Binbin Zheng-Lin, MD, MSc

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.

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.

 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%).

 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 

 G12C. The efficacy of adagrasib is being evaluated by the KRYSTAL-1 trial (NCT03785249), a multicohort phase 1/2 study enrolling patients with 

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.

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.

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.

 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 

 mutations in patients with PDAC. In a recent case report, autologously administered 

 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.

Approximately 6% to 9% of PDAC tumors harbor a germline pathogenic and likely pathogenic variant (P/LPV) of 

 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.

In 2019, the FDA approved olaparib (Lynparza), an oral PARP inhibitor, as maintenance therapy in patients with metastatic germline 

-mutated PDAC who had a platinum-sensitive disease, which was defined as no disease progression after 16 weeks of first-line platinum-based therapy.

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; 

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; 

 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; 

 < .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).

As key differences to the POLO trial, inclusion criteria in this study incorporated participants with locally advanced PDAC tumors, and those with germline 

 P/PLVs, as well as germline and somatic 

 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 

 alteration. None of the 7 patients with a germline 

 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.

 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.

In 2017, the FDA approved pembrolizumab as the first tissue-agnostic therapy for all tumors with MSI-H and/or dMMR.

 Two additional agents, entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), received approvals for advanced solid tumors with 

 fusion regardless of the primary tumor histology.

 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 

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 

 gene amplifications and mutations occur in up to 3.7% of tumors, whereas 

 fusion are detected in less than 1% of cases.

 In LIBRETTO-001 (NCT03157128), a phase 1/2, open-label, basket trial, the authors included a tumor-agnostic sub-cohort with 45 patients with 

 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.

 mutation occurs in approximately 3% of all PDAC tumors, being 

V600E the most common alteration. Combined BRAF-MEKinhibition with respective dabrafenib and trametinib received FDA approval for all 

 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.

 Notably, from all 131 patients enrolled in both trials, only the latter included 3 patients with 

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.

mutatedPDAC remains anecdotal. In the KYT registry, 1 patient with 

mutatedPDAC received dabrafenib/trametinib as second-line treatment and showed sustained response for eleven months. One other patient with 

 fusion remained less than one month on fourth-line dabrafenib/trametinib due to intolerance.

Prospectively, the single-arm phase 2 BrafPanc trial (NCT04390243) aims to examine the efficacy of encorafenib/binimetinib in locally advanced and metastatic 

V600E-mutant PDAC tumors, and the study is in active recruitment and is estimated to complete in December 2024.

Sacituzumab govitecan (Trodelvy), an antibody-drug conjugate targeting to trop-2, is currently approved for patients with advanced urothelial carcinoma and breast cancer.

 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.

 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 

, 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, 

 = .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, 

 In the nimotuzumab arm, grade 3 AE included neutropenia (11.1%) and thrombocytopenia (6.7%), but no grade 4 AEs were reported.

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.

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Articles

The landscape for patients with pancreatic ductal adenocarcinoma has shifted due to novel targeted therapies that are opening new options for patients. 

Binbin Zheng-Lin, MD, MSc | Authors

Articles

Pancreatic Cancer Awareness Month: Novel Targeted Therapy in PDAC