Lung Trials - AC Flashcards
Adjuvant
IMPower010
(Adjuvant NSCLC)
P: completely resected stage IB (tumours ≥4 cm) to IIIA NSCLC (AJCC 7), post adjuvant chemotherapy (1-4 cycles cis+pem/gem/doce/vin). Only 11% stage IB in the end, 41% stage IIIA
I: adjuvant atezolizumab (1200 mg every 21 days; for 16 cycles ~1 year) vs Placebo
O: Hierarchical testing,
Primary outcome of DFS in PDL1 >1% II-IIIA (HR 0·66, sig),
therefore moved to DFS overall II–IIIA population (median 42.3 vs 35.3 months,+ 7 months, 0·79, sig). OS immature.
Special notes: Driven by PDL1 positive, >50% (DFS 0.43) and >1% (0.66), with subgroup PDL1 <1% HR 0.97. Subgroups included small number Alk + (no benefit) and EGFR + (no benefit)
Safety: 93% any grade (71% of those on BSC), grade 3/4 22% (vs 12% BSC) - most common hepatitis (2%), CIP (1%).
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext
Adjuvant
KN091 (PEARLS)
(Adjuvant NSCLC)
P: resected (R0 resection) NSCLC IB (>4cm) to IIIA (AJCC7), post optional adjuvant chemotherapy (strongly recommended II or above, max of 4 cycles). 14% 1B, 29% IIIA
I: Pembro 200mg q3 week x 18 cycles (1 year) vs placebo.
O: **DFS positive for overall population (53.6 vs 42 month, +7.5 month, 0.76). **
Note: Subgroups quite random, PDL1 status did not impact, nearther did stage with IIIA getting ?least benefit. Does not match other trials, felt to be statistical noise at present
Note: Pending funding, likely not to be preferred over IMPower010 at present
KN671
(Periop NSCLC)
P: resectable stage II, IIIA, or IIIB (N2 stage), AJCC8
I: Neoadjuvant pembro 200mg q3 or placebo plus 4 cycles neoadjuvant chemotherapy, surgery within 20 weeks of therapy start, Adjuvant (4-12 weeks post) pembro 200mg q3 or placebo up to 13 cycles (for 17 total).
C: Placebo
O: EFS at 24 month 62% vs 40% (0.58), OS maturing, pCR 30% vs 11% after the neoadjuvant portion
Safety: Gr3/4 45% vs 37%.
Other: R0 resections in 92% vs 84% (favour pembro). ~balanced nonsquamous (56) and squamous (43). More benefit in Stg III and PDL1 positive
First results reported in March 2023, right at cutoff, probably won’t be asked. I have not included other peri-op IO trials, ie: Aegean (Peri-op Durva, PDL1 like atez) or Neotorch (periop Toripallimimab, PD1) as they were only presented at ASCO 2023 to my knowledge. Latter is interesting as it was 77% sqaumous.
CM816
(Neoadj NSCLC)
P: Stage IB (4cm) to IIIA RESECTABLE NSCLC (AJCC 7) that were EGFR and ALK negative
I: Neoadjuvant Nivolumab 360mg plus chemotherapy q3 weeks x 3 cycles platinum based chemotherapy, vs neoadjuvant chemotherapy alone x 3, followed by surgery within 6 weeks. Adjuvant chemotherapy was optional.
C: Placebo
O: primary end points were event-free survival and pathological complete response. **pCR rate 24% vs 2.2%, mEFS 31.6 vs 20.8 (+11mo, 0.63). **
Safety: Gr3/4 33.5% vs 36.9% (chemo alone)
Note: Important, these patients were all judged up front resectable, NOT a trial of downsizing for borderline resectable/unresectable stage III tumours (those should get CRT per PACIFIC)
Note: Driven by PDL1 >1% (0.41, vs 0.85 for <1%) at stage IIIA (0.54), vs IB-II (0.87). 83.2% vs 75.4% of nivo vs placebo went for surgery, surgical outcomes equal or favour nivo (BUT compared to neoadjuvant chemotherapy, which is NOT prev SOC, up front surgery is) - those who didn’t reach surgery split between irAE, progression on therapy and logistical reasons/choice.
https://www.nejm.org/doi/full/10.1056/NEJMoa2202170
NADIM II
(PeriOp NSCLC)
P: resectable stage IIIA-IIIB NSCLC
I: Neoadjuvant nivolumab plus platinum-based chemotherapy (experimental group) or chemotherapy alone (control group), followed by surgery. Patients in the experimental group who had R0 resections received adjuvant treatment with nivolumab for 6 months.
