Recent Advances in Perioperative Immunotherapies in Lung Cancer
Abstract
:1. Introduction
2. Treatment Outcomes of Early-Stage NSCLC before the ICI Era
3. Overview of ICIs
4. Adjuvant ICI Treatments vs. Neoadjuvant ICI Treatments
4.1. Advantages and Disadvantages of Neo-Adjuvant Immunotherapies
4.2. Advantages and Disadvantages of Adjuvant Immunotherapies
4.3. Necessity of Adjuvant Immunotherapy following Neoadjuvant Immunotherapy plus Surgical Resection
5. Evidence of Neo-Adjuvant Immunotherapies
5.1. ICI Monotherapies
5.2. ICI Combinations
Phase: Trial Name (Registry ID) Study Start Date (Reference) | Target Stage | N | ICI | pCR Rate | MPR Rate | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|---|---|
pII: NEOSTAR (NCT03158129) June 2017 [37] | I–IIIA | 44 | N vs. N + I | N: 9% N + I: 29% | N: 22% N + I: 38% | RFS Median was not reached | Median was not reached |
pII: NEOpredict-Lung (NCT04205552) March 2020 [39] | IB–IIIA | 60 | N vs. N + R | pCR or MPR rates N: 28% N + R: 32% | both arms 12 m DFS 91% [95% CI: 78–97%] | both arms 12 m OS 96% [95% CI: 83–99%] | |
pII: JHU and MSKCC Study (NCT02259621) September 2014 [36] | IB (≥4 cm)–IIIA | 9 | N + I (+two additional doses of N) | 22% | NA | 2y RFS 33% | NA |
5.3. Combination Therapies with ICI plus Cytotoxic Chemotherapies
5.4. ICI Sandwich Therapies (Neoadjuvant ICI plus Chemotherapy Followed by Adjuvant ICI Monotherapy)
5.5. Combination Therapies with Chemoradiotherapy (CRT)
6. Evidence of Adjuvant Immunotherapies
7. Implications for Clinical Practice
8. Future Directions
8.1. Prognostic Biomarkers
8.2. Predictive Biomarkers
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Phase: Trial Name (Registry ID) Study Start Date (Reference) | Target Stage | Inclusion Criteria (Biomarker) | N | ICI | Response Rate | pCR Rate | MPR Rate | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|---|---|---|---|
pII: CheckMate 159 September 2014 (NCT02259621) [29] | I (>4 cm)–IIIA | - | 21 | N | NA | 10% | 45% | 5 y RFS 60% | 5 y OS 80% |
pII: LCMC3 (NCT02927301) April 2017 [30] | IB–IIIB | w/o EGFR/ALK | 181 | A | NA | 6% [95% CI: 3–11] | 20% [95% CI: 14–28] | 3 y DFS: 72% [95% CI: 62–79] | 3 y OS: 80% [95% CI: 71–87] |
pII: PRINCEPS (NCT02994576) December 2016 [33] | IA (≥2 cm)–IIIA | - | 30 | A | NA | 0% | 14% | NA | NA |
pII: IONESCO (NCT03030131) January 2017 [31] | IB (≥4 cm)–IIIA (non N2) | - | 46 | D | PR: 9% SD: 78% PD: 13% | 7% | 19% | 12 m DFS: 78.3% | 12 m OS: 89.1% |
pII: New York- Presbyterian and Weill Cornell Medical Center Study (NCT02904954) December 2016 [32] | I–IIIA | - | 60 | D vs. D + SBRT (8Gy × 3fr) | D PR: 3% SD: 80% PD: 10% D + SBRT PR: 50% SD: 50% | D: 0% D + SBRT: 27% | D: 6% D + SBRT: 26% | NA | NA |
pII: POTENTIAL (jRCT2061180016) January 2019 [34] | I | w/o EGFR or ALK or ROS1 | 50 | N | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing |
Phase: Trial Name (Registry ID) Study Start Date (Reference) | Target Stage | N | ICI | Response Rate | pCR Rate | MPR Rate | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|---|---|---|
