Pancreatic cancer remains an incorrigible foe, but recent advances in genomic profiling and targeted drug development are slowly improving the outlook for patients, according to Eileen M. O’Reilly, MD, Winthrop Rockefeller Endowed Chair in Medical Oncology and Section Head, Hepato-pancreaticobiliary & Neuroendocrine Cancers, Memorial Sloan Kettering Cancer Center, New York.
“From the POLO study, we have proof of principle that targeting BRCA leads to improvements in outcome in a genomically selected patient population.”— Eileen M. O’Reilly, MD
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In a presentation at the 2021 ESMO World Congress on Gastrointestinal Cancers, Dr. O’Reilly brought listeners up to date on the actionable genome, including new treatments for rare mutations.1 She also described the potential for enhancing immunotherapy and discussed novel agents that tackle pancreatic cancer in whole new ways.
Key Genomic Group: HRD-Associated Genes
According to a combined data set of almost 1,500 tumors from the Know Your Tumor program and Caris Life Sciences, about 17% of tumors harbor driver mutations.2,3 In these samples, the spectrum of DNA damage repair alterations ranged from the more common ones, such as ATM (3.6%–4.5%) and BRCA2 (2.9%–3.3%), to very rare potentially actionable mutations, such as BARD1 (0.2%) and CHEK1 (0.2%).
The key genomic subgroup in pancreatic cancer remains the 15% to 20% of patients with homologous repair deficiency (HRD). In these patients, platinum agents and inhibitors of poly (ADP ribose) polymerase (PARP) are established therapies. This group primarily includes patients with germline BRCA1/2 or PALB2 mutations (5%–8%) or somatic mutations in BRCA1/2 or PALB2 (2%–3%) for whom first-line FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) and cisplatin/gemcitabine are standard treatments, as is maintenance olaparib (for BRCA1/2 germline mutations).
“From the POLO study,4 we have proof of principle that targeting BRCA leads to improvements in outcome in a genomically selected patient population,” Dr. O’Reilly said. In POLO, patients with metastatic germline BRCA-mutant tumors received platinum therapy and were then randomly assigned to olaparib or placebo. Median progression-free survival was doubled with olaparib (hazard ratio [HR] = 0.53), with sustained improvement shown over time. Median overall survival was not superior, but by 2 years, a separation of the survival curves began favoring the PARP inhibitor.5 “These data support the use of a PARP inhibitor as a valid maintenance option in this setting,” she said.
Recent findings for another PARP inhibitor, rucaparib, demonstrate that there is benefit for PARP inhibitor maintenance too.6 With maintenance, platinum-responding patients with somatic or germline BRCA or PALB2 mutations had a median progression-free survival of 13.2 months and a median overall survival of 23.5 months. “The findings also extend the value of PARP inhibition from germline to somatic mutations and to patients with PALB2 mutations,” added Dr. O’Reilly.
The next step is to move PARP inhibitors into earlier treatment. Adjuvant olaparib is being evaluated in the APOLLO EA2192 trial of 157 patients with BRCA or PALB2 somatic or germline mutations.
For the subset of patients with other HRD alterations, such as ATM (5%), studies are evaluating platinum and PARP inhibitors, immunotherapy, agents targeting vascular endothelial growth factor, and inhibitors of the DNA damage response kinase ATR.
KRAS-Targeting Approaches
KRAS-mutated tumors constitute 92% to 94% of pancreatic cancers, but only the KRAS G12C allele, which occurs in 1% to 2% of pancreatic tumors, can currently be targeted. For this, the small-molecule inhibitor sotorasib demonstrated activity in a pivotal study by Hong et al, in which 1 of 12 patients with pancreatic cancer responded and 9 achieved stable disease.7
Other G12C allele inhibitors are now in development, including MRTX-849 and JNJ-74699157. Inhibitors of SOS1, which is a KRAS activator and important feedback node, show promise in combination with MAPK inhibitors.
“I’m excited to see proof of principle for KRAS targeting in pancreas cancer and other malignancies, [but] resistance tends to occur early and often…, so it’s pretty clear we are going to need combination strategies.”— Eileen M. O’Reilly, MD
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“I’m excited to see proof of principle for KRAS targeting in pancreas cancer and other malignancies. But as we see with pancreas cancer, resistance tends to occur early and often. This was noticeable even in this targeted subset, so it’s pretty clear we are going to need combination strategies,” Dr. O’Reilly commented.
