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CCO Independent Conference Highlights of the Virtual 2021 Gastrointestinal (GI) Cancers Symposium

Axel Grothey Headshot
Axel Grothey, MD
Manish A. Shah, MD
Released: March 10, 2021

Pancreatic Cancer

Alliance A021501: Neoadjuvant mFOLFIRINOX With or Without RT in Borderline Resectable Pancreatic Cancer

Axel Grothey, MD:
Adjuvant therapy is associated with an approximately 20-month median OS in patients with borderline resectable pancreatic adenocarcinoma. One adjuvant used in treating pancreatic adenocarcinoma is modified leucovorin/5-fluorouracil/irinotecan/oxaliplatin (mFOLFIRINOX). The Alliance A021501 study was a multicenter, randomized phase II trial of adult patients with borderline resectable pancreatic adenocarcinoma evaluating mFOLFIRINOX in the neoadjuvant setting with or without RT (N = 126).[46,47]

Patients had an ECOG PS of 0 or 1 and normal physiologic parameters. All patients initially received 4 cycles of mFOLFIRINOX and either continued mFOLFIRINOX for 4 additional cycles (N = 65) or continued mFOLFIRINOX for 3 cycles, followed by 1 cycle of stereotactic body RT (N = 55). Patients then underwent resection surgery followed by 4 cycles of FOLFOX. The primary endpoint was the 18-month OS rate. Key secondary endpoints were event-free survival, safety, R0 resection rate, and pathologic CR rate. At ASCO GI 2021, Katz and colleagues[46] presented results from this study.

Alliance A021501: Baseline Patient Characteristics

Axel Grothey, MD:
Both arms were well balanced by randomization. The mean patient age was about 63 years, and half of the patients were female. The majority of patients were White, and slightly more than half had an ECOG PS of 0. Median CA19-9 was 167 U/mL in the mFOLFIRINOX arm and 260 U/mL in the mFOLFIRINOX plus stereotactic body RT group at baseline.

Alliance A021501: OS and EFS

Axel Grothey, MD:
Median OS was 29.8 months (95% CI: 21.1-not estimable) in the arm receiving mFOLFIRINOX alone and 17.1 months (95% CI: 12.8-24.4) in the mFOLFIRINOX plus RT arm, with an 18-month OS rate of 66.4% and 47.3%, respectively. Median event-free survival was 15.0 months (95% CI: 11.2-21.9) and 10.2 months (95% CI: 6.7-17.3), respectively. These data are puzzling because the only difference between the arms is the replacement of 1 mFOLFIRINOX cycle with 1 cycle of RT, and we did not expect a big difference in outcome.

Alliance A021501: Preoperative Treatment-Related AEs

Axel Grothey, MD:
About 35 patients (60%) in each arm experienced ≥ 1 grade ≥ 3 AE preoperatively. Preoperative grade ≥ 4 AEs occurred in 11 patients (17%) receiving mFOLFIRINOX alone compared with only 5 patients (9%) receiving mFOLFIRINOX plus RT. This difference could be due to the patients in the mFOLFIRINOX alone arm receiving 1 extra cycle of chemotherapy. Five patients (13%) experienced grade ≥ 3 AEs from RT. Overall, I do not think there are toxicity concerns with these regimens.

Alliance A021501: Surgery and Pathology

Axel Grothey, MD:
In the mFOLFIRINOX alone arm, 32 of 65 patients (49.2%) underwent surgery vs only 19 patients (34.5%) in the mFOLFIRINOX plus RT arm. It is not clear whether the reduced frequency of patients going to surgery in the mFOLFIRINOX plus RT arm is due to stereotactic body RT or RT in general. The inflammatory response to RT may also preclude less-experienced surgeons from performing surgery.

Of the patients who underwent surgery, about 95% underwent pancreatoduodenectomy (Whipple surgery), and a third underwent superior mesenteric vein/portal vein resection. R0 resection was achieved in 15 patients (88%) in the mFOLFIRINOX arm and 9 patients (74%) in the mFOLFIRINOX plus RT arm. Two patients (11%) in the mFOLFIRINOX plus RT arm achieved pathologic CR vs no patients in the mFOLFIRINOX alone arm.

