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.
FLAURA
(Met NSCLC, 2018)
P: 1st line mutated EGFR (exon19/L858R)
● Stable CNS mets allowed
● Also stratified based on race
● Randomize 1:1
I: Osimertinib 80 mg daily
C: Gefitinib/ erlotinib
O:
● Primary endpoint PFS
● mPFS 18.9 m vs 10.2 mo (HR 0.46)
● RR 80% vs 76% (not significant)
● Improved duration of response
● At 58% maturity- mOS 38.6 mo vs 31.8 mo (HR 0.80, +7 months)
Note: Grade 3 tox lower, Response
improved whether CNS mets or not
IPASS
(2009)
P: 1st line with clinical EGFR+ phenotype (adeno, non-smoker/light smoker, trial in East Asia population) - results
of EGFR+ vs mutation negative
I: Gefitinib 250 mg daily
C: Carbo/ taxol
O:
EGFR mutant:
● Primary endpoint mPFS, 9.6 vs 6.3
months (HR 0.48)
● RR 71% vs 47%
No OS difference
EURTAC
(2012)
P: 1st line EGFR mut (del 19, L858R)
I: Erlotinib 150 mg
C: Platinum doublet
O:
● Primary endpoint PFS
● RR 58 vs 15%
● mPFS 9.7 vs 5.2 mo
(HR 0.37)
mOS was not significant due to 60% cross-over
LUX-Lung-3
P: 1st line EGFR mutations
I: Afatinib 40 mg
C: Cis/Pem
O:
● Primary endpoint PFS, mPFS 11.1 vs 6.9 months (HR 0.58)
- Common mutations (Del19/L858R), median PFS was 13.6 vs 6.9 months
● RR 56% vs 23%
No OS difference
Note: Reterospective analysis of Lux-Lung 2/3/6 for uncommon mutations showed RR 71%, as a result Afatinib is only EGFRi approved for uncommon mutation in Canada
LUX-Lung 7 (2016)
P: 1st line EGFR common mutations
I: Afatinib 40 mg
C: Gefitinib 250 mg
O:
● Primary endpoint PFS
● mPFS 10.9 vs 11mo (HR 0.75) NS
● mOS was 27.9 vs 24.5 mo (NS)
Disease outcomes trend modestly improved, but more toxicity
ARCHER 1050 (2018)
P: 1st line EGFR common mutations - CNS mets excluded
I: Dacomitinib 45 mg
C: Gefitinib 250 mg
O:
● Primary endpoint PFS
● mPFS 14.7 vs 9.2 (HR 0.59)
● mOS 34.1 vs 26.8 mo (HR 0.76)
Note: improved outcomes, but hard to tolerate and rarely used/no clear niche in 2023 - Grade 3-4 dermatitis, diarrhea more common
AURA3 (2016)
P: 2nd line T790M mutation, ~30% with CNS
mets
I: Osimertinib 80mg
C: Platinum/ peme
O:
● Primary endpoint PFS
● RR71vs31%
● mPFS 10.1 vs
4.4 mo (HR 0.3)
● mOS 26.8 mo vs 22.5
mo (HR 0.87)- non significant, high crossover rate
Safety: Better tolerated then chemo
Bloom
P: Phase II, enrolled patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy.
I: Osimtertinib at double dose (160mg) - idea was to improve CNS concentration
C: Single arm
O: ORR neuroradiologic BICR were 62% (95% CI, 45% to 78%) and DOR 15.2 months (95% CI, 7.5 to 17.5 months), respectively. Overall, ORR by investigator was 41% (95% CI, 26% to 58%), and median DoR was 8.3 months (95% CI, 5.6 to 16.5 months). Median investigator-assessed PFS was 8.6 months (95% CI, 5.4 to 13.7 months) with 78% maturity; median OS was 11.0 months (95% CI, 8.0 to 18.0 months) with 68% maturity.
Note: Doubling dose is an option for progressing CNS disease on osimertinib, tolerance needs monitoring closely. RT low threshold
ALEX (2017)
P: First line NSCLC with Alk translocation
I: Alectinib 600mg BID
C: Crizotinib
O:
● Primary outcome PFS, mPFS 34.8 mo vs 10.9 mo (HR 0.43)
● RR 72vs 61%
● Intracranial RR 81% vs 50% (HR 0.32)
● 5 year OS data still immature in May 2020 update (37% of events recorded)- but thus far alectinib 62.5% vs 45.5% (HR 0.67)
Safety/Notes: ● Patients with brain mets had
significant benefit compared to crizotinib
● Less frequent grade 3/4 toxicities with alectinib
Note: J-ALEX in Japanese patients showed 300mg BID = 600mg BID in Asian pop; many will have low threshold to lower dose in Asian patients for toxicities.
Profile 1014 (2016)
P: First line Alk translocation NSCLC
I: Cirtoztinib 250mg
C: Cis/Carbo+Pem
O: PFS 10.9 vs 7 months (0.45), RR 74% vs 41%, OS NR vs 47.5 month (NS, LOTS of crossover)
ASCEND-4 (2017)
P: Phase III 1st line ALK positive
I: Ceritinib 750 mg BID
C: Cis/ carbo-pem
O:
● Primary endpoint PFS, mPFS 16.6 mo vs 8.1 mo (HR 0.55)
● RR 73% vs 26%
Note: Later ASCEND-8 showed reduced dose with food (450mg) prolonged PFS and reduced toxicities
CROWN (2020)
P: 1st line ALK pos
I: lorlatinib
C: Crizotinib
O:
● Primary endpoint PFS, mPFS not reached vs 9.3 mo (0.28, highly significant)
● RR 76 vs 58%
● Intracranial RR 82 vs 23%, 71% had intracranial complete response
● 12 month OS immature (0.72, trending apart)
Note: Very effective due to CNS pen, but significant neuropsychiatric side effects, neuropathy, hypertrig and other metabolic side effects, need careful monitoring and prompt treatment/dose reduction
Solomon et al., Lancet 2018
P: Phase II with subset of ALK pos patients previously treated with ≥1 ALK inhibitor
I: Lorlatinib 100 mg daily
C: Single Arm
O:
● Primary endpoint overall and intracranial RR
● ORR was 47%, CRv2%, PR 45%
● Intracranial RR 63%
● Post crizotinib (vs other later gen TKIs), ORR 73%, mPFS 11.1 mo
Shaw, NEJM, 2014
P: ROS1 positive NSCLC, expansion cohort from Phase I, first and second line patients
I: Crizotinib 250mg BID
C: Single Arm
O: PFS 19.2 months, RR 72$, DOR 24.7 months, median OS 51 months!
Note: Other ROS TKI is Entrectinib, combined analysis of ALKA-372-001, START RK-1/2 showed remarkably similar RR (77%, DOR 24.6), but better CNS activity expected from NTRK data. Loralatinib also has activity, not funded.
Planchard et al, 2017
P: BRAF V00E mut NSCLC
I: Dabrafenib 150mg BID plus Trem 2mg daily
C: Single Arm
O: PFS 14.6 with ORR 64% in original publication, 2020 updated OS showed 18.2 months if prior therapy, 17.3 months for treatment naive (ie: no difference 1st or 2nd line).
Note: pCORD recommended, but not yet funded
CODEBREAK 200
After Phase I/II Codebreak 100 showed promising activity, phase III Codebreak 200
P: KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.
Note: Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation, previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation.
I: sotorasib (960 mg once daily)
C: intravenous docetaxel (75 mg/m2 once every 3 weeks)
O: met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months vs 4·5 months; hazard ratio 0·66). No OS reported, no funded.
