluated in the absence and presence of bemcentinib in preclinical NSCLC mouse models with STK11 mutations.¹³ Inhibition of AXL, a tyrosine kinase receptor that regulates the immune microenvironment, with bemcentinib resulted in expansion of tumor-associated T cells (TCF1+PD-1+CD8 T cells) and restored therapeutic response to anti–PD-1 ICI. This indicates AXL is a critical and targetable driver of immune suppression in STK11-mutant NSCLC, and inhibition of AXL rescues therapeutic benefit and presents a new clinical strategy in combination with anti–PD-1 therapy.^14,15

A separate phase 2 trial (BGBC008, NCT03184571) evaluating the combination of pembrolizumab (Keytruda) with bemcentinib in patients with previously treated advanced NSCLC is under way and already 3 of 3 patients with identified STK11 mutations have demonstrated objective clinical response to the combination.¹³

Gandara commented, “Bemcentinib is very interesting moving forward because it appears more active and less toxic than other drugs. The question would be, do we find decreased response rates or increased toxicities with subsequent use?”

Everolimus A phase 2 study (NCT02352844) evaluated treatment with everolimus (Afinitor) in 12 patients with histologically confirmed advanced solid tumors with mutations in various genes, including STK11, who had failed at least 1 line of standard-of-care systemic therapy. Eight patients were evaluable for response after 2 cycles of 10 mg everolimus orally for 28 days. One patient experienced complete response and another experienced stable disease (SD); overall the agent was well tolerated. The patient with SD had a diagnosis of lung adenocarcinoma with STK11 mutation, suggesting everolimus could have activity in patients with lung adenocarcinoma with STK11 mutations. Further studies are required to determine any true association.¹⁶

Talazoparib

Among the Lung Cancer Master Protocol for precision medicine clinical trials in patients with advanced NSCLC is an ongoing phase 2 trial (NCT04173507) evaluating talazoparib (Talzenna) in combination with avelumab (Bavencio) in patients with stage IV or recurrent nonsquamous NSCLC with an STK11 gene mutation. Enrollment has completed and results are pending with an estimated primary completion date of January 31, 2022. The study enrolled approximately 47 patients who received oral talazoparib daily and an intravenous infusion of avelumab over 60 minutes on days 1 and 15. The primary outcome measures are best objective response rate (up to 3 years) and disease control rate (at 12 weeks after registration).

CB-839

Another phase 2 trial (BeGIN, NCT03872427) is recruiting and aims to evaluate the glutaminase inhibitor telaglenastat hydrochloride (CB-839 HCl) in patients with solid tumors or malignant peripheral nerve sheath tumors with NF1, KEAP1/NRF2, or LKB1 alterations. Telaglenastat blocks glutamine activity required for the growth of cells. Theoretically, when this activity is blocked the growth of cancer cells will stop. The primary objective of the study is best overall response rate achieved by 6 months of CB-839 HCl treatment. Estimated enrollment is 108 patients with an estimated primary completion date of August 31, 2022.

Sotorasib

In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib (Lumakras) demonstrated an objective response rate of 37.1% (95% CI, 28.6%-46.2%) and a median PFS of 6.8 months (95% CI, 5.1-8.2) in patients with pretreated KRAS G12C–mutated NSCLC. In patients with wild-type STK11, the ORR was 39.1% (95% CI, 27.6%-51.6%) and 40.0% (95% CI, 23.9%-57.9%) for STK11-mutated disease.17 Median PFS for STK11-mutated disease with concurrent wild-type KEAP1 (n=22) was 11.0 months with a median OS of 15.3 months. This indicates STK11 status does not have a significant impact on the efficacy of sotorasib.

A phase 2 study (NCT04933695) has been proposed to evaluate the tumor objective response rate of sotorasib in patients with stage IV NSCLC whose tumors have a PD-L1 tumor proportion score less than1% and/or that harbor a STK11 comutation. The estimated enrollment is 170 patients with an estimated primary completion date of June 23, 2023. Gandara commented, “In terms of sotorasib, at first it was thought that STK11 mutations decrease activity of the drug, but recently we’ve seen KEAP1 is the bad actor.”

Adagrasib

Treatment with adagrasib (MRTX849) in the phase 1/2 KRYSTAL-1 study (NCT03785249) revealed durable responses and broad disease control in patients with KRAS G12C–mutant advanced NSCLC. Results presented at the European Lung Cancer Virtual Congress 2021 showed that 600 mg twice daily yielded a partial response rate of 45% (23/51) and 51% had SD (26/51). The objective response rate in patients with STK11 comutations was 64% (9/14). Patients with STK11 comutations possessed minimal expression of immune transcripts (CD4 and CD8) at baseline but had increases after treatment with adagrasib indicating a potential immune response to therapy.18 The FDA granted a breakthrough therapy designation to adagrasib for the treatment of patients with previously treated KRAS G12C–mutant NSCLC based on results from KRYSTAL-1.¹⁹

Evaluation of adagrasib is ongoing in the phase 3 KRYSTAL-10 trial (NCT04793958) evaluating adagrasib with cetuximab (Erbitux) vs chemotherapy in patients with advanced colorectal cancer with a KRAS G12C mutation. Another phase 3 trial is under way evaluating adagrasib vs docetaxel (Taxotere) in patients with advanced NSCLC with KRAS G12C mutation (KRYSTAL-12, NCT04685135). A phase 2 trial is also under way evaluating adagrasib as monotherapy and in combination with pembrolizumab for patients with NSCLC harboring a KRAS G12C mutation (KRYSTAL-7, NCT04613596). Data regarding subpopulations with STK11 mutations likely will follow.

