ASCO 2024 Updates in Lung Cancer

31 May - 4 Jun, 24

ASCO 2024

Chicago, IL

31 May - 4 Jun, 24

ASCO 2024

Chicago, IL

Lorlatinib Versus Crizotinib in Patients with Advanced ALK-Positive Non–Small Cell Lung Cancer: 5-Year Outcomes from the Phase III CROWN Study

Background

Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non–small cell lung cancer (NSCLC) in the phase III CROWN study.

Aim

To report long-term outcomes from CROWN after 5 years of follow-up.

Methods

296 patients with ALK-positive NSCLC were randomly assigned 1:1 to receive-
1. Lorlatinib 100 mg once daily (n = 149)
2. Crizotinib 250 mg twice daily (n = 147)
Efficacy outcomes, safety, and biomarker analyses.

Results

Lorlatinib vs Crizotinib:

Median follow-up - 60.2 and 55.1 months
mPFS - Not reached (95% CI, 64.3 to NR) vs 9.1 months (95% CI, 7.4 to 10.9) (HR 0.19 [95% CI, 0.13 to 0.27]
5-year PFS - 60% (95% CI, 51 to 68) vs 8% (95% CI, 3 to 14)
Median time to intracranial progression - NR (95% CI, NR to NR) vs 16.4 months (95% CI, 12.7 to 21.9) (HR, 0.06 [95% CI, 0.03 to 0.12]).
Safety profile was consistent with that in prior analyses.
Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment.

Conclusion

After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA8503.

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Bevacizumab in Combination with Chemotherapy for Treating Patients with Advanced RET+ Non-small Cell Lung Cancer

Background

RET inhibitors (RETi) are currently the preferred first-line treatment in advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC).
Despite impressive efficacy of RETi, resistance is inevitable, and the optimal therapy beyond RETi remains unclear.
Immunotherapy has shown limited efficacy in these patients.

Aim

To investigate the impact of adding bevacizumab to chemotherapy regimens on treatment outcomes.

Methods

Multicenter, retrospective study
N= 185 patients with RET+ advanced NSCLC who received
1. Platinum-doublet chemotherapy (D) (+/-anti-PD-L(1) agents (ICB)) or
2. Non-platinum monotherapy (M), with or without bevacizumab (Bev)
Non-platinum agents were limited to pemetrexed, paclitaxel, or docetaxel. Only the first administration of the regimen was considered.
Objective responses (OR), progression-free survival (PFS), and overall survival (OS) from the start of treatment were compared between patients receiving and not receiving Bev.

Results

Of 185 patients
1. Patients received Bev in doublet chemotherapy (D+Bev, none with ICB) - 20
2. Patients did not receive Bev in doublet chemotherapy (D, 68 with ICB) - 165
Single-agent chemotherapy - 40 patients [with 8 on Bev (M+Bev) and 32 without (M)]
D+Bev patients were –
1. Younger (median age: 54 vs. 61 years, p=0.026)
2. Less often treated with RETi (55% vs. 79%, p=0.023)
3. With no other demographic or disease-related group differences
Median treatment line-
1. D+Bev and D - 1 [IQR 1-1]
2. M+Bev – 3
3. M - 2 (p=0.3)
Numerically more M+Bev patients had brain metastases (25% vs. 13%, p=0.6).
D+Bev vs D (+/-ICB)
1. OR - 55% vs 47% (p=0.7)
2. mPFS - 17 vs. 8.8 months, p=0.018
3. D+Bev still showed a significant advantage in mPFS compared to D+ICB (17 months vs 9.7 months, p=0.05).
4. mOS - 51.4 vs 38.7 months (p=0.89)
5. Multivariate analysis revealed that Bev use was independently associated with longer PFS (HR 0.4, p=0.01)
6. ECOG>1 (HR 4.3, p<0.0001) and male sex (HR 1.7, p=0.01) were associated with shorter PFS.
M+Bev vs M group
1. OR - 13% vs 25% (p=0.6)
2. mPFS - 2.4 vs 4.1 months (p=0.06)
3. mOS - 12.1 vs 39 months (p=0.06)

Conclusion

Bevacizumab with platinum-doublet chemotherapy seems to outperform platinum-doublet with or without ICB in progression-free survival. Prospective research is needed to evaluate the extent of bevacizumab's benefit for RET+ NSCLC.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No 8647.

