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CHECKMATE 577: ADJUVANT NIVOLUMAB IN RESECTED ESOPHAGEAL OR GASTROESOPHAGEAL JUNCTION CANCER (EC/GEJC) POST-NEOADJUVANT CHEMORADIOTHERAPY (CRT)

CheckMate 577 (NCT02743494)4 is a Phase III trial investigating the safety and efficacy of adjuvant nivolumab (NIVO), an anti-PD-1 monoclonal antibody, in resected esophageal or gastroesophageal junction cancer (EC/GEJC) in patients with residual pathologic disease post-neoadjuvant chemoradiotherapy. Early results were promising, nivolumab improved disease-free survival (DFS) by more than two-fold (22.4 vs 11.0 months) over placebo, and <10% of patients in the treatment group discontinued nivolumab due to serious treatment-related adverse events (TRAEs) versus 3% in the control group.

At the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting the expanded efficacy and safety analyses from the CheckMate 577 trial were presented5.  Participants were randomised 2:1 to nivolumab (n = 532) and placebo groups (n = 262). Median progression-free survival 2 (PFS2; time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was not reached following treatment with nivolumab and reported as 32.1 months for placebo.

Total recurrence (locoregional and distant) was 41% versus 56% in nivolumab and placebo groups, respectively, and median distant metastasis-free survival was 28.3 versus 17.6 months in nivolumab and placebo groups, respectively.

Quality of life (QoL), measured by FACT-ECS and FACT-G7, was maintained in patients treated with nivolumab.

The results from the CheckMate 577 trial suggest that adjuvant nivolumab is effective in treating EC/GEJC in patients with residual pathologic disease post-CRT; adjuvant nivolumab demonstrated an acceptable safety profile and QoL was maintained. This provides further support for the use of nivolumab as a new standard of care in patients with EC/GEJC post-CRT.

CLARIDHY: IVOSIDENIB IN PATIENTS WITH AN ISOCITRATE DEHYDROGENASE 1 (IDH1) MUTATION AND PREVIOUSLY TREATED CHOLANGIOCARCINOMA (CCA)

Cholangiocarcinoma (CCA) is a rare cancer for which there are few treatment options available6. Isocitrate dehydrogenase 1 (IDH1) mutations increase production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis, and occur in around 20% of intrahepatic CCAs.

At the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting, Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, New York, NY, presented the final results from ClarIDHy7, a Phase III multicenter randomized double-blind study of ivosidenib versus placebo in patients with previously treated CCA harbouring an IDH1 mutation (NCT02989857).

Ivosidenib is a first-in-class inhibitor of the mutant IDH1 enzyme. Participants were randomized 2:1 to receive 500 mg ivosidenib oral (PO) daily (QD) (n = 126) or matched placebo stratified by prior systemic therapies (n = 61).

The primary endpoint of progression-free survival (PFS) by an independent radiology centre was met with a significant improvement in the ivosidenib group, the secondary endpoints of median overall survival (mOS) and overall response rate (ORR) were also met; mOS, adjusted using the rank-preserving structural failure time (RPSFT) model to account for 70% crossover of patients from placebo to ivosidenib, was 5.1 months versus 10.3 months in the placebo and ivosidenib groups, respectively; ORR and stable disease was 2.4% and 50.8% for ivosidenib versus to 0% and 27.9% for placebo.

The safety profile of ivosidenib was favourable; common all-grade treatment-emergent adverse events (TEAEs, ≥ 15%) in the experimental arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥3 TEAEs occurred in 50% of patients treated with ivosidenib, versus 37% in the placebo arm.  7% of patients in the treatment group experienced an adverse event leading to treatment discontinuation relative to 9% in the control group.

The final results of the ClarIDHy trial demonstrate the clinical benefit of ivosidenib in patients with IDH1 mutation and previously treated CCA.

