Pancreatic Cancer Awareness Month: Novel Targeted Therapy in PDAC

With significant advances in precision medicine in oncology, only an exceedingly small percentage of pancreatic ductal adenocarcinoma (PDAC) cases benefit from targeted therapy based on tumor biomarker selection. Over the last 2 years, emerging agents with novel molecular targets continue to show promising clinical activity.

As our knowledge of the tumor genomic landscape broadens, the ability to test for actionable genetic variants has become commonplace in our daily practice. Presently, the National Comprehensive Cancer Network (NCCN) recommends inherited (germline) mutation testing to all patients with PDAC, and somatic molecular profiling in all patients with locally advanced or metastatic disease.¹

With precision medicine changing the therapeutic paradigm for most solid tumors, its benefit applies to a dismally small percentage of advanced PDAC. Since the last American Society of Clinical Oncology (ASCO) update on metastatic PDAC in 2020, emerging trials with novel targeted agents continue to demonstrate encouraging results.²

Strategies for KRAS Targeting

The KRAS gene is quasi-ubiquitously mutated in over 90% of PDAC tumors. Within this gene, an activating G12D substitution occurs most frequently in 40% of cases, followed by G12V (30%), G12R (up to 20%), and G12C (1%-3%).^3,4 Once considered “non-druggable”, KRAS gene inhibition is making its way into clinical trials and to the clinic. With a focus on small deactivating molecules and adoptive cell therapy the number of PDAC tumors eligible for targetable therapy may exponentially grow soon.

Adagrasib (MRTX849) and sotorasib (Lumakras) are 2 oral small molecules that inhibit specifically and irreversibly KRAS G12C. The efficacy of adagrasib is being evaluated by the KRYSTAL-1 trial (NCT03785249), a multicohort phase 1/2 study enrolling patients with KRAS G12C-mutant advanced solid tumors.

Within the gastrointestinal tumor subgroup, a preliminary analysis included 12 individuals with PDAC who had received a median of 3 prior lines of therapy. Clinical activity was evaluable in 10 patients, 5 of which achieved a partial response (PR), and the remaining 5 patients attained stable disease (SD). Median progression-free survival (PFS) was 6.6 months (95% CI, 1.0-9.7) in the pancreas-specific cohort.⁵

In another combined phase 1/2 trial (NCT03600883) with 38 patients with PDAC, sotorasib monotherapy achieved a PR in 8 (21%) patients and a SD in 24 (63.1%) patients. Median PFS and overall survival (OS) were 3.98 (95% CI, 2.8-5.6) and 6.9 months (95% CI, 4.9-9.1), respectively.⁶

Gastrointestinal toxicities and fatigue were reported with both agents, but adagrasib also caused QTc prolongation, whereas the sotorasib study observed cases of hepatotoxicity, pleural effusion, and pulmonary embolism.5,6 Of notable significance, the identification of MRTX1133, a specific KRAS G12D inhibitor, may significantly expand the applicability of KRAS inhibition in PDAC tumors.⁷ The safety and efficacy of this treatment remain to be examined in ongoing clinical trials.

Adoptive cell therapy has also been employed to target specific KRAS mutations in patients with PDAC. In a recent case report, autologously administered KRAS G12D–reactive tumor-infiltrating lymphocytes was given to a 71-year-old patient with recurrent PDAC. Conditioning regimen to support in vivo T cell expansion included tocilizumab and cyclophosphamide prior to cell infusion, and high-dose interleukin-2 after infusion.

