Zofia Piotrowska, MD:

The phase III PALOMA-3 study compared 1600 mg SC vs 1050 mg IV administration of amivantamab every week for 4 weeks and then every 2 weeks thereafter. In each arm, amivantamab was combined with 240 mg PO lazertinib. Enrolled patients (N = 418) had locally advanced or metastatic NSCLC with classic EGFR ex19del or L8558R mutations who had disease progression on or after both osimertinib and platinum-based chemotherapy.^16,17

The primary endpoint was pharmacokinetic noninferiority and key secondary endpoints were ORR (noninferiority), PFS (superiority), DoR, and safety.  OS was an exploratory endpoint in this trial.

Zofia Piotrowska, MD:
The arms in this trial were well balanced.^16,17 The median age of enrolled patients was 61-62 years, and approximately 67% were female. Enrolled patients had a median number of 2 prior lines of therapy, and 34% had a history of brain metastases.

Zofia Piotrowska, MD:
The PALOMA-3 study met its primary endpoint of pharmacokinetic noninferiority.^16,17 The pharmacologic outcomes were equivalent between SC and IV amivantamab. In addition, the response efficacy was comparable between the 2 formulations, with confirmed ORRs of 27% in both arms, which met the noninferiority criteria defined for this endpoint.

Of note, SC amivantamab showed some advantages. The median PFS was 6.1 months compared with 4.3 months for IV amivantamab (HR: 0.84; 95% CI: 0.64-1.10; P = .20). This did not meet superiority criteria, but the median PFS was numerically improved. In an exploratory analysis of OS, an improvement was observed with an HR of 0.62 (95% CI: 0.42-0.92; nominal P = .02) favoring SC over IV amivantamab. These findings, although secondary endpoints, provide intriguing insights.

Zofia Piotrowska, MD:
The administration time was much shorter with the SC formulation at <5 minutes vs 2-5 hours for the IV formulation.^16,17 There were higher rates of patient-reported satisfaction with the SC formulation with many rating the SC administration as convenient or very convenient compared with IV administration.

Overall treatment-emergent AEs were comparable between the 2 cohorts. Almost all patients (99%) had a treatment-emergent AE, 52% to 56% experienced a grade ≥3 treatment-emergent AE, and approximately 30% had a serious treatment-emergent AE. In the SC arm, 7 treatment-emergent AEs led to death, compared with 10 in the IV arm of the trial.

Zofia Piotrowska, MD:
Looking specifically at the different types of AEs, the main difference is seen in the bottom-right: IRRs occurred in 66% of patients with IV amivantamab, which is comparable with previous studies of this drug, and only 13% of patients who received SC amivantamab.^16,17 This serves as proof of concept that administering this drug subcutaneously mitigates IRR risk, significantly benefiting patients in terms of time, toxicity, chair time, and convenience.

However, when examining other AEs associated with amivantamab, including those related to EGFR inhibition such as paronychia, rash, and stomatitis, there was no difference between the 2 arms. Cumulative edema and hypoalbuminemia were also seen at similar frequencies in both formulations. Therefore, I think SC amivantamab is likely here to stay and although it reduces the risk of IRRs, it does not mitigate other AEs that require close monitoring.

Zofia Piotrowska, MD:
When we look more closely at the symptoms associated with IRRs, you can see in this tornado plot that they were much less common with SC amivantamab than with IV administration.

Venous thromboembolism (VTE) risk with the combination of amivantamab and lazertinib has been observed in previous studies. Prophylactic anticoagulation is recommended for patients treated with this combination for the first 4 months of treatment. In PALOMA-3, patients who received prophylactic anticoagulation had a lower risk of VTE, which is encouraging.^16,17 Of interest, in PALOMA-3 there was a slightly lower rate of VTE with the SC formulation of amivantamab compared with the IV formulation, regardless of prophylactic anticoagulation (14% vs 9%, respectively). Although we do not have a clear explanation for why the route of administration would affect VTE risk, this appears to be an additional benefit of SC amivantamab. However, anticoagulation prophylaxis will likely still be required.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Staying consistent with EGFR-mutated disease, we also saw the primary analysis findings from the WU-KONG1 study at ASCO 2024. WU-KONG1 is a phase II trial evaluating sunvozertinib, an EGFR TKI, in 184 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations previously treated, including with platinum-based chemotherapy.²⁰ Sunvozertinib, a promising TKI known for its potent CNS activity, was administered in a randomized dose-finding phase followed by expansion at the optimal dose. Patients were initially randomized to receive either 200 mg/day or 300 mg/day, with subsequent expansion focusing on the 300 mg/day dose. The analysis, which included 111 patients from the expansion cohort, had the primary endpoint of ORR by independent review committee and secondary endpoints DoR by independent review committee and investigator-assessed ORR.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The study population consisted mostly of patients with metastatic disease (96.0%), 60.7% of enrolled patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, and 23.7% presented with baseline brain metastasis. All participants had previously undergone platinum-based chemotherapy for advanced NSCLC. In addition, 48.6% had received prior immunotherapy, and 13.1% had been treated with amivantamab or an EGFR TKI.²⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Among the patients with available response data, ORR was 53.3%, with confirmed ORR of 44.9%, which is very exciting in this heavily treated population.²⁰