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KRYSTAL-12: Phase 3 Study of Adagrasib versus Docetaxel in Patients with Previously Treated Advanced/Metastatic Non-small Cell Lung Cancer (NSCLC) harboring a KRASG12C Mutation.

Background

Adagrasib (ADA) is a potent covalent inhibitor of KRASG12C with favorable properties such as long half-life (23 h), dose-dependent pharmacokinetics, and brain penetrance.

In the phase 1/2 KRYSTAL-1 trial, ADA demonstrated deep and durable responses with promising PFS and OS in patients (pts) with previously treated KRASG12C-mutated NSCLC.

Aim

To report the primary analysis from KRYSTAL-12 (NCT04685135), a randomized, open-label phase 3 trial of ADA compared with docetaxel (DOCE) in pts with KRASG12C-mutated locally advanced or metastatic NSCLC who had previously received a platinum-based chemotherapy, concurrently or sequentially with anti-PD-(L)1 therapy.

Methods

N= 301 Pts with KRASG12C-mutated locally advanced or metastatic NSCLC, previously treated with platinum-based chemotherapy and anti-PD-(L)1 therapy, were randomized 2:1 to receive-
1. ADA (600 mg BID orally; tablet formulation) or
2. DOCE (75 mg/m2 Q3W IV), with the ability to crossover to ADA upon disease progression
Stratified by region [non-Asia Pacific vs Asia Pacific] and sequential vs concurrent chemoimmunotherapy)
No washout period was required between prior anti-PD-(L)1 therapy and study treatment.
Primary endpoint - PFS assessed per BICR according to RECIST v1.1
Secondary endpoints - ORR by BICR, duration of response (DOR), OS, 1-year OS rate, and safety.

Results

Baseline characteristics were generally similar between treatment arms.
Median follow-up - 9.4 mo (data cutoff 31 Dec, 2023)
ADA vs DOCE:
1. mPFS - 5.49 vs 3.84 mo (HR 0.58 [95% CI, 0.45–0.76]; P < 0.0001)
2. ORR - 31.9% [95% CI, 26.7–37.5] vs 9.2% [95% CI, 5.1–15.0]; OR 4.68 [95% CI, 2.56–8.56]; P < 0.0001);
3. Median DOR - 8.31 (95% CI, 6.05–10.35) vs 5.36 (95% CI, 2.86–8.54) mo, respectively.
4. Treatment-related adverse events (TRAEs) - 94.0% vs 86.4%
5. Grade ≥3 TRAEs - 47.0% vs 45.7%
6. TRAEs led to discontinuation - 7.7% vs 14.3%

Conclusion

In the phase 3 KRYSTAL-12 trial, ADA demonstrated a statistically significant and clinically meaningful improvement in PFS and ORR over DOCE in pts with previously treated KRASG12C-mutated NSCLC. Safety profile of ADA was consistent with previous reports and with no new safety signals. These results further support ADA as an efficacious treatment option for pts with previously treated KRASG12C-mutated locally advanced or metastatic NSCLC.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA8509.

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Randomized Double-blind Placebo-controlled Trial Evaluating Pregabalin for Chronic Cough in Patients with Lung Cancer.

Background

Chronic cough is a distressing symptom that detracts from the quality of life (QoL) of patients with cancer.
Developing effective therapies for cough is an unmet need, with no approved medicines available.

Aim

To assess the effect of neuromodulators like pregabalin that may act centrally as cough suppressants.