The patient then had a PR, with a 62% reduction of metastases at 1 month and a 72% reduction at 6 months. In the same study, the authors also reported the outcome of a second patient treated with the same product, albeit with a different manufacturing process and preconditioning regimen. This patient experienced grade 3 cytokine release syndrome and a grade 2 immune effector cell-associated neurotoxicity syndrome. However, despite persistently high levels of T cell in the peripheral blood, the patient experienced disease progression and passed at 6 months after cell infusion.⁸

Targeting DNA Damage Repair Pathway

Approximately 6% to 9% of PDAC tumors harbor a germline pathogenic and likely pathogenic variant (P/LPV) of BRCA1/2 genes.^9,10 Loss of BRCA1/2 function leads to deficient repair of DNA double-strand break in tumor cells. As a result, these cells experience sensitized response to DNA-damaging treatments with platinum and PARP inhibitors.^11,12 

In 2019, the FDA approved olaparib (Lynparza), an oral PARP inhibitor, as maintenance therapy in patients with metastatic germline BRCA1/2-mutated PDAC who had a platinum-sensitive disease, which was defined as no disease progression after 16 weeks of first-line platinum-based therapy.¹³

This approval was based on clinical benefits seen in the preliminary results from the POLO study (NCT02184195). In this double-blind randomized trial participants had platinum-sensitive stage IV PDAC and olaparib (Lynparza) showed a superior PFS compared with placebo with a median PFS of 7.4 months (95% CI, 4.1-11.0) and 3.8 months (95% CI, 3.5-4.9), respectively (HR, 0.53; 95% CI, 0.35-0.81; P = .0035).¹²

Final OS data had a 70.1% data maturity and was published in July 2022. There was no significant difference in OS between olaparib and placebo with a median OS of 19.0 and 19.2 months, respectively (HR, 0.83; 95% CI, 0.56-1.22; P = .3487).¹⁴ Nevertheless, olaparib exhibited an adequate safety profile and was associated with significantly longer median time to first subsequent cancer therapy or death (HR, 0.44; 95% CI, 0.30-0.66; P < .0001). Moreover, the estimated 3-year survival in the olaparib arm was 33.9% compared with the placebo group at 17.8%.

Beyond olaparib, the efficacy of continuous rucaparib (Rubraca) was examined in a recent single-arm phase 2 study (NCT03140670).¹⁵ As key differences to the POLO trial, inclusion criteria in this study incorporated participants with locally advanced PDAC tumors, and those with germline PALB2 P/PLVs, as well as germline and somatic BRCA1/2 variants. In 42 patients with evaluable disease, median PFS and OS were 13.1 and 23.5 months, respectively. Overall, an objective response was seen in 15 (35.7%) patients. Three responders had a germline PALB2 variant, 11 had a germline BRCA2 variant, and one had a somatic BRCA2 alteration. None of the 7 patients with a germline BRCA1 variant responded. Median duration of response was 17.3 months.

A recent phase 1b/2 study also explored maintenance immunotherapy plus PARP inhibition in platinum-sensitive PDAC tumors. Participants with advanced disease were randomized to receive niraparib with either nivolumab (Opdivo; n = 46) or ipilimumab (Yervoy; n = 45). The primary end points included PFS at 6 months, which was 20.6% (95% CI, 8.3%-32.9%) in the nivolumab doublet arm, and 59.6% (95% CI, 44.3%-74.%9) in the ipilimumab doublet group.¹⁶ Grade 3 or higher treatment-related adverse events (AEs) occurred in 22% and 50% of the participants in nivolumab and ipilimumab arms, respectively.

The most common severe AEs were hypertension, anemia, and thrombocytopenia. Of note, as allowed by the study protocol, over 80% of participants in both groups did not harbor an DNA damage repair pathway variant. Moreover, the authors did not report tumor status of microsatellite instability-high (MSI-H) and mismatch repair deficiency (dMMR), which are positive response predictors for immunotherapy.

New Tumor-Agnostic Opportunities

In 2017, the FDA approved pembrolizumab as the first tissue-agnostic therapy for all tumors with MSI-H and/or dMMR.¹⁷ Two additional agents, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), received approvals for advanced solid tumors with NTRK fusion regardless of the primary tumor histology.^18,19 Presently, these agents are indicated for second-line treatment of patients with metastatic PDAC tumors. Nevertheless, the clinical benefit of these treatments is limited by the small portion of patients with qualifying molecular alterations (<1% of patients have an MSI-H/dMMR tumor, and <0.5% with a NTRK fusion).⁹

Two additional regimens, selpercatinib (Retevmo) and dabrafenib (Tafinlar)/trametinib (Mekinist), have received tumor-agnostic regulatory approval, albeit their use in PDAC has yet to be endorsed by the NCCN or ASCO guidelines.