Of note, patients who were previously treated with amivantamab, an EGFR and MET–targeting antibody, showed a comparable response rate to those without prior amivantamab treatment (50.0% vs 53.8%). These results support the use of sunvozertinib, independent of prior amivantamab treatment, and this advancement is very exciting.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Only 6% of patients discontinued treatment because of AEs, whereas approximately 36% required dose reductions. AEs were predominantly mild to moderate, with the most frequent being grade 1/2 and generally manageable. The primary AE reported was diarrhea, affecting 17% of patients.²⁰

Zofia Piotrowska, MD:
At ASCO 2024, there was a dedicated session focusing on KRAS-mutated NSCLC. Among the interesting data presented were the results of KRYSTAL-12. This was a randomized phase III confirmatory study of patients with advanced or metastatic KRAS G12C–positive NSCLC who had received prior immunotherapy and platinum chemotherapy.²³ Patients (N = 453) were randomized 2:1 to receive either adagrasib 600 mg twice daily or the control arm of docetaxel 75 mg/kg every 3 weeks. Crossover was allowed from the docetaxel arm at disease progression.

The primary endpoint of the study was PFS, and the secondary endpoints were ORR, DoR, OS, safety, and patient-reported outcomes.

Zofia Piotrowska, MD:
Baseline characteristics were well balanced between the arms of this trial. The median age of patients in the adagrasib arm was 64 years compared with 65 years in the docetaxel arm. Most of enrolled patients were male (64% vs 72%, respectively) and from the non-Asia/Pacific (74%). Histology was mostly adenocarcinoma (94% vs 97%) and more than three quarters of patients were former smokers (76% vs 74%) who previously received concurrent chemoimmunotherapy (73%).²³

Zofia Piotrowska, MD:
KRYSTAL-12 was a positive study. Median PFS with adagrasib was 5.5 months vs 3.8 months with docetaxel, with a PFS HR of 0.58 (95% CI: 0.45-0.76; P <.0001). At the 6-month landmark, 45% of patients remained progression free compared with 30% of those treated with docetaxel.²³ These are exciting data, but compared with outcomes in ALK-positive and EGFR-positive lung cancers, there is still room for improvement. Although these data are promising, I hope for even greater benefits for patients with KRAS mutations in the future.

Zofia Piotrowska, MD:
When we look at PFS by subgroup, all patients benefited from adagrasib compared with docetaxel, regardless of PD-L1 status, presence of brain metastases, and other factors.²³

Zofia Piotrowska, MD:
Tumor response was higher in patients treated with adagrasib compared with docetaxel. We observed a response rate of 32% in the adagrasib arm vs 9% in the docetaxel arm, which aligns with expectations for second-line docetaxel and beyond. The median DoR was longer for adagrasib at 8.3 months compared with 5.4 months for docetaxel.²³

CNS activity is important for patients with advanced and metastatic disease, and we have some data on intracranial activity with adagrasib. For patients with baseline CNS metastases, the intracranial ORR was 24% with adagrasib and 11% with docetaxel, indicating some activity, although slightly lower than with systemic activity.

In the cohort of patients with CNS evaluable metastases, 25 patients in the adagrasib arm and 9 patients in the docetaxel arm had CNS evaluable disease. The intracranial ORR with adagrasib was 40% compared with 11% in the docetaxel arm. This is encouraging, but we must consider the small sample size and remain cautious until larger datasets provide a clearer understanding of the overall CNS activity of adagrasib.

