ASCO Urges Routine dMMR Testing for Second-Line Metastatic Pancreatic Cancer

Davendra Sohal, MD, MPH

Based on fresh studies in the setting of metastatic pancreatic cancer, the American Society of Clinical Oncology (ASCO) now recommends routine testing for mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H) for candidates for checkpoint inhibitor therapy.

The updates to the guidelines, which were last reviewed in 2016, include a recommendation for the PD-1 immune checkpoint inhibitor pembrolizumab (Keytruda) for patients who test positive for dMMR or MSI-H.¹

For patients who received first-line treatment with gemcitabine plus nab-paclitaxel (Abraxane) and meet other criteria, additional updates call for using fluorouracil plus irinotecan when the secondline combination of fluorouracil plus nanoliposomal irinotecan is unavailable. Those additional criteria include an ECOG performance status (PS) of 0-1, a favorable comorbidity profile, patient preference for this treatment, and a support system for aggressive medical therapy. Fluorouracil plus oxaliplatin (Eloxatin) also may be considered as second-line therapy for patients who had first-line treatment with nab-paclitaxel.¹

Table. Updated ASCO Recommendations for Metastatic Pancreatic Cancer in Second Line

Testing for MSI

The changes reflect the ASCO expert panel’s attempt to recommend the appropriate therapy for patients with metastatic pancreatic cancer who experience either disease progression or intolerable toxicity with prior regimens.The updates are based in part by findings of 2 studies. One, a phase II study by Le et al, explored the efficacy of PD-1 inhibition in patients with advanced dMMR cancers across 12 solid tumor types, including pancreatic cancer.² The other, the phase III PANCREOX trial, evaluated survival outcomes for patients with advanced pancreatic cancer assigned to fluorouracil and oxaliplatin administered as modified FOLFOX6 (mFOLFOX6; infusional fluorouracil, leucovorin, and oxaliplatin) versus fluorouracil plus leucovorin.“For second-line treatment of metastatic pancreatic cancer, our first recommendation now is to consider testing for MSI in patients who are candidates for checkpoint inhibitor therapy,” Davendra Sohal, MD, MPH, director of the Clinical Genomics Program at Cleveland Clinic Taussig Cancer in Ohio and cochair of the expert panel that wrote the new guidelines, said in a podcast. “Any standard form of testing is acceptable, whether immunohistochemistry [IHC], polymerase chain reaction [PCR], or next-gen sequencing.”

In the study by Le et al, across the 12 tumor types, 86 patients with previously treated disease were enrolled and received 10 mg/kg of pembrolizumab every 14 days. All patients had evidence of dMMR as assessed by either PCR or IHC. Seventy-eight patients were evaluable for response. The overall objective response rate (ORR) for this cohort was 53% (95% CI, 42%-64%), and the disease control rate was 77% (95% CI, 66%-85%). Eighteen patients (21%) had a complete response (CR).²

Among the 8 patients with pancreatic cancer, 2 (25%) had a CR and 3 (37%) had a partial response (PR), for an ORR of 62% and a disease control rate of 75%. One patient had stable disease, and 2 were not evaluable. Median progression-free survival (PFS) and median overall survival (OS) had not been reached in this ongoing study.

“A small, nonrandomized study such as that of Le at al would generally be considered low quality due to the risk of bias associated with nonrandomized study designs and the indirectness resulting from the small number of patients with pancreatic cancer included in the study,” the panel wrote. “Nonetheless, the magnitude of the effect across disease sites in the population of patients with dMMR tumors is strong, and on this basis, the expert panel rated the study quality as intermediate.”

In PANCREOX, adults were randomly assigned to mFOLFOX6 (n = 54) or infusional fluorouracil/ leucovorin (n = 54) at 12 medical centers in Canada.³ All patients were included in the intent-to-treat (ITT) analysis. After a median follow-up of 8.8 months, PFS was nearly identical in the ITT population for mFOLFOX6 versus the fluorouracil/leucovorin cohort (3.1 vs 2.9 months; HR, 1.00; 95% CI, 0.66-1.53; P = .989). The PR rate was 13.2% in the mFOLFOX6 arm compared with 8.5% in the infusional arm (P = .361). There were no CRs, and the ORR was similar between the study arms.

“With 108 patients, the primary outcome of overall survival was 9.9 months in the control [fluorouracil/leucovorin] arm and, surprisingly, [just] 6.1 months in the [mFOLFOX6] arm [HR 1.78; 95% CI, 1.08-2.93; P = .024],” Sohal said. “This study informed our recommendation for the chemotherapy regimens in the second-line setting.”

Grade 3/4 adverse events (AEs) were experienced by 63% of patients in the mFOLFOX6 group and 11% of patients in the fluorouracil/ leucovorin group. The most common grade 3/4 AEs with mFOLFOX6 were neutropenia (32.7%) and fatigue (14.2%) in contrast with neutropenia (3.8%), fatigue (1.9%), and thrombocytopenia (1.9%) in the fluorouracil/ leucovorin arm.