Other strategies are under consideration to target KRAS beyond G12C, such as the G12D and G12V alleles. One uses small-interfering RNA encompassed in a prolonged delivery system called LODER (LOcal Drug EluteR); the compound is slowly released endoscopically over 12 to 16 weeks.
In a mouse model, siG12D-LODER impeded the tumor growth and prolonged survival,8 a finding that led to a human trial in which siG12D-LODER (on a chemotherapy backbone) elicited partial responses.9 A randomized phase III trial in locally advanced pancreatic cancer is planned.
KRAS Wild-Type Subset
Of increasing clinical relevance, about 20% to 30% of the KRAS wild-type subset have potentially targetable driver mutations, especially fusions in NRG1, NTRK, ROS1, ALK, FGFR, and RET.10 The benefit of targeting NRG1 was shown, for example, in a study of 12 patients, of whom 42% responded to zenocutuzumab (MCLA-128), a bispecific humanized IgG1 monoclonal antibody; 100% of patients had declines in CA 19-9, and one patient experienced extended disease control.11 Dr. O’Reilly also described a patient with an RDX-MET fusion who remains stable on crizotinib therapy after more than 1 year.
“Fusions are rare in pancreatic cancer but are enriched in the KRAS wild-type population, and when they do occur and can be targeted, patients can do well,” she said. Alterations in the MAPK pathway (ie, BRAF and HER2) also appear in this subset in a much higher percentage than in patients with KRAS-mutated disease (< 1%), and tumors with microsatellite instability (MSI-high) are enriched.
Targeting ‘Early-Onset’ Cancer
Targeting of some aspect of the genome is actually more fruitful in younger patients (≤ 50) than older ones, as younger patients are more likely to have germline alterations in BRCA1 (28%), BRCA2 (27%), and RAS wild-type tumors (16%), which often harbor other variants. This was shown in the profiling of 450 patients by Varghese et al, who also found that the presence of a pathogenic variant was associated with improved 12-month overall survival: 72% vs 55% in the absence of a variant.12 These findings are informative for targeted treatment opportunities, Dr. O’Reilly commented.
Improving Immunogenicity
Immunotherapy has not yet proven effective in this malignancy. Clearly, in unselected patients, the use of one or two checkpoint inhibitors “does not move the needle forward,” Dr. O’Reilly pointed out.
Nevertheless, there have been efforts to enrich subsets of patients for a better immune response. These patients could be those with a high tumor mutational burden (TMB ≥ 10 mut/mb), the 1% with MSI-high tumors, and perhaps patients with BRCA mutations, who tend to have higher levels of “genomic instability,” in part due to higher TMBs, greater expression of PD-L1, and more MSI-high tumors. These groups of patients might benefit from chemoimmunotherapy, she said.
One approach may be to give a checkpoint inhibitor with a PARP inhibitor. Dr. O’Reilly’s group is evaluating olaparib plus pembrolizumab as maintenance therapy in the phase II POLAR trial, stratifying patients into three groups according to mutation status: those with DNA damage–repair gene mutations, noncore mutations (beyond BRCA1/2, PALB2), or no identified mutations but excellent response to platinum therapy.
Other researchers are evaluating the benefit of combining the CD40 antibody sotigalimab (APX005M) with chemotherapy alone or chemotherapy plus nivolumab. A recent phase II study found the best 1-year overall survival was achieved with gemcitabine/nab-paclitaxel plus nivolumab (57%), followed by gemcitabine/nab-paclitaxel plus sotigalimab (51%). However, for chemotherapy plus both nivolumab and sotigalimab, 1-year survival was somewhat disappointing (41%) and did not meet the primary endpoint of 1-year survival > 35%.13,14
Indeed, studies of such approaches, to date, have not clearly met their predefined outcomes, Dr. O’Reilly said. However, there may be a “signal” for chemotherapy plus a single checkpoint inhibitor based on this latter study and a phase II trial in which a signal was shown with gemcitabine/nab-paclitaxel plus pembrolizumab.15 “I think there will be trials building on this space,” she predicted. Circulating tumor DNA, tumor subtyping, and immune profiling may be other ways to enrich subgroups for chemoimmunotherapies, she added.