Zofia Piotrowska, MD:
Of note, approximately 48% of patients in the adagrasib arm required dose reduction because of treatment-related AEs, and 59% needed dose interruption. Common AEs in the adagrasib arm included diarrhea, nausea, vomiting, and elevated aspartate aminotransferase and alanine aminotransferase levels. Most of these AEs with adagrasib were low-grade, with relatively few grade ≥3 AEs, but they can still be troublesome for patients. In addition, 23% of patients in the adagrasib arm reported decreased appetite. There were also higher rates of increased blood creatinine in the adagrasib arm compared with the docetaxel arm (21% any grade vs 1% any grade). It is important to closely monitor patients for gastrointestinal toxicities and liver function test abnormalities when starting treatment with adagrasib.²³

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Next, we discuss the EVOKE-01 trial. This was a global, multicenter, open-label phase III trial comparing sacituzumab govitecan with docetaxel in patients with previously treated advanced NSCLC.²⁵ Patients (N = 603) were enrolled following chemotherapy and treatment with an anti–PD-1 or PD-L1 agent, with those having oncogene-driven tumors receiving ≥1 approved targeted therapy. Eligible patients were required to have ECOG PS 1/2 and no brain metastasis.

Patients were randomly assigned to receive either sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 every 21 days or docetaxel 75 mg/m² IV on Day 1 every 3 weeks. The study’s primary endpoint was OS, and secondary endpoints included PFS, ORR, DoR, disease control rates, safety, and quality-of-life assessments. For this analysis, the median follow-up period was 12.7 months.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Baseline characteristics in the arms of this trial were well balanced. Just less than one half of patients had received 2 or 3 or more lines of therapy, and approximately 12% had a history of brain metastasis. Approximately 27% had squamous subtype and 7% had oncogene addicted tumors.²⁵

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Although the primary endpoint of OS did not show a statistically significant difference between the 2 treatment arms, patients receiving sacituzumab govitecan trended toward better outcomes compared to those treated with docetaxel. The median OS was 11.1 months vs 9.8 months, respectively (HR: 0.84; 95% CI: 0.68-1.04; 1-sided P = .0534).²⁵ This was not statistically significant as the observed P value needed to be below 0.02 because of the 1-sided nature of the test. However, the 12-month OS was numerically higher in the sacituzumab govitecan group at 47% compared with 37% with docetaxel.²⁵

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
OS was similar across different subgroups, with a slight advantage in patients with squamous histology compared with those with nonsquamous histology, but this difference was not statistically significant.²⁵

No subgroup demonstrated a statistically significant and clinically meaningful benefit. A potential exception might be patients who did not benefit from their most recent immunotherapy regimen, although it remains unclear what that means clinically.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The median PFS was comparable between both treatment arms, at 4.1 months for sacituzumab govitecan compared with 3.9 months for docetaxel. ORR was 13.7%, with sacituzumab govitecan and 18.1% with docetaxel. Disease control rates were similar (approximately 67%) and there was a slightly longer median DoR with sacituzumab govitecan at 6.7 months compared with 5.8 months with docetaxel.²⁵

Quality of life had a modest 1-month improvement in favor of sacituzumab govitecan, which also had advantages in reduced deterioration in shortness of breath and higher overall satisfaction scores.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Regarding safety, sacituzumab govitecan was better tolerated than docetaxel. Discontinuation due to treatment-related AEs was observed in approximately 10% for the sacituzumab govitecan group and 17% for the docetaxel group. Similarly, dose reductions because of treatment-related AEs occurred in 29% and 39%, respectively. Diarrhea occurred more frequently in patients treated with sacituzumab govitecan, with a 10% incidence of grade 3 diarrhea compared with 4% with docetaxel.²⁵

However, of interest, neutropenia was less frequent and less severe with sacituzumab govitecan compared with docetaxel (25% vs 37%, respectively), whereas other AEs were generally comparable between the 2 treatments.²⁵

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Another exciting update came from the Beamion LUNG-1 phase Ia/Ib study in patients with HER2-altered solid cancers cancer. Patients in this trial (N = 83) were treated with zongertinib, a HER2 TKI, known for its low toxicity. The phase Ia study initially involved dose escalation from 15 mg twice daily up to 360 mg once daily in patients with advanced solid tumors and HER2 aberrations, followed by the phase Ib dose expansion specifically targeting patients with NSCLC and a HER2 tyrosine kinase domain (TKD) mutation. The primary endpoint during the dose-escalation phase was maximum tolerated dose and dose-limiting toxicities, and the secondary endpoint in the dose escalation phase was ORR. During the dose-expansion phase of the trial, the primary endpoint was treatment ORR.³⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
During the dose-finding phase in patients with advanced solid tumors and HER2 aberrations, most patients had received >2 previous lines of therapy, with 52% having NSCLC and 56% of patients having a HER2 mutation as their HER2 aberration.³⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
During the dose-escalation phase, various dose-limiting AEs including edema, diarrhea, transaminitis, and low blood counts were observed. Of interest, the maximum tolerated dose of zongertinib was not reached, whether administered twice daily or once daily. For the dose-expansion phase, daily doses of 120 mg and 240 mg were selected for optimization.³⁰