Looking Ahead STK11 will continue to be evaluated for potential ways to target and for use as a biomarker for therapy. “ is clearly a gene of interest,” Gandara said, “primarily in lung adenocarcinoma, which is 75% of all our cases. Right now, I don’t think anyone would exclude a patient from [IO] based on [an] STK11 mutation. It’s something undergoing further evaluation.

_REFERENCES

_{1. STK11. My Cancer Genome. Accessed December 6, 2021. https:// bit.ly/3zn7K5s}

_{2. Laderian B, Mundi P, Fojo T, Bates SE. Emerging therapeutic implications of STK11 mutation: case series. Oncologist. 2020;25(9):733- 737. doi:10.1634/theoncologist.2019-0846}

_{3. Faubert B, Vincent EE, Griss T, et al. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α. Proc Natl Acad Sci U S A. 2014;111(7):2554-2559. doi:10.1073/ pnas.1312570111}

_{4. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015;5(5):378-389. doi:10.1016/j.apsb.2015.05.007}

_{5. Zhao RX, Xu ZX. Targeting the LKB1 tumor suppressor. Curr Drug Targets. 2014;15(1):32-52. doi:10.2174/1389450114666140106095811}

_{6. Esteve-Puig R, Gil R, Gonzalez-Sanchez E, et al. A mouse model uncovers LKB1 as an UVB-induced DNA damage sensor mediating CDKN1A (p21WAF1/CIP1) degradation. PLoS Genet. 2014;10(10):e1004721. doi:10.1371/journal.pgen.1004721}

_{7. Arbour KC, Jordan E, Kim HR, et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res. 2018;24(2):334-340. doi:10.1158/1078-0432. CCR-17-1841}

_{8. Proulx-Rocray F, Routy B, Nassabein RM, et al. The prognostic impact of KRAS, TP53, STK11 and KEAP1 mutations and the influence of the NLR in NSCLC patients treated with immunotherapy. J Clin Oncol. 2021;39(suppl 15):e21010. doi:10.1200/JCO.2021.39.15_suppl.e21010}

_{9. Shire NJ, Klein AB, Golozar A, et al. STK11 (LKB1) mutations in metastatic NSCLC: prognostic value in the real world. PLoS One. 2020;15(9):e0238358. doi:10.1371/journal.pone.0238358}

_{10. Skoulidis F, Carter BW, Zhang J, Wistuba II, Papadimitrakopoulou V, Heymach J. Association of STK11/LKB1 mutations with primary resistance to PD-1/PD-L1 axis blockade in PD-L1 positive non-squamous NSCLC. J Clin Oncol. 2018;36(suppl 15):9028. doi:10.1200/ JCO.2018.36.15_suppl.9028}

_{11. Papillon-Cavanagh S, Doshi P, Dobrin R, Szustakowski J, Walsh AM. STK11 and KEAP1 mutations as prognostic biomarkers in an observational real-world lung adenocarcinoma cohort. ESMO Open. 2020;5(2):e000706. Published correction appears in ESMO Open. 2020;5(3):e000706corr1.}

_{12. Tango Therapeutics prospectus. Tango Therapeutics. October 7, 2021. Accessed December 6, 2021. https://ir.tangotx.com/ node/6831/html#toc}

_{13. BerGenBio receives FDA Fast Track designation for bemcentinib in STK11-mutated advanced/metastatic non-small cell lung cancer (NSCLC). News release. BerGenBio. November 9, 2021. Accessed December 6, 2021. https://bit.ly/32kAu2m}

_{14. BerGenBio presents pre-clinical and clinical data on bemcentinib in STK11-positive NSCLC at SITC annual meeting 2021. News release. BerGenBio. November 9, 2021. Accessed December 6, 2021. https://bit.ly/3edl3vt}

_{15. Li H, Liu Z, Liu L, et al. 602 AXL targeting with bemcentinib restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through innate immune cell mediated expansion of TCF1+ CD8 T cells. J Immunother Cancer. 2021;9(suppl 2):A632. doi:10.1136/jitc-2021- SITC2021.602}

_{16. Devarakonda S, Pellini B, Verghese L, et al. A phase II study of everolimus in patients with advanced solid malignancies with TSC1, TSC2, NF1, NF2 or STK11 mutations. J Thorac Dis. 2021;13(7):4054- 4062. doi:10.21037/jtd-21-195}

_{17. 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}

_{18. Riely GJ, Ou SHI, Rybkin I, et al. 99O_PR 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}

_{19. 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 KRASG12C mutation. News release. Mirati Therapeutics. June 24, 2021. https://bit.ly/3yKaGJa}