Methods

Randomized double-blind placebo-controlled study in the Department of Medical Oncology at Tata Memorial Hospital (Mumbai, India)
N= 166 patients with locally advanced/metastatic non-small-cell lung cancer (NSCLC) with at least 2 weeks history of moderate or severe cough.
ECOG PS 0-2
Creatinine clearance > 60 mL/min
Randomization was 1:1 to –
1. Pregabalin 300 mg orally daily or
2. Matching placebo, both administered for 9 weeks
Primary endpoint - Difference in cough severity as measured by Visual Analog Scale (VAS) after 9 weeks treatment
Secondary endpoints - Cough severity on day 7 and week 9 measured by VAS, and Manchester Cough in Lung Cancer Scale (MCLCS); side-effects, and QoL assessed by EORTC QLQ C30 and LC13. Means of the change from baseline scores were calculated for patients in each arm and compared between two arms.

Results

Median age - 56 years (IQR, 47-62.5)
Male - 112 (67.5%)
Metastatic NSCLC - 149 (89.8%)
Baseline cough severity –
1. Grade 2 - 127 (76.5%)
2. Grade 3 - 37 (22.6%)
Median cough duration - 163 days
The therapy was well tolerated in both arms, with no difference in grade > 3 toxicities between the two arms; P=0.908.
Systemic cancer-directed therapy was started in 95.2% and 91.4% of patients in the pregabalin and placebo arms, respectively; P=0.328.
Subjective improvement in cough reported by week 9 - 45 (57%) vs 40 (52.6%); P=0.846.
The mean VAS score (in mm) –

	Pregabalin	Placebo
Baseline	71.58	71.74	P=0.530
Day 7	45.32	46.23
Week 9	19.73	21.18

Cough assessment by mean MCLCS scores -

	Pregabalin	Placebo
Baseline	27.63	27.28	P=0.455
Day 7	23.49	23
Week 9	17.39	17.34

No significant difference in QoL between the two arms.
Mean LCCO (cough symptom question on QLQ LC13) score

	Pregabalin	Placebo
Baseline	75.9	66.3	P=0.150
Day 7	54.2	54
Week 9	36.4	31.4

Conclusion

Pregabalin does not lead to a significant decrease in cough in patients with lung cancer. Systemic cancer-directed therapy is the most effective antitussive therapy for cancer-induced cough.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No LBA12082.

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BEAT-SC: A Randomized Phase III Study of Bevacizumab or Placebo in Combination with Atezolizumab and Platinum-based Chemotherapy in Patients with Extensive-stage Small Cell Lung Cancer (ES-SCLC).

Background

Atezolizumab combined with carboplatin and etoposide is approved as first-line treatment for patients with ES-SCLC, based on results from the Phase I/III IMpower133 trial (NCT02763579).
The VEGF inhibitor bevacizumab (bev) is approved for the treatment of many tumor types and has synergistic effects when combined with atezolizumab, as demonstrated by the Phase III IMpower150 study (NCT02366143) in non-small cell lung cancer.

Aim

To evaluate the efficacy and safety of bev combined with atezolizumab and platinum-based chemotherapy in patients with ES-SCLC from Japan and China. Here, we report the primary analysis for progression-free survival (PFS) and the first interim analysis for overall survival (OS) from BEAT-SC.

Methods

N= 333 patients had measurable ES-SCLC, were aged ≥20 y (≥18 y for patients from China), ECOG PS 0/1 and had no prior systemic treatment for ES-SCLC.
Patients were randomized 1:1 to receive –
1. 4 cycles (21 days/cycle) of induction therapy with bev combined with atezolizumab + cisplatin or carboplatin + etoposide (ACE) followed by maintenance therapy with bev + atezolizumab or
2. Placebo combined with ACE followed by maintenance therapy with placebo + atezolizumab, respectively
Primary endpoint - Investigator-assessed PFS (INV-PFS).
Secondary endpoints - OS and safety.