pII: Sidney Kimmel Study (NCT03366766) December 2017 [42] | IB (≥4 cm)–IIIA | 13 | N + CDDP + PEM or GEM | CR: 8% PR: 38% SD: 54% | 38% | 85% | NA | NA |
pII: Columbia University Study (NCT02716038) June 2016 [41] | IB–IIIA | 30 | A + CBDCA + nab-PTX | PR: 63% SD: 30% PD: 7% | 33% | 57% | 17·9 m [95% CI: 14.3–not reached] | Median not reached |
pIII: CheckMate 816 (NCT02998528) March 2017 [23] | IB (>4 cm)–IIIA | 358 | N + PT-DC vs. PT-DC | NA | N + PT-DC: 24% PT-DC: 2.2% | N + PT-DC: 36.9% PT-DC: 8.9% | Median EFS N + PT-DC: 31.6 m [95% CI: 30.2– not reached] PT-DC: 20.8 m [95% CI: 14.0–26.7] HR: 0.63 [97.38% CI: 0.43–0.91] p = 0.005 | Median not reached |
Phase: Trial Name (Registry ID) Study Start Date (Reference) | Target Stage | N | ICI | Response Rate | pCR Rate | MPR Rate | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|---|---|---|
pIII: AEGEAN (NCT03800134) December 2018 [24] | IIA–IIIB | 740 | <Neoadjuvant> D or Placebo + PT-DC ↓ <Adjuvant> D or Placebo | NA | D + Chemo: 17.2% Chemo: 4.3% (p = 0.000036) | NA | Median EFS D + Chemo: NR [95% CI: 31.9–NR] Chemo: 25.9 m [95% CI: 18.9–NR] HR: 0.68 [95% CI: 0.53–0.88], p = 0.003902 | NA |
pIII: Neotorch trial (NCT04158440) April 2020 [47] | II–III | 404 | <Neoadjuvant> T or Placebo + PT-DC ↓ <Adjuvant> T or Placebo + PT-DC either single agent T or placebo | NA | T: 24.8% Placebo: 1.0% | T: 48.5% Placebo: 8.4% | EFS HR = 0.40 [95% CI: 0.277–0.565, p < 0.0001] | NA |
pIII: KEYNOTE-671 (NCT03425643) April 2018 [22] | II, IIIA or IIIB (N2) | 797 | <Neoadjuvant> P or PT-DC ↓ <Adjuvant> P or Placebo | NA | P: 18.1% placebo: 4.0% | P: 30.2% placebo: 11.0% | 24 m EFS P: 62.4% placebo: 40.6% HR = 0.58 [95% CI: 0.46–0.72, p < 0.001] | 24 m OS P: 80.9% placebo: 77.6% HR = 0.58 [p = 0.02, which did not meet the significance criterion] |
pII: NADIM (NCT03081689) April 2017 [44] | IIIA | 46 | <Neoadjuvant> N + PTX + CBDCA ↓ <Adjuvant> N | CR: 4% PR: 72% SD: 24% | 63% | 83% | PFS 12 m: 95.7% [95% CI: 83.7–98.9] 18 m: 87.0% [95% CI: 73.3–93.9] 24 m: 77.1% [95% CI: 59.9–87.7] | 12 m: 97.8% [95% CI: 85.5–98.7] 18 m: 93.5% [95% CI: 81.1–97.8] 24 m: 89.9% [95% CI: 74.5–86.2] |
pII: NADIM II (NCT03838159) May 2019 [48] | Resectable IIIA or IIIB | 86 | <Neoadjuvant> N +PTX + CBDCA or PTX + CBDCA ↓ <Adjuvant> N or follow up | N + Chemo: 75% Chemo: 48% RR: 1.56 [95% CI: 1.04–2.34] | N + Chemo: 37% Chemo: 7% RR: 5.34 [95% CI: 1.34–21.23] p = 0.02 | N + Chemo: 53% Chemo: 14% RR: 3.82 [95% CI: 1.49–9.79] | 24 m PFS N + Chemo: 67.2% Chemo: 40.9% HR = 0.47 [95% CI: 0.25–0.88] | 24 m OS N + Chemo: 85% Chemo: 63.6% HR = 0.43 [95% CI: 0.19–0.98] |
pII: SAKK 16/14 (NCT02572843) June 2016 [43] | IIIA (N2) | 67 | <Neoadjuvant> CDDP + DTX→ D ↓ <Adjuvant> D | CR: 7% PR: 52% SD: 26% PD: 7% | 18% | 62% | 12 m EFS 73% [two-sided 90%CI: 63–82] | Median not reached |
pIII: IMpower030 (NCT03456063) April 2018 [49] | II, IIIA, or select IIIB (T3N2) | 302 | <Neoadjuvant> A or Placebo+ PT-DC ↓ <Adjuvant> A or BSC/scheduled observational follow-up | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing |
pIII: CheckMate-77T (NCT04025879) November 2019 [50] | IIA–IIIB (T3N2 only) | 452 | <Neoadjuvant> N + CBDCA or PT-DC ↓ <Adjuvant> N | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing |
Phase: Trial Name (Registry ID) Study Start Date (Reference) | Target Stage | N | ICI | Response Rate | pCR Rate | MPR Rate | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|---|---|---|
pII: SQUAT trial (WJOG12119L) December 2019 [51] | IIA–IIIB (N2) | 30 | <Neoadjuvant> D + wPTX + CBDCA + Radiotherapy (50Gy2G × 25fr) ↓ <Adjuvant> D | PR: 47% SD: 47% PD: 14% PD: 6% | 23% [95% CI: 9–42] | 63% [95% CI: 44–80] | NA | NA |
pI: Cleveland Clinic Study (NCT02987998) May 2017 [53] | IIIA | 9 | <Neoadjuvant> P + CDDP + VP-16 + Radiotherapy (45Gy × 25fr) ↓ <Adjuvant> P | PR: 75% PD: 25% | 67% | NA | 6 m PFS 55.6% [95% CI: 31–99] | 3y OS 64%: [95% CI: 39–100] |
pII: The INCREASE trial (EudraCT-Number: 2019–003454-83) December 2019 [55] | T3-4 (N0–2) | 26 | <Neoadjuvant> [Day1] I + N + PT-DC + Radiotherapy * [Day22] N + PT-DC + Radiotherapy * | PR: 12.5% SD: 87.5% | 63% | 79% | NA | NA |
pIb: Yonsei University Study (NCT03694236) February 2019 [52] | III | 30 | <Neoadjuvant> D + wPTX + CBDCA + Radiotherapy (45Gy × 25fr) ↓ <Adjuvant> D | ORR: 50% | 41% | 74% | NA | NA |
pII: SAKK 16/18 (NCT04245514) July 2020 | IIA–IIIB (N2) | 90 | <Neoadjuvant> D + wPTX + CBDCA + Radiotherapy (2Gy × 20fr or 5Gy × 5fr or 8Gy × 3fr) ↓ <Adjuvant> D | Ongoing | Ongoing | Ongoing | Ongoing | Ongoing |
Phase: Trial Name Study Start Date (Registry ID) (Reference) | Target Stage | N | ICI | DFS/EFS PFS/RFS | OS |
---|---|---|---|---|---|
pIII: IMpower010 (NCT02486718) October 2015 [3,57] | IB (≥4 cm)–IIIA | 1005 | A vs. BSC | DFS in stage II–IIIA & PD-L1 TPS ≥ 1% HR = 0.66 [95% CI: 0.50–0.88, p = 0.0039] DFS in stage II–IIIA & PD-L1 TPS ≥ 50% HR = 0.47 [95% CI: 0.29–0.75] | OS in stage II–IIIA & PD-L1 TPS ≥ 1% HR = 0.71 [95% CI: 0.49–1.03, p = 0.067] OS in stage II–IIIA & PD-L1 TPS ≥ 50% HR = 0.43 [95% CI: 0.24–0.78, p = 0.0045] |
pIII: PEARLS/ KEYNOTE-091 (NCT02504372) November 2015 [4] | IB (≥4 cm) –IIIA | 1177 | P vs. Placebo | median DFS HR 0.76; [95% CI 0.63–0.91, p = 0.0014] | 3 y OS HR 0.87; [95% CI 0.67–1.15, p = 0.17] |
pIII: ANVIL (NCT02595944) July 2016 | IB (≥4 cm)–IIIA | 903 | N vs. Placebo | Ongoing | Ongoing |
pIII: BR31 (NCT02273375) February 2015 | IB (≥4 cm) –IIIA | 1360 | D vs. Placebo | Ongoing | Ongoing |
pIII: ALCHEMIST-IO (NCT04267848) June 2020 [57] | IB (T≥4 cm)– IIIA | 1263 | <Arm A> PT-DC ↓ ± PORT ↓ Observation <Arm B> PT-DC ↓ ± PORT ↓ P <Arm C> PT-DC + P ↓ ± PORT ↓ P | Ongoing | Ongoing |
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Fukuda, S.; Suda, K.; Hamada, A.; Tsutani, Y. Recent Advances in Perioperative Immunotherapies in Lung Cancer. Biomolecules 2023, 13, 1377. https://doi.org/10.3390/biom13091377
Fukuda S, Suda K, Hamada A, Tsutani Y. Recent Advances in Perioperative Immunotherapies in Lung Cancer. Biomolecules. 2023; 13(9):1377. https://doi.org/10.3390/biom13091377
Chicago/Turabian StyleFukuda, Shota, Kenichi Suda, Akira Hamada, and Yasuhiro Tsutani. 2023. "Recent Advances in Perioperative Immunotherapies in Lung Cancer" Biomolecules 13, no. 9: 1377. https://doi.org/10.3390/biom13091377