Forty-five percent of patients required oxaliplatin dose reduction, most often due to hematologic toxicity (77%). Furthermore, patients assigned to mFOLFOX6 were more likely to require dose delays (77% vs 44%; P = .003).

Conflicting Data on Oxaliplatin

Based on the PANCREOX findings, the panel also recommended gemcitabine (Gemzar) plus nab-paclitaxel for second-line therapy for patients who received FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) in the first line and meet other criteria for aggressive chemotherapy. Fluorouracil plus nanoliposomal irinotecan is recommended for patients who received gemcitabine plus nab-paclitaxel in the first line. The panel said that gemcitabine or fluorouracil should be offered to patients with either an ECOG PS of 2 or a comorbidity profile that precludes other regimens.The authors of the previous guidance from 2016 noted a lack of high-quality evidence to guide second-line therapy, and prior recommendations were developed from data for patients who received gemcitabine monotherapy. The updated guideline continues to recommend that choice of therapy depending on patient tolerance and condition.

Previous guidance advised the combination of fluorouracil and oxaliplatin, based on CONKO-003, a study that demonstrated improved OS with the OFF (oxaliplatin, folinic acid, and fluorouracil) regimen. The PANCREOX trial, using mFOLFOX6, did not find a benefit with the oxaliplatin combination.

“The combination of fluorouracil plus oxaliplatin can be considered as an option in this setting, but we have noted a qualifying statement about the PANCREOX study, the results of which are inconsistent with the CONKO003 study using the same agents as the OFF regimen,” Sohal said. “Given these conflicting results…the recommendation for its use in the second-line setting has been softened.”

CONKO-003 was a randomized, open-label phase III trial conducted at 16 locations in Germany. Adults (n = 168) with pancreatic cancer who had progressed following gemcitabine therapy were recruited from January 2004 to May 2007. The last follow-up was in December 2012.⁴

Patients were assigned to either 200 mg/m² of folinic acid and 2000 mg/m² of fluorouracil (FF) on days 1, 8, 15, and 22 or OFF, which included the FF regimen plus 85 mg/m² of oxaliplatin on days 8 and 22. Treatment continued until progression or unacceptable toxicity.

At a median follow-up of 54.1 months, OS was 5.9 months in the OFF arm compared with 3.3 months for FF (HR, 0.66; 95% CI, 0.48-0.91; P = .010). Median time to progression was also significantly longer with OFF (2.9 vs 2.0 months; HR, 0.68; 95% CI, 0.50-0.94; P = .019).

Safety results in CONKO-003 also differed greatly from the PANCREOX findings. In CONKO-003, pain was the most common grade 3 AE in both arms. Three (4.0%) patients in the OFF arm experienced grade 3 neuropathy, and 2 in the FF arm experienced grade 4 pain. Most nonhematologic and hematologic AEs were grade 1/2. Ten percent of patients required dose reductions of oxaliplatin, compared with 45% in PANCREOX, and 81% of patients received a full dose of oxaliplatin.

The 2 studies used different dosing regimens, and roughly 75% of patients in PANCREOX received gemcitabine in the frontline compared with 100% in CONKO-003, but the guideline authors could not find a conclusive explanation for the differences in the findings. A qualifying statement acknowledged the controversy: “Considering the inconsistency of these results, although fluorouracil plus nanoliposomal irinotecan is preferred, the expert panel continues to support the use of fluorouracil plus oxaliplatin as an option where the availability of fluorouracil plus nanoliposomal irinotecan is limited or where residual toxicity from firstline therapy or comorbidities precludes the use of fluorouracil plus nanoliposomal irinotecan,” they wrote.

The panel left in place recommendations made in 2016 calling for every patient with metastatic pancreatic cancer to undergo a multiphase computed tomography scan and an evaluation for baseline PS and comorbidity. Sohal stressed the importance of communication between patient and provider about the value of clinical trials and palliative care early in treatment.

“[Although] chemotherapy forms the backbone of treatment, it is [just] 1 component,” he said. “The use of supportive care or palliative care is strongly encouraged for all patients with metastatic pancreatic cancer in order to maximize not just the quantity but also the quality of life.”

References

1. Sohal DPS, Kennedy EB, Khorana A, et al. Metastatic pancreatic cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(24):2545-2556. doi: 10.1200/JCO.2018.78.9636.
2. Le DT, Durham JN, Smith KN, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409-413. doi: 10.1126/science.aan6733.
3. Gill S, Ko YJ, Cripps C, et al. PANCREOX: A randomized phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016;34(32):3914-3920. doi: 10.1200/JCO.2016.68.5776.
4. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423-9. doi: 10.1200/ JCO.2013.53.6995.