 

 

KEYNOTE-177: PEMBROLIZUMAB VS CHEMOTHERPY IN PATIENTS WITH MICROSATELLITE INSTABILITY-HIGH/MISMATCH REPAIR DEFICIENT (MSI-H/DMMR) METASTATIC COLORECTAL CANCER (MCRC)

KEYNOTE-177 (NCT02563002)1 is a Phase III, randomized open-label clinical trial investigating the efficacy and safety of first-line pembrolizumab versus chemotherapy in patients with microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Results of the second interim analysis (IA2) were published in January 2021 which reported a longer progression-free survival (PFS) in patients who received first-line pembrolizumab than in those who had received chemotherapy. The final overall survival results of the KEYNOTE-177 trial were presented at the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting.2

Patients were randomized 1:1 to receive pembrolizumab or mFOLFOX6/FOLFIRI ± bevacizumab/cetuximab. The primary endpoint of PFS was met, with a median PFS of 16.5 months in the pembrolizumab group versus 8.2 months in the chemotherapy group. Although pembrolizumab showed a trend towards a reduction in the risk of death relative to chemotherapy, the co-primary endpoint of overall survival (OS) was not met as the difference between the two groups was not enough to be considered significant (HR 0.74; 95% CI, 0.53-1.03; P=0.0359; α = 0.0246, one-sided). This was largely attributed to the high rate of crossover of patients from chemotherapy to anti-PD1/anti-PD-L1 therapies (60% crossover in the intention-to-treat population).

Treatment-related adverse events (TRAEs) occurred in 79.7% of patients in the pembrolizumab group relative to 98.6% of patients in the chemotherapy group, with grade ≥3 TRAEs occurring in 21.6% and 66.4% of patients in each group, respectively.

In conclusion, the results from the KEYNOTE-177 trial suggest that pembrolizumab is more effective than standard of care chemotherapy in patients with MSI-H/dMMR mCRC, putting pembrolizumab in a good position to be approved for first-line use.

NETTER-1: Lutetium-177-DOTATATE in patients with midgut neuroendocrine tumours (NETs)

Lutetium-177-DOTATATE is a form of radioligand therapy that utilizes the beta emitter lutetium-177 to kill cancer cells and the peptide DOTATATE to target somatostatin receptors, which are frequently overexpressed by neuroendocrine tumors (NETs).8

NETTER-1 (NCT01578239) is a Phase III study of lutetium-177-DOTATATE versus high-dose long-acting octreotide, a synthetic somatostatin analog, in patients with somatostatin receptor-positive midgut NETs. Patients were randomized to receive 4 cycles of lutetium-177-DOTATATE 7.4 GBq (200mCi) every 8 ± 1 weeks, long-acting octreotide 30mg and best supportive care (BSC) or high-dose long-acting octreotide 60mg every 4 weeks and BSC. Initial results showed that the primary endpoint of progression-free survival (PFS) was met; median PFS was not reached in the Lutetium-177-DOTATATE arm versus 8.4 months in the control arm.9

At the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting, the final results from the NETTER-1 trial were presented by Jonathan Strosberg, MD, Moffitt Cancer Center, Tampa, FL.10

Median overall survival (mOS) was greater in the lutetium-177-DOTATATE arm, 48.0 months (95% CI: 37.4, 55.2) versus 36.3 months (95% CI: 25.9, 51.7) in the control arm with a hazard ratio (HR) of 0.84 (95% CI: 0.60, 1.17,) ; however, this difference was not statistically significant (p = 0.30).

This may be attributed to the high rate of crossover of patients from the control arm to radioligand therapy after progression. Two patients in the lutetium-177-DOTATATE arm developed myelodysplastic syndrome (MDS); no new adverse events (AEs) emerged during long-term follow-up.

In conclusion, lutetium-177-DOTATATE provided a significant improvement in PFS and a clinically meaningful; improvement in mOS in patients with somatostatin receptor-positive midgut NETs.

PREOPANC: PREOPERATIVE CHEMORADIOTHERAPY (CRT) VERSUS IMMEDIATE SURGERY IN PANCREATIC CANCER

Chemoradiotherapy (CRT) involves the administration of chemotherapy agents, such as the DNA replication inhibitor gemcitabine, concurrently or sequentially with radiotherapy, such as external beam radiation therapy (XRT). Neoadjuvant CRT (NCRT) has been shown to be effective in treating esophageal carcinoma11; however, its role in pancreatic cancer is untested.