Novel Therapies in Development
Finally, Dr. O’Reilly described a variety of approaches that target metabolism and stroma, which are being evaluated in the following trials:
- Phase III AVENGER: first-line modified FOLFIRINOX plus devimistat vs modified FOLFIRINOX alone (n = 500). Devimistat, an antimitochondrial agent, has received Orphan Drug designation.
- Phase III LAPIS: first-line chemotherapy with or without pamrevlumab (n = 280). Pamrevlumab is a connective tissue growth factor antagonist that has received Orphan Drug designation for Duchenne muscular dystrophy.
- Phase II randomized study: first-line gemcitabine/nab-paclitaxel with or without zolbetuximab, a monoclonal antibody against isoform 2 of Claudin-18.
- Phase III TYBECA-1: second-line chemotherapy with or without eryaspase (n = 500). Eryaspase provides encapsulated asparaginase within erythrocytes to minimize toxicity.
In the immunotherapy space, results are pending for various arms of the MORPHEUS trial of gemcitabine/nab-paclitaxel and atezolizumab plus anti-TIGIT (TIGIT is associated with a suppressed immune response), bevacizumab, and tocilizumab (anti–interleukin-6 antibody). An ongoing phase III trial of cytotoxic therapy is evaluating NALIRIFOX (liposomal irinotecan, 5-FU, leucovorin, oxaliplatin) vs gemcitabine/nab-paclitaxel (n = 750) in the front line. “We await the results of these key studies,” she said.
DISCLOSURE: Dr. O’Reilly has received institutional research funding from Genentech/Roche, Celgene/BMS, BioNTech, BioAtla, AstraZeneca, Arcus, Elicio, and Parker Institute; has served as a consultant for Cytomx Therapeutics (data and safety monitoring board [DSMB]), Rafael Therapeutics (DSMB), Sobi, Silenseed, Tyme, -Seagen, Molecular Templates, Boehringer Ingelheim, BioNTech, Ipsen, Polaris, -Merck, IDEAYA, Cend, AstraZeneca, Noxxon, BioSapien, Thetis, and Cend Therapeutics; and her spouse has served as a consultant for Bayer, Genentech/Roche, Celgene/BMS, and Eisai.
REFERENCES
2. 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 24:5018-5027, 2018.
3. Philip P, Xiu J, Hall MJ, et al: Enrichment of alterations in targetable molecular pathways in KRAS wild-type pancreatic cancer. 2020 ASCO Annual Meeting. Abstract 4629. Presented May 20, 2020.
4. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2017.
5. Golan T, Hammel P, Reni M, et al: Overall survival from the phase 3 POLO trial: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. 2021 Gastrointestinal Cancers Symposium. Abstract 378. Presented January 22, 2021.
6. 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 39:2497-2505, 2021.
7. Hong DS, Fakih MG, Strickler JH, et al: KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.
8. Khvalevsky EZ, Gabai R, Rachmut IH, et al: Mutant KRAS is a druggable target for pancreatic cancer. PNAS 110:20723-20728, 2013.
9. Golan T, Khvalevsky EZ, Hubert A, et al: RNAi therapy targeting KRAS in combination with chemotherapy for locally advanced pancreatic cancer patients. Oncotarget 6:24560-24570, 2015.
11. Schram AM, Drilon AEA, Macarulla T, et al: A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion–positive advanced solid tumors. 2020 ASCO Annual Meeting. Abstract TPS3654. Presented May 25, 2020.
13. O’Hara MH, O’Reilly EM, Varadhachary G, et al: CD40 agonist monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: An open-label, multicentre, phase 1b study. Lancet Oncol 22:118-131, 2021.
14. O’Hara MH, O’Reilly EM, Wolff RA, et al: Gemcitabine and nab-paclitaxel ± nivolumab ± CD40 agonistic monoclonal antibody APX005M (sotigalimab), in patients with untreated metastatic pancreatic adenocarcinoma: Phase 2 final results. 2021 ASCO Annual Meeting. Abstract 4019. Presented May 28, 2021.
15. Weiss GJ, Blaydorn L, Beck J, et al: Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma [erratum in Invest New Drugs 37:797, 2019]. Invest New Drugs 36:96-102, 2018.