Alliance A021501: Surgical AEs

Axel Grothey, MD:
Readmissions occurred in 5 patients (16%) in the mFOLFIRINOX alone arm and 8 patients (42%) in the mFOLFIRINOX plus RT arm. Wound infections occurred in 2 patients (6%) in the mFOLFIRINOX alone arm and 3 patients (16%) in the mFOLFIRINOX plus RT arm. Other than the trend toward more readmissions and wound infections with RT, surgical AEs were similar between the arms. Overall, both approaches were well tolerated in terms of perioperative complications.

Alliance A021501: Clinical Implications

Axel Grothey, MD:
The inferiority of the RT arm was an interesting result that no one expected. Fewer patients went to surgery when they had RT, which was also unexpected and should be explored more. Some patients may still benefit from intensity-modulated RT in this borderline resection setting. At West Cancer Center, I am very selective in terms of which patients receive RT.

POLO: Maintenance Olaparib in Patients With Metastatic Pancreatic Cancer and Germline BRCA Mutation: Final OS

Axel Grothey, MD:
PARP inhibition may be a potential treatment option for the 7% of patients with pancreatic cancer who have a BRCA1/2 mutation. The POLO study was a randomized, placebo-controlled, double-blind phase III trial of the PARP inhibitor olaparib vs placebo in patients with metastatic pancreatic cancer and deleterious/suspected deleterious germline BRCA1/2 mutation (N = 154).[48-50] Patients had undergone ≥ 16 weeks of first-line platinum-based therapy (mainly FOLFIRINOX) without progression. Patients were randomized 3:2 to receive olaparib (n = 92) at 300 mg twice daily or placebo (n = 62). Patients continued until disease progression or unacceptable toxicity. The primary endpoint was PFS by blinded independent central review (modified RECIST v1.1), and key secondary endpoints were PFS2, time to study treatment discontinuation or death, time to first subsequent cancer therapy or death, time to second subsequent cancer therapy or death, and safety and tolerability. Olaparib was approved as maintenance therapy for patients with metastatic pancreatic adenocarcinoma and known or suspected deleterious germline BRCA mutations whose disease had not progressed on ≥ 16 weeks of first-line platinum-based chemotherapy based on the primary analysis of POLO[51] In an update at ASCO GI 2021, Golan and colleagues[48] reported final OS data and other secondary endpoints.

POLO: Final OS

Axel Grothey, MD:
Final OS was not statistically different for maintenance therapy with olaparib vs placebo (median OS: 19.0 months vs 19.2 months; HR: 0.83; 95% CI: 0.56-1.22; P = .3487). Only 15% of patients crossed over from placebo to olaparib, so the OS data are not a contaminated crossover effect. Some patients had a long‑term benefit and were progression free after 4 years, so the question is which patients receive the long‑term benefit.

POLO: Long-term Survivors (≥ 2 Years)

Axel Grothey, MD:
After more than 2 years, survival was 73.5% (n = 25) in the olaparib group vs 41.2% (n = 7) in the placebo group. Although there was no difference in median OS, there were clearly more long term survivors receiving olaparib. Again, the question remains regarding which patients benefit long-term.

POLO: AEs (≥ 15%)

Axel Grothey, MD:
Patients receiving olaparib experienced more AEs than patients receiving placebo, particularly grade ≥ 3 AEs (48.9% vs 24.6%), especially anemia and fatigue. Rates of AEs leading to discontinuation were also higher in the olaparib group (8.9% vs 1.6%). The AEs observed are not prohibitive and are consistent with previous data on PARP inhibitors in other cancers. Very few patients had grade ≥ 3 AEs, so this treatment is tolerable long-term as a single agent.

POLO: Clinical Implications

Axel Grothey, MD:
The POLO data are a little underwhelming in terms of OS data. The key issue is to identify which patients have a long‑term benefit from PARP inhibition, because those patients will have a higher benefit–AE ratio. I would like to see future clinical trials focus on those patients.

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