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
IMPower130/150
(Met NSCLC)
Similar IO+chemo trials of first Chemo (Carbo/Nab-paclitaxel) with Atez and/or Bev. 130 evaluated Chemo +/- Atez, 150 evaluated three reigmens of Carbo/nP +/- Atez +/- Bev (ACP, BCP and ABCP)
P: Chemotherapy-naive patients with metastatic nonsquamous NSCLC
I: As above
O:
In 130, mOS 18·6 in ACP, vs 13·9 months with CP alone (0·79, PFS also improved).
In 150, adding Bev did not improve OS vs ACP alone (ie: ABCP similar OS to ACP, around 19 months).
Important Subgroup: In the EGFR mutation subgroup, the quadruplet (ABCP) improved OS vs BCP (NE ABCP vs 18·7 months, 0·61), a difference not seen with ACP alone. Speculated that VEGFi may sensitize EGFRi to IO (consistent lack of response in IO trials), but only a subgroup. The Liver met subgroup also had improved OS with ACBP vs ACP.
NB: No atez regimen is currently reimbursed
KN189
(Met NSCLC)
P: Phase III previously untreated metatstatic Non-squam NSCLC, any PDL1
I: Pembrolizumab + cis/carbo + pem Q3wk x 4 then maintenance pembro/pem max 2 years
C: Placebo in place of Pem
O: Primary endpoint PFS and OS. Updated OS 22 vs 10.7 mo (HR 0.56), mPFS 17 vs 9 mo (HR 0.49). PDL1 hi subgroups benefited most, approved for all PDL1 expression
Safety: Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups.
KN407
(Met NSCLC)
P: Phase III, stage IV squamous, stratified PDL1 < 1% and 1%+
I: 200 mg of pembrolizumab q3w x up to 35 cycles
C: saline placebo
O: Dual primary endpoints: OS and PFS, exploratory endpoint based on PDL. OS: 17.1 vs 11.6 months, HR 0.71. PFS: 6.4 vs 4.8 months, HR 0.56. OS consistent
regardless of PDL1 expression.
Safety: Similar. Gr3/4 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group.
S
CM9LA
(Met NSCLC)
P: Phase III PS 0-1, stage IV or recurrent NSCLC, 1st line, sq (1/3) or NSq (2/3rds)
I: Nivo (360mg q3w)/ipi (1mg/kg q6w)/plat doublet q3w x 2 cycles, then IPI AND NIVO both given as maintenance until progression
C: Platinum Doublet chemotherapy alone x 4
O: mOS 15.6 vs 10.9 (0.66), PFS also prolonged. Consistent across PDL1 groups and histologies.
Safety: Grade 3–4 (47%) vs (38%) at 13.2 months median follow up (hence differences vs KN trials above etc)
Note: Some experts note the lack of early drop off vs chemotherapy, and a longer ‘tail’ of the survival curve, and the particular benefit seen in ECOG 0 and asyx CNS met subgroups. Approved in Canada, hard to find a fit enough but high risk patient, clinically uncommon to use.
CM227
(Met NSCLC)
P: Phase III, advanced or recurrent NSCLC
I: Nivo/ipi or Nivo alone
< 1% they got nivo/ipi, nivo/chemo
C: Platinum doublet
O: PD-L1 > 1% mOS 17.1 with nivo/ipi vs 14.9 with chemo , 2-year OS 40.0% and 32.8%, respectively. Median duration of
response 23.2 mo with nivo/ipi vs 6.2 months with chemo. PD-L1 < 1%, with a median duration of 17.2 mo nivo/ipi vs 12.2 mo with chemo. **Among all the patients in the trial, the median duration of overall survival was 17.1 Nivo/Ipi vs 13.9 months with chemotherapy. **
S: Similar, grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.
NB: Approved for any PDL1 status, but no clear niche for this regimen unless patient fit but refusing chemotherapy. Nivo arm results not highlighted.
KN010
(Met NSCLC)
P: PDL1 >1% NSCLC (any histology), post platinum doublet, no prior IO
I: Pembro 2mg/mg q3 week
C: Docetaxel
O: OS benefit seen, well tolerated
Not funded
CM057
P: Non-sqaumous NSCLC, post platinum doublet, no prior IO
I: Nivolumab
C: Docetaxel
O: OS beneift observed, 12.2 vs 9.4 months
(0.75), 1 year OS 50% vs 39%. No mPFS difference
Safety: 10% gr3/4 vs 54% with Doce
NB: Technically approved/funded for all NSq NSCLC in second line or later, including EGFRmut - controvertial whether to trial this, given consistent lack of benefit across IO studies
TAX317
P: NSCLC post-Plat chemotherapy
I: randomized to receive either docetaxel 100 mg/m2 (D100) or 75 mg/m2 (D75) intravenously every 3 weeks,
C: best supportive care (BSC).
O: Median survival was 9.0 months with D75 versus 4.6 months for BSC (P = 0.016); 1-year survival was 40% for D75 versus 16% for BSC (P = 0.016). Only 8% response rate with D75, all PR. No benefit to D100.
Conclusion: Quality-of-life analysis showed significant improvement in several disease-related symptoms in patients who received docetaxel.