C: Placebo
O: pCR 37% vs 7%, PFS at 24 month 67% vs 41% (+26%, 0.47), OS at 24 months 85% vs 64% (+11%, 0.43). 93% of the nivo group recieved surgery vs 69% in control (!!)
Safety: Gr 3/4 19% vs 10% (?very low??)
Other: NOTE differences vs CM816, periop with 6 months adjuvant, and ALL stage III (no earlier stages). Surgical rates were very difference between arms. This is the only Periop/Neoadjuvant trial with published significant OS data at present (trends in others).
https://www.nejm.org/doi/full/10.1056/NEJMoa2215530
ADURA
(Adjuvant NSCLC)
Phase III
P: nonsquamous NSCLC with postsurgical pathological stage IB, II, or IIIA; and a centrally confirmed EGFR mutation (Ex19del or L858R), either alone or in combination with other EGFR mutations) on examination of tissue. R0 resections only. ADJUVANT Chemo was optional.
I: Adjuvant osimertinib (80 mg once daily) or placebo for up to 3 years
C: Placebo
O: Primary outcome of **DFS in stage II/IIIA median NR vs 20.5months (HR 0.17, highly significant), ** while secondary DFS in full IIT also significant 0.21). OS newly reported 2023 ASCO (unlikely asked), at 5 years IIA to III 85% vs 73% (0.49, sig), full pop also significant. Also 82% reduction in CNS disease recurrence or death.
Safety: Adverse events in 98% vs 89%, grade 3 20% vs 13%. 11% of osimertinib group discontinued due to adverse events by 2 years.
Other: Outcomes (OS) did not differ significant with or without adjuvant chemotherapy; as chemotherapy was NOT randomized, and likely recieved by higher risk pts, most have taken this to mean still try to give adjuvant chemo x 4 cycles first to elligible patients if can, but is not mandatory.
Other: First successful adjuvant targeted therapy trial, multple attemps with 1st/2nd gen EGFRi (RADIANT erlotinib 2 years, BR. 19 gefitinib 2 years, SELECT erlotinib 2 years) all failed, with early PFS seperation then quick joining of curve on/once off therapy.
https://www.nejm.org/doi/10.1056/NEJMoa2027071?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
PACIFIC
(NSCLC curative)
P: histologically or cytologically documented stage III, locally advanced, unresectable NSCLC (AJCC 7), post 2+ cycles of CRT (platinum-based doublet concurrent with 54-66Gy RT, ~60Gy over 30#, no more then 35% of the lung could recieve 20Gy)
I: Duralumab 10mg/kg q2 vs placebo for up to 12 months. Start within 1-42 days of CRT completion.
O: Original pub co-primary outcome of median PFS 16.8 months vs 5.6mo (+11 months, 0.52), ~50% reduction progression/death. Update at ESMO 2020 was mOS 47.5 vs 29 months (0.72), with 45% alive at 5 years.
Safety: Gr3/4 30% durva vs 26% placebo, 15.4% of durva discontinued due to AE. Most common reason for discontinuation was pneumonitis, in 4.8% vs 2.6% placebo group.
Note: Balanced IIIA (52%) and IIIB (45%), squamous (47%) and non-sq (53%). Most common doublet cis partners were etop (22%), vin (16%), doce (5%), pem only 2%. Most common carbo (40%) partners were taxol (33%), while only 1.5% got pem. Take home: Pem is not the most common partner, even for adeno, and many would save it for recurrence, using carbo/taxol or cis/etop or vin.
https://www.nejm.org/doi/full/10.1056/nejmoa1709937
LACE Metanalysis
(NSCLC adjuvant)
Published in 2008, combined 5 recent adjuvant chemotherapy trials for 4584 patients: IALT (stage I-III NSCLC adjuvant cis/vin or etop, 4% OS benefit at 5yrs over surgery alone), BR.10 (IB-II, cis/vin, 15% OS benefit at 5yrs), ANITA (IB-IIIA, cis/vin, 10% OS benefit) and CALGB (stage IB/T2N0 only, carbo/taxol, DFS beneefit only overall, but if >4cm then 5-7% OS benefit).
LACE results: overall survival benefit of 5.4% from adjuvant chemotherapy at 5 years (HR 0.89, driven by 6.9% reduction in lung cancer death balanced by a small increase in death from other causes). Stage IA did not benefit (1.40), IB was non-sig (0.93, >4cm benefited in individual trials), II/III 0.83 (sig). Interpretation is to recommend adjuvant chemotherapy for primary tumours IB if >4cm, and all stage II/IIIs who are resected.
JIPANG
(NSCLC adjuvant)
P: Resected II-IIIA non-squamous NSCLC (AJCC 7), 3-8 weeks post-operative.