Diarrhea was the most common AE seen in 42% of patients, mostly of low-grade severity, with only 1% of patients experiencing grade ≥3 diarrhea, which is a large improvement compared with other TKIs studied in lung cancer. Rash was only seen in 12% of patients, with no cases of grade ≥3 rash. Finally, only 3% of patients experienced grade ≥3 alanine aspartate increase.³⁰

These findings support the idea that zongertinib is very tolerable, with no reported instances of ILD or significant pneumonitis. This is a promising drug with the potential to advance forward.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
During the initial dose-escalation phase, tumor response rate was 35% across all patients, with a higher rate of 44% observed in 41 patients with NSCLC.³⁰

Similarly, the response rate in patients with prior treatment with the HER2-targeted ADC trastuzumab deruxtecan (T-DXd) was 36% and 38% in patients with prior anti-HER2 treatment.³⁰

When looking at specific mutations, patients with any HER2 insertion mutations had a 56% response rate, the response rate was 62% in patients with HER2 TKD mutations, and 69% in patients with the HER2 A775_G776insYVMA insertion mutation.³⁰ The sample sizes here were small, but these findings are incredibly promising to move zongertinib forward.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The overall median DoR was 12.7 months across all patients with various tumor subtypes, and 15.8 months in patients with NSCLC. The median PFS in patients with NSCLC was 13.8 months in twice-daily dosing and 12.3 months in once-daily dosing. At the data cutoff point, 46% of patients enrolled in the dose-escalation phase were still receiving treatment.³⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Data from 23 patients with HER2-mutated NSCLC currently enrolled in the dose-expansion study was presented with an ORR of 74%, which is the highest reported thus far. In terms of safety, it demonstrated high tolerability, two thirds of patients experienced at least 1 treatment-related AE but only 10% experienced a grade ≥3 AE.³⁰ These promising outcomes are fantastic and led to the study passing the first futility analysis and the study will continue to expand.

Zofia Piotrowska, MD:

CROWN-5 was a randomized international phase III study where patients with previously untreated metastatic stage IIIB/IV ALK-positive lung cancer were randomized to either first-line lorlatinib starting at 100 milligrams daily, or crizotinib.^36,37 The primary endpoint was PFS. At ASCO, we saw the results of a post hoc analysis of PFS, ORR, DoR, and other outcomes at the 5-year landmark. A key aspect of this study was that serial brain MRIs were used.

Zofia Piotrowska, MD:
Here is the 5-year PFS update. At this 5-year post hoc analysis, PFS was determined by investigator assessment and not by blinded review, which ended at the 3-year time point. There was a dramatic separation of these 2 PFS curves, beginning early after treatment initiation. At 60 months, 60% of patients who received first-line lorlatinib remained progression free compared with 8% being progression free in the crizotinib arm. PFS also favored lorlatinib over crizotinib among all patient subgroups, including those with and without baseline brain metastases. The HR for PFS for patients with baseline brain metastases was a striking 0.08 (95% CI: 0.04-0.19) and 0.24 (95% CI: 0.16-0.36) for those without brain baseline brain metastases, so positive for both.^36,37

Keep in mind, these are patients with newly diagnosed ALK-positive NSCLC who have been on a first-line treatment strategy for 5 years or longer. This is exciting and a huge advancement for our patients.

Zofia Piotrowska, MD:
At 5 years, 92% of patients in the intent-to-treat population and 96% of those patients who did not have baseline brain metastases remained without intracranial progression.^36,37 For patients with baseline brain metastases, 80% were without intracranial progression at 5 years.

There were a few patients who had progression on lorlatinib, and when looking at resistance mechanisms, bypass pathways were predominant rather than ALK resistance mutations, which have been previously reported with crizotinib resistance.³⁸  This is a small data set, but it will be interesting to see how these data unfold. The question will be: What are the options for patients who receive first-line lorlatinib and then experience progressive disease?

Zofia Piotrowska, MD:
When we have patients on a frontline treatment for 5 years or longer, safety is critical. Unique AEs to lorlatinib that we have to be aware of include hypercholesterolemia, hypertriglyceridemia, edema, peripheral neuropathy, and cumulative weight gain. Here, we also saw that 42% of patients in the lorlatinib arm developed CNS AEs such as cognitive or mood effects, most commonly.^36,37

From my experience, CNS AEs can be troublesome for patients, and we should watch closely for these AEs. When patients are receiving lorlatinib for a long time, it will be important to monitor lipid profiles and for cumulative weight gain and CNS AEs.