At the American Society of Clinical Oncology (ASCO) 2021 Virtual Meeting, Casper H. Van Eijck, MD, PhD, Erasmus University Medical Center, Rotterdam, Netherlands, discussed the long term-results from the randomized Phase III PREOPANC trial (NTR3709) evaluating the efficacy of preoperative CRT versus immediate surgery in resectable pancreatic cancer (RPC) and borderline resectable pancreatic cancer (BRPC).12 Patients were randomized to receive CRT, with gemcitabine and Gy radiotherapy, followed by surgery and adjuvant gemcitabine (n=119) or immediate surgery followed by adjuvant gemcitabine (n=127) and were stratified by RPC/BRPC.

The primary endpoint of overall survival by intention-to-treat (ITT) was met; 3- and 5-year overall survival ITT was 27.7% and 20.5% in the preoperative CRT group versus 16.5% and 6.5% in the immediate surgery group. Moreover, preoperative CRT improved distant metastasis-free interval, locoregional failure-free interval and disease-free survival. No difference in the effect of treatment was found between patients with RPC or BRPC.

In summary, preoperative gemcitabine-based CRT improves long-term overall survival in RPC and BRPC compared to immediate surgery.

References

  1. Shiu K-K, Andre T, Kim TW et al. KEYNOTE-177: Phase III randomized study of pembrolizumab versus chemotherapy for microsatellite instability-high advanced colorectal cancer. JCO. 2021 Jan 20;39(3_suppl):6–6.
  2. Andre T, Shiu K-K, Kim TW et al. Final overall survival for the phase III KN177 study: Pembrolizumab versus chemotherapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). JCO. 2021 May 20;39(15_suppl):3500–3500.
  3. Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. Journal of Hematology & Oncology. 2019 Sep 5;12(1):92.
  4. Kelly RJ, Ajani JA, Kuzdzal J et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191–203.
  5. Kelly RJ, Ajani JA, Kuzdzal J et al. Adjuvant nivolumab (NIVO) in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiotherapy (CRT): Expanded efficacy and safety analyses from CheckMate 577. JCO. 2021 May 20;39(15_suppl):4003–4003.
  6. Lowery MA, Abou-Alfa GK, Valle JW et al. ClarIDHy: A phase 3, multicenter, randomized, double-blind study of AG-120 vs placebo in patients with an advanced cholangiocarcinoma with an IDH1 mutation. JCO. 2017 May 20;35(15_suppl):TPS4142–TPS4142.
  7. Zhu AX, Macarulla T, Javle MM et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. JCO. 2021 Jan 20;39(3_suppl):266–266.
  8. Zhou H-Y, Zheng S-P, Li A-L et al. Clinical evidence for association of neoadjuvant chemotherapy or chemoradiotherapy with efficacy and safety in patients with resectable esophageal carcinoma (NewEC study). EClinicalMedicine. 2020 Jul 1 [cited 2021 Jun 16];24. Available from: https://doi.org/10.1016/j.eclinm.2020.100422
  9. Van Eijck CHJ, Versteijne E, Suker M et al. Preoperative chemoradiotherapy to improve overall survival in pancreatic cancer: Long-term results of the multicenter randomized phase III PREOPANC trial. JCO. 2021 May 20;39(15_suppl):4016–4016.
  10. Mittra ES. Neuroendocrine Tumor Therapy: 177Lu-DOTATATE. American Journal of Roentgenology. 2018 Aug 1;211(2):278–85.
  11. Strosberg JR, Wolin EM, Chasen B, et al. NETTER-1 phase III: Efficacy and safety results in patients with midgut neuroendocrine tumors treated with 177Lu-DOTATATE. JCO. 2016 May 20;34(15_suppl):4005–4005.
  12. Strosberg JR, Caplin ME, Kunz PL et al. Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors. JCO. 2021 May 20;39(15_suppl):4112–4112.