I: Adjuvant cis 75mg/m2 + pemetrexed 500mg/m2 x4 vs cis (80mg/m2) plus vin (25mg/m2 d1/8) x 4.
O: Superiority design, primary outcomes mRFS and OS both equal (0.98), negative trial. However, less toxicity (grade 3 neutropenia) with cis/pem.
Note: Cis/Pem is most commonly used adjuvant chemotherapy for adenocarcinoma
RTOG 9410, Curran et al 2011
(Role RT in locally advanced NSCLC)
P: Stage III NSCLC unresectable
I: 3 arm trial with two experimental arms. Arm 2: Cisplatin/ vinblastine for 5 weeks with RT daily fractions starting day 1 (concurrent chemoRT), Arm 3: cisplatin lower dose weekly/ etoposide daily x 10 weeks with RT twice daily fractions beginning on day 1 (hyperfractionated)
C: Arm 1: Sequential CRT with cis/vinblastine
O: mOS Arm 1:15 months, Arm 2: 17 months, Arm 3: 16 months - ie: concurrent > sequential, hypofractionation didn’t help
Auperin metanalysis 2010
Locally advanced NSCLC
6 trials of concurrent vs sequential CRT in unresectable locally advanced NSCLC, 5.4% absolute benefit at 3 years favouring concurrent (0.84 HR for death), and 4.5% benefit at 5 years maintained
SWOG 9019
(JCO 2002, locally advanced lung cancer)
P: Phase II single arm stage IIIB
I: Concurrent chemoRT with cis/etoposide x 2, then definitive RT and consolidative cis/etoposide x 2
O: mOS of 15 months, proved feasibility and safety of cis/etop with CRT
Note: Cis 50mg/m2 day 1, 8, 29 and 36, Etop 50mg/m2 day 1-5, 29-33. Post-RT, another two consolidation CT cycles (no longer included).
Liang et al.
(2017, locally advanced lung cancer)
P: Phase III, Stage III NSCLC unresectable
I: Weekly Carbo (AUC 2) and Pacitaxel (45mg/m2) concurrent with RT
C: cis/etop concurrent with RT
O: Primary endpoint OS, 3 yearOS higher in cis/etoposide arm (41 vs 26%, 15% difference), trend towards improved mOS with cis/etop 23 vs 21 mo
Safety: Cis/etop higher toxicities, esp gr3/4 esophagitis (20.0% versus 6.3%).
Note: Along with prior studies, Beloni et al 2005, established CRT with carbo/taxol - some favour cis/etop given 3 year data, others favour carbo/taxol for toxicities given real world population.
Note: Phase III data, establishes both regimens WITHOUT consolidative chemotherapy (post-CRT cycles given in older trials)
PROCLAIM
(2016, locally advanced lung cancer)
P: Phase III Stage IIIA/B nonsquam NSLCLC
I: Concurrent cis 75mg/m2 + pemetrexed 500mg/m2 q 3 weeks x 3 cycles with RT (66Gy, 33 fractions) then 4 cycles consolidation pem
C: Concurrent cis 50mg/m2 d1/8 + etop 50mg/m2 d1-5 q4 x 2 cycles with RT (same dose as experimental) then consolidation 2 cycles
O: Superiority trial, primary outcome negative for OS, 5 yr OS 27% vs 20%, OR 0.63, median 26.8 vs 25 (~2 years). Small PFS benefit was seen (5 year PFS 22% vs 11%).
Safety: favoured cis/pem, Gr3/4 64% vs 76.8% (driven by 20.6% esophagitis with cis/etop and 44.5% neutropenia, compared to 15.5 and 24.4 with pem). Many have adopted cis/pem for adeno CRT based on this, other choices also reasonable.
KN024
(Metastatic NSCLC)
P: Phase III PDL1 > 50% 1st line, squam AND nonsquam mNSCLC
I: Pembro 200mg (flat dose) q3 week
C: Platinum doublet
O: Primary endpoint PFS, mPFS 10.3 mo vs 6.0 mo (HR 0.50). Secondary: ORR 45 vs 28%, mOS 30 vs 14.2 mo (HR 0.62)
Safety: Pembro better tolerated, gr3-5 31.2% v 53.3%.
IMPower110
(met NSCLC)
P: Phase III PDL1 >1% 1st line mNSCLC all histologies, first line
I: Atez 1200mg q3
C: Platinum doublet
O: Subgroup EGFR and ALK wild-type tumors PD-L1 >50% (205 patients), + 7.1 OS with atez (20.2 months vs. 13.1 months, 0.59; P=0.01). Smaller difference in PDL1>5%, 18.2 vs 14.9 (0.72)
Note: All atez regimens not funded in Canada NSCLC
Note: confusing with IMPower010 being the adjuvant study, NB