Approximately one quarter of patients on the study required dose reduction and 62% required dose interruption manage some of the above-mentioned toxicities.³⁵

In this trial, it is important to note that PFS and time to intracranial progression did not markedly differ among those with or without dose reductions in the first 16 weeks of therapy.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Finally, we wrap up this section with the final analysis of DESTINY-Lung02. This study was a randomized, noncomparative phase II trial designed for dose optimization T-DXd.^39,40 Patients were randomized in a 2:1 ratio to receive either T-DXd 5.4 mg/kg or 6.4 mg/kg IV every 3 weeks. In total, 152 patients were enrolled on the trial, and among those, 102 patients received T-DXd at 5.4 mg/kg IV dose and 50 patients received T-DXd at 6.4 mg/kg IV dose.

The primary endpoint of ORR was assessed along with various secondary endpoints.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
In DESTINY-Lung02, the median age of enrolled patients was 60 years, with approximately 44% being former smokers.⁴⁰ Approximately three quarters of the patients received prior PD-1/PD-L1 therapy, and approximately 35% had more than 2 prior lines of therapy for advanced or metastatic disease.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The confirmed ORR for patients in the T-DXd 5.4 mg/kg arm and T-DXd 6.4 mg/kg arm was observed to be 50% and 56%, respectively.⁴⁰ This finding is reassuring as the initial report showed a lower response rate for patients in the 5.4 mg/kg arm compared with those in the higher dose of 6.4 mg/kg. It is nice to see that even with a lower, safer dose—which is the current recommended dose—the response rates are similar and there was not an appreciable improvement with dose escalation. In addition, the median DoR was similar at 12.6 months for the T-DXd 5.4 mg/kg arm and 12.2 months for the T-DXd 6.4 mg/kg arm. This finding represents a step forward for patients as it offers an effective treatment while at a more tolerable dose.

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Response rates were similar across various subgroups analyzed, including those with prior anti–PD-1/PD-L1 therapy alone or in combination with chemotherapy, those with CNS metastases at baseline, or across the number of prior lines of therapies. These data suggest that there is no subgroup of patients who would benefit from dose escalation to the higher and more toxic dose of 6.4 mg/kg.

These findings justify the clear evidence of T-DXd as a standard second-line treatment following platinum-based therapy when administered at a dose of 5.4 mg/kg.⁴⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
The median PFS was 10.0 months and 12.9 months for the lower and higher doses, respectively, with a similar 12-month PFS of 45% and 53%, respectively. Similarly, the median OS was 19.0 months vs 17.3 months for the T-DXd 5.4 mg/kg and T-DXd 6.4 mg/kg doses, respectively, along with similar OS rates between groups at 12 and 18 months.⁴⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
In terms of toxicity, the T-DXd 5.4 mg/kg arm was much safer when compared with the T-DXd 6.4 mg/kg arm. It had fewer dose reductions (17% vs 34%), fewer dose interruptions (30% vs 54%), and fewer discontinuations (15% vs 26%).

The lower dose treatment also had fewer treatment-related AEs, including nausea, neutropenia, fatigue, and fewer grade ≥3 hematologic events. The median treatment duration was similar between both groups, 7.7 months observed with the lower dose and 8.3 months with the higher dose. All in all, this confirms that the lower dose is less toxic.⁴⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
There has been considerable interest toward drug-related ILD, and adjudicated drug-related ILD was included in this study's final analysis. Fewer than one half of all patients experienced a drug-related ILD or pneumonitis event, with a 15% incidence rate of any grade observed in the 5.4 mg/kg treatment arm compared with 32% in the 6.4 mg/kg arm, with most of these incidences being of low grade.

Timing of T-DXd therapy after previous immunotherapy may play a role in development of ILD or pneumonitis. For example, 20% of cases were observed in patients who had received immunotherapy within 3 months prior to starting T-DXd at the lower dose, but the incidence dropped to 11% when immunotherapy was administered >3 months before starting T-DXd. However, this trend was not seen with the T-DXd 6.4 mg/kg dose. In patients without prior checkpoint inhibitor treatment, the incidence was 15% in the lower dose group and 27% in the higher dose group. These findings show improvement and is a very important outcome of lung toxicity.⁴⁰

Natasha Leighl, MD, MMSc, FRCPC, FASCO:
Health-related quality-of-life measures were maintained and stable through cycle 26 of treatment across both dose levels, indicating similarity in both treatment-related quality of life and antitumor efficacy.⁴⁰ The only difference previously noted was the fewer occurrence of AEs associated with the lower recommended dose.