Selpercatinib is an orally available highly selective RET kinase inhibitor approved for the treatment of locally advanced or metastatic solid tumors with a RET gene fusion.²⁰ In PDAC, RET gene amplifications and mutations occur in up to 3.7% of tumors, whereas RET fusion are detected in less than 1% of cases.^21,22 In LIBRETTO-001 (NCT03157128), a phase 1/2, open-label, basket trial, the authors included a tumor-agnostic sub-cohort with 45 patients with RET fusion–positive solid tumors. Eleven out of 12 patients with PDAC had evaluable response, and of these 6 achieved a PR with an overall response rate 54.5% (95% CI, 23.4-83.3).

At data cutoff, median duration of response was not reached; 1 patient had remained on oral selpercatinib for over 40 months. The most common grade 3 or higher AEs attributed to selpercatinib were hypertension (22%), elevated alanine aminotransferase (16%), and elevated aspartate aminotransferase (13%). Dose reduction and then discontinuation were warranted in 14 (31%) and 1 (2%) of patients, respectively.²³

BRAF mutation occurs in approximately 3% of all PDAC tumors, being BRAF V600E the most common alteration. Combined BRAF-MEKinhibition with respective dabrafenib and trametinib received FDA approval for all BRAF V600E-mutant solid tumors.²⁴ This histology-agnostic indication in adults was supported by clinical benefit observed in 2 clinical trials, the phase 2 ROAR (Rare Oncology Agnostic Research) basket study and the NCI-MATCH (NCT02465060) study.^25,26 Notably, from all 131 patients enrolled in both trials, only the latter included 3 patients with BRAF V600E-mutant PDAC tumors. Of these, 2 had evaluable disease including 1 case of SD and 1 had disease progression. Their response duration was not reported.

Additional data on BRAF-MEK–targetedtherapy in BRAF V600E-mutatedPDAC remains anecdotal. In the KYT registry, 1 patient with BRAF V600E-mutatedPDAC received dabrafenib/trametinib as second-line treatment and showed sustained response for eleven months. One other patient with BRAF fusion remained less than one month on fourth-line dabrafenib/trametinib due to intolerance.²⁷ Prospectively, the single-arm phase 2 BrafPanc trial (NCT04390243) aims to examine the efficacy of encorafenib/binimetinib in locally advanced and metastatic BRAF V600E-mutant PDAC tumors, and the study is in active recruitment and is estimated to complete in December 2024.

Additional Targets Under Study

Sacituzumab govitecan (Trodelvy), an antibody-drug conjugate targeting to trop-2, is currently approved for patients with advanced urothelial carcinoma and breast cancer.^28,29 In the phase 1/2 IMMU-132-01 (NCT01631552) basket trial with patients with recurrent metastatic epithelial tumors; 16 patients had metastatic PDAC at enrollment. At a median follow-up of 9 months, 7 of these patients attained an SD, but the duration of response was not reached.³⁰ In the overall safety population (n = 495), grade 3/4 neutropenia occurred in 42% of the patients, while 5% experienced febrile neutropenia, but 1 case of treatment-related death was reported due to aspiration pneumonia.

In a Chinese randomized trial with patients with locally advanced or metastatic PDAC and a wild-type KRAS, nimotuzumab, anti-EGFR humanized monoclonal antibody, combined gemcitabine was compared with gemcitabine or placebo. Although the ORR between the 2 groups were not statistically significant, the nimotuzumab regimen showed superior median OS compared with control at 10.9 vs 8.5 months, respectively (HR, 0.50; 95% CI, 0.06-0.94, P = .025). Subgroup analyses revealed additional OS benefit in patients who did not have a surgical history at 15.8 vs 6.0 months (HR, 0.40; 95% CI, 0.19-0.84) and those who did not require treatment for biliary obstruction at 11.9 vs 8.5 months (HR, 0.54; 95% CI, 0.33-0.88, P = .037).³¹ In the nimotuzumab arm, grade 3 AE included neutropenia (11.1%) and thrombocytopenia (6.7%), but no grade 4 AEs were reported.

Future Perspective

Presently, cytotoxic therapy remains the foundation for the treatment of patients with PDAC tumors. However, emerging targeted therapies continue to show clinically meaningful benefit in a growing subset of PDAC tumors. Moreover, the number of trials based on PDAC tumor biomarker selection is experiencing an exponential growth, therefore, it is imperative to universally test for inherited and somatic alterations in patients diagnosed with PDAC.

^References:

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^{8. 9. The KRASG12D inhibitor MRTX1133 elucidates KRAS-mediated oncogenesis. Nat Med. 2022 Oct;28(10):2017-2018. doi:10.1038/s41591-022-02008-6}

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^{12. Pishvaian MJ, Bender RJ, Halverson D, et al. Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative. Clin Cancer Res. 2018 Oct 15;24(20):5018-5027. doi:10.1158/1078-0432.CCR-18-0531}

^{13. O'Reilly EM, Lee JW, Zalupski M, et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation. J Clin Oncol. 2020 May 1;38(13):1378-1388. doi:10.1200/JCO.19.02931}

^{14. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019 Jul 25;381(4):317-327. doi:10.1056/NEJMoa1903387}

^{15. Brown TJ, Reiss KA. PARP Inhibitors in Pancreatic Cancer. Cancer J. 2021 Nov-Dec 01;27(6):465-475. doi:10.1097/PPO.0000000000000554}

^{16. Kindler HL, Hammel P, Reni M, et al. Overall Survival Results From the POLO Trial: A Phase III Study of Active Maintenance Olaparib Versus Placebo for Germline BRCA-Mutated Metastatic Pancreatic Cancer. J Clin Oncol. 2022 Dec 1;40(34):3929-3939. doi:10.1200/JCO.21.01604}

^{17. Reiss KA, Mick R, O'Hara MH, et al. Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. J Clin Oncol. 2021 Aug 1;39(22):2497-2505. doi:10.1200/JCO.21.00003}

^{18. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. 2017 May 30, 2017. https://bit.ly/2lDQSG0}

^{19. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. December 14, 2018. Accessed: November 29, 2022. https://bit.ly/3EQvG4u}

^{20. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. August 16, 2019. Accessed: November 29, 2022. https://bit.ly/2ZzlkDl}

^{21. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. September 21, 2022. Accessed: November 29, 2022. https://bit.ly/3XIU2Wl}

^{22. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET Aberrations in Diverse Cancers: Next-Generation Sequencing of 4,871 Patients. Clin Cancer Res. 2017 Apr 15;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679}

^{23. Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013 Apr 2;6(269):pl1. doi:10.1126/scisignal.2004088}

^{24. Subbiah V, Wolf J, Konda B, et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol. 2022 Oct;23(10):1261-1273. doi:10.1016/S1470-2045(22)00541-1}

^{25. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA. June 23, 2022. Accessed: November 29, 2022. https://bit.ly/3OOSvKe}

^{26. Subbiah V, Lassen U, Élez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet Oncol. 2020 Sep;21(9):1234-1243. doi:10.1016/S1470-2045(20)30321-1}

^{27. Salama AKS, Li S, Macrae ER, et al. Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol. 2020 Nov 20;38(33):3895-3904. doi:10.1200/JCO.20.00762}

^{28. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020 Apr;21(4):508-518. doi:10.1016/S1470-2045(20)30074-7}

^{29. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. April 13, 2021. Accessed: November 29, 2022. https://bit.ly/3gQ6HpK}

^{30. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. 2022 November 1. https://bit.ly/3ONtPC2}

^{31. Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021 Jun;32(6):746-756. doi:10.1016/j.annonc.2021.03.005}

^{32. Qin, S., Bai y, Wang Z, et al. Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. J Clin Oncol. 2022;40(17_suppl): p. LBA4011-LBA4011. doi:10.1200/JCO.2022.40.17_suppl.LBA4011}