Results

Median age - 65 y
Male - 82.6%
Patients from China - 57.7%
Patients received carboplatin - 91.8%
Current or former smokers - 87.6%
Data cutoff (June 30, 2023; median follow-up, 10.2 mo) bev + ACE vs placebo + ACE
Median INV-PFS - 5.7 mo vs 4.4 mo (HR, 0.70; 95% CI: 0.54, 0.90; P=0.0060)
mOS - 13.0 vs 16.6 mo for placebo + ACE (HR, 1.22; 95% CI: 0.89, 1.67; P=0.2212)
Bev + ACE was well-tolerated and treatment-related adverse events (TRAEs) were generally similar between treatment arms (Table).

n (%)	Bev + ACE (n=166)	Placebo + ACE (n=164)
All-grade AE	165 (99.4)	163 (99.4)
Any-grade TRAE^a	165 (99.4)	162 (98.8)
Grade 3/4 TRAE^a	142 (85.5)	141 (86.0)
Grade 5 TRAE^a	5 (3.0)	8 (4.9)
Serious TRAE^a	58 (34.9)	56 (34.1)
AE leading to study drug withdrawal	34 (20.5)	27 (16.5)
AE leading to study drug modification/interruption	127 (76.5)	119 (72.6)
TR-AESI^a	65 (39.2)	52 (31.7)

AESI, AE of special interest. ^aAEs related to any study drug.

Conclusion

BEAT-SC met its primary endpoint, demonstrating that the addition of bev to ACE significantly increased PFS vs placebo + ACE. OS data were immature at the first interim OS analysis, and the numerical OS improvement of bev + ACE was not shown vs placebo + ACE; OS follow-up will continue. No new safety signals were observed.

Reference

American Society of Clinical Oncology (ASCO) 2024 Congress. 31st May – 4th June 2024. Chicago, IL. Abstract No 8001.

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ADRIATIC: Durvalumab (D) as Consolidation Treatment (tx) for Patients (pts) with Limited-stage Small-cell Lung Cancer (LS-SCLC).

Background

The standard of care (SoC) for pts with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI).
ADRIATIC (NCT03703297), a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter, global study.

Aim

To assess D ± tremelimumab (T) as consolidation tx for pts with LS-SCLC who had not progressed after cCRT and report results for D vs PBO from the first planned interim analysis (IA).

Methods

N= 730 pts with stage I–III LS-SCLC (stage I/II inoperable) and WHO performance status 0/1, and had not progressed after cCRT.
PCI was permitted before randomization.
Pts were randomized 1–42 days after cCRT to
1. D 1500 mg + PBO, D 1500 mg + T 75 mg followed by D (D±T arms)
2. or PBO + PBO every 4 weeks (Q4W) for 4 cycles followed by PBO Q4W until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months (mo).
The first 600 pts were randomized in a 1:1:1 ratio; subsequent pts were randomly assigned 1:1 to D or PBO.
Randomization was stratified by stage (I/II vs III) and receipt of PCI (yes vs no).
Dual primary endpoints - OS and PFS (blinded independent central review per RECIST v1.1) for D vs PBO.
Alpha-controlled secondary endpoints - OS and PFS for D+T vs PBO.

Results

D vs PBO arms:
1. Radiation schedule once daily - 73.9% vs 70.3%
2. Radiation schedule twice daily - 26.1% vs 29.7%
3. Patients received PCI - 53.8% in each arm.
data cutoff for IA 15 Jan 2024
Median duration of follow-up - 37.2 (0.1–60.9) and 27.6 (0.0–55.8) mo
1. mOS - 55.9 [95% CI 37.3 – not estimable] vs 33.4 [25.5–39.9] mo (HR 0.73 [95% CI 0.57–0.93]; p=0.0104
2. 24-mo OS rate - 68.0% vs 58.5%;
3. 36-mo OS rate 56.5% vs 47.6%
4. mPFS -16.6 [95% CI 10.2–28.2] vs 9.2 [7.4–12.9] mo (HR 0.76 [95% CI 0.61–0.95]; p=0.0161;
5. 18-mo PFS rate - 48.8% vs 36.1%
6. 24-mo PFS rate 46.2% vs 34.2%)
Tx benefit was generally consistent across predefined pt subgroups for both OS and PFS.
Grade 3/4 all-cause adverse events (AEs) - 24.3% vs 24.2% of pts
AEs led to tx discontinuation - 16.3% vs 10.6%
AEs led to death - 2.7% vs 1.9%
Any-grade pneumonitis/radiation pneumonitis - 38.0% vs 30.2% (maximum grade 3/4 in 3.0% vs 2.6%).

Conclusion

D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT.