CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 25, 2023
Expiration: August 24, 2024
Treatment of EGFR-Mutated Advanced NSCLC
Heather Wakelee, MD, FASCO:
All patients with advanced EGFR-mutated NSCLC are given EGFR TKIs in the first line. The standard approach is osimertinib, which is approved by the FDA for first-line treatment of adult patients with metastatic NSCLC whose tumors have EGFR ex19del or exon 21 L858R mutations.1 Other EGFR TKIs—such as erlotinib, gefitinib, afatinib, and dacomitinib—are sometimes used in other parts of the world.
Disease progression is inevitable with first-line EGFR TKI therapy, and a major question is how to improve outcomes for patients after disease progression. One approach is to give CT to try to extend the benefit of the EGFR TKI. An alternative approach is to add ICIs, given that combination ICI plus CT is the first-line SoC in patients with advanced NSCLC without actionable driver mutations. Data from both of these scenarios were reported at ASCO 2023 in the setting of EGFR-positive advanced NSCLC.
AGAIN (JCOG1404/WJOG8214L): First-line EGFR TKI vs EGFR TKI With Inserted CT for Advanced EGFR-Positive, Nonsquamous NSCLC
Heather Wakelee, MD, FASCO:
Years ago, when we were first exploring how to combine CT and EGFR TKIs, there was an approach called “intercalating” where you would alternate giving EGFR-targeted therapy and then CT. The rationale for the intercalation strategy is that survival can be improved by using CT to kill off resistant clones early on in EGFR TKI therapy.
The phase III FASTACT-2 trial showed a treatment benefit for intercalated erlotinib plus CT (n = 226) vs placebo plus CT (n = 225) in patients with activating EGFR mutations (median OS: 31.4 months vs 20.6 months, HR: 0.48, 95% CI: 0.27-0.84, P = .0092; median progression-free survival [PFS]: 16.8 months vs 6.9 months, HR: 0.25, 95% CI: 0.16-0.39, P <.0001).22 Ultimately, the approach was not widely adopted.
Reported at ASCO 2023, the phase III AGAIN (JCOG1404/WJOG8214L) trial explored intercalating CT with an EGFR TKI in patients with advanced EGFR-positive, nonsquamous NSCLC.23 The study design called for 2 months of EGFR TKI therapy, then a pause for 3 cycles of cisplatin plus pemetrexed CT, followed by reinitiation of the EGFR TKI until progression. The study, which was carried out in Japan, started with gefitinib (153 patients received gefitinib alone; 155 patients received gefitinib with inserted CT) but later switched to osimertinib (97 patients received osimertinib alone; 96 patients received osimertinib with inserted CT) as the EGFR TKI. The primary endpoint was OS, with key secondary endpoints of PFS, ORR, and safety.
AGAIN (JCOG1404/WJOG8214L): PFS and ORR
Heather Wakelee, MD, FASCO:
Unfortunately, osimertinib plus inserted CT did not significantly improve PFS vs osimertinib alone (median PFS: 25.2 months vs 20.4 months; HR: 0.812; 95% CI: 0.572-1.155; P = .2475).23
However, there was an improvement in PFS for the older EGFR TKI, gefitinib, plus inserted CT vs gefitinib alone (median PFS: 14.4 months vs 9.6 months; HR: 0.687; 95% CI: 0.544-0.867; P = .0015). Of note, median PFS for gefitinib was generally shorter than osimertinib, regardless of CT insertion, so we do not tend to use gefitinib in areas where osimertinib is available.
AGAIN (JCOG1404/WJOG8214L): OS (Primary Endpoint)
Heather Wakelee, MD, FASCO:
The real take-home message from this study is that the OS improvement with EGFR TKI plus inserted CT vs EGFR TKI alone was negative, both for gefitinib (median OS: 45.6 months vs 43.2 months; HR: 1.016; 95% CI: 0.774-1.332; P = .9124) and osimertinib (median OS: not evaluable [NE] vs NE; HR: 0.835; 95% CI: 0.484-1.442; P = .5154).23 Intercalation of CT within the scheme of EGFR TKI therapy in patients with advanced EGFR-positive, nonsquamous NSCLC failed to improve survival.
The ongoing phase III FLAURA2 study (NCT04035486) is testing first-line osimertinib with or without pemetrexed plus platinum-based CT in patients with EGFR-positive, locally advanced, or metastatic NSCLC. A press release from the study sponsor stated that there was significant, clinically meaningful improvement in PFS for the combination arm, but we have to wait to see the full data from that study. At this time, the standard therapy is just to give the EGFR TKI alone, without intercalation or in combination with CT.
KEYNOTE-789: Pemetrexed/Platinum CT With or Without Pembrolizumab in TKI-Resistant, Metastatic, EGFR-Positive, Nonsquamous NSCLC
Heather Wakelee, MD, FASCO:
The phase III KEYNOTE-789 trial was designed to determine the utility of CT plus IO after disease progression with an EGFR TKI.24 Patients with EGFR-positive, metastatic, nonsquamous NSCLC with progressive disease on prior EGFR TKI therapy (N = 492) were randomized to receive CT (platinum-based plus pemetrexed) and either placebo or pembrolizumab, and then they continued to receive pembrolizumab or placebo plus pemetrexed. Patients on the placebo arm were allowed to cross over to pembrolizumab upon disease progression verified by blinded independent central review (BICR).
The dual primary endpoints of the study were PFS (by BICR) and OS, with secondary endpoints of ORR and duration of response (DoR) by BICR, safety, and patient-reported outcomes.
KEYNOTE-789: PFS and OS (Coprimary Endpoints)
Heather Wakelee, MD, FASCO:
Unfortunately, this trial was not positive. Pembrolizumab plus CT did not significantly improve median PFS (5.6 months vs 5.5 months; HR: 0.80; 95% CI: 0.65-0.97; P = .0122) compared with placebo plus CT; the P value did not meet the predefined efficacy boundary.24
KEYNOTE-789: OS (Coprimary Endpoints)
Similarly, pembrolizumab plus CT did not lead to significant improvement in median OS compared with placebo plus CT (15.9 months vs 14.7 months; HR: 0.84; 95% CI: 0.69-1.02; P = .0362).
KEYNOTE-789 Final Analysis: OS Across Subgroups
Heather Wakelee, MD, FASCO:
Looking at the subgroup analysis, nothing stands out.24 Based on this study, CT plus IO is not a recommended approach in patients with EGFR-positive metastatic, nonsquamous NSCLC with disease progression following treatment with an EGFR TKI.
Clinical Implications for EGFR-Positive Advanced NSCLC
Heather Wakelee, MD, FASCO:
Single-agent osimertinib is currently our first-line regimen for EGFR-positive advanced NSCLC, but we still are looking at what can be added to it. We are waiting on data to determine whether adding a VEGF inhibitor will give a stronger benefit. In exploratory analyses of the phase III Impower150 trial, bevacizumab (VEGF receptor TKI) plus atezolizumab, carboplatin, and paclitaxel showed improved OS in patients with metastatic nonsquamous NSCLC and an EGFR mutation.25
The ongoing randomized phase II RAMOSE trial (NCT03909334) also is looking at osimertinib plus ramucirumab (anti-VEGF receptor antibody) in EGFR-mutated advanced NSCLC. Toward the answer of how to manage patients with disease progression after EGFR TKI therapy, we recently saw data from the phase III ORIENT-31 trial that evaluated the combination of sintilimab (PD-1 inhibitor) plus a bevacizumab biosimilar and CT. This study was done in China and was a positive trial, with the triplet resulting in improved median PFS vs CT alone (7.2 vs 4.3 months; HR: 0.51; 95% CI: 0.39-0.67; P <.0001).26
In the AGAIN trial, insertion of CT into EGFR TKI therapy was not positive. Dr Reckamp, what were your thoughts on this trial?
Karen Reckamp, MD:
We conducted trials with these types of intercalated regimens before we knew about EGFR mutations and without significant benefit. However, most studies are not seeing improvement in OS when adding CT to frontline osimertinib and, again, the toxicity and lack of OS benefit really limit its use. We do need better treatments, and we need to find ways to determine which patients might not do as well and treat them more aggressively, but we do not have those answers yet.
Heather Wakelee, MD, FASCO:
What do you see as the best strategy after progression on EGFR TKI therapy?
Karen Reckamp, MD:
The earliest studies evaluatingsingle-agent ICI therapy that included patients with EGFR mutations and ALK alterations showed response rates in the range of 5% or less.27-29 Even when PD L1 expression is high, we generally do not see tumor responses, likely because of T cell infiltrates and other reasons for immune system inactivity. In KEYNOTE-789, addition of pembrolizumab to CT was not helpful in patients who had previously progressed on EGFR TKI therapy. The results provide additional evidence that clinical benefit really is not seen with IO plus CT for patients with EGFR mutations. It is likely that CT alone is enough for these patients, avoiding the potential for added immune related toxicity that would come from IO. We need better ways to use IO in these patients, but anti-PD1 and anti-PDL1 inhibitors are probably not the answer.
MET Inhibitors in NSCLC
Heather Wakelee, MD, FASCO:
For patients with osimertinib resistance and EGFR-positive NSCLC, targeted therapy may be beneficial. If tumors have high MET expression, MET inhibitors such as amivantamab-vmjw (bispecific anti-EGFR and anti-MET antibody) can be quite effective. Amivantamab-vmjw was granted accelerated approval by the FDA for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based CT.30
We have been using amivantamab-vmjw, and it has shown some utility in clinical trials. In long-term results of the phase I CHRYSALIS study, amivantamab monotherapy showed an ORR of 37%, median DoR of 12.5 months, median PFS of 6.9 months, and median OS of 23 months in 114 patients with advanced NSCLC with EGFR exon 20 insertion mutations who had progression on previous SoC platinum CT.31 Another cohort in the phase I CHRYSALIS study (20 patients with newly diagnosed EGFR-mutated [ex19del or L858R] NSCLC) showed an ORR of 100% with amivantamab-vmjw plus lazertinib (EGFR TKI).32 The long-term follow-up for this cohort (median = 33.6 months) presented at ASCO 2023 showed that one half of the patients were progression free and still receiving treatment, with median DoR, PFS, and OS not estimable.
The phase I/Ib CHRYSALIS-2 study looked at safety, tolerability, and efficacy of lazertinib with amivantamab-vmjw in patients with EGFR-mutated advanced NSCLC who had progressed on prior SoC therapy (osimertinib plus platinum CT).33 The most recent update at ASCO 2022 showed an ORR (by BICR) of 36% in 50 efficacy-evaluable patients, with a manageable safety profile. At ASCO 2023, data also showed that although amivantamab targets both MET and EGFR, high MET-expressing tumors are the ones that tend to benefit the most.34 Earlier work has shown that the presence of EGFR alterations helped, as well. I think we are still working to understand the biomarkers for amivantamab-vmjw.
Staying on the theme of MET inhibition, let us move on to more data from ASCO 2023.
INSIGHT 2: Study Design
Karen Reckamp, MD:
A study reported at ASCO 2023 looked at MET inhibition for patients who had disease progression on osimertinib. The single-arm phase II INSIGHT 2 study looked at combination tepotinib (MET inhibitor) plus osimertinib in 122 patients with locally advanced or metastatic, EGFR-positive NSCLC who had developed MET amplification upon tumor progression on prior osimertinib therapy.35 Patients received both drugs until disease progression or unacceptable toxicities. The primary endpoint was ORR by IRC in centrally detected MET- amplified tumors by fluorescence in situ hybridization (FISH). Secondary endpoints included ORR by IRC in centrally detected MET-amplified tumors by blood based next-generation sequencing (NGS), safety, and then confirmed complete response, DoR, disease control rate (DCR), PFS, and OS.
INSIGHT 2: Patient Disposition
Karen Reckamp, MD:
This study prescreened 472 patients and tested for MET amplification in 451, 175 of whom were MET amplification positive.35 Of the 122 patients who went on to receive the combination therapy, 98 tested positive by tumor based FISH, and 31 were positive by blood-based NGS (24 patients were positive by both detection methods).
INSIGHT 2: Baseline Characteristics
Karen Reckamp, MD:
This population was predominantly female (59.8%), younger (median age of 61 years), Asian (59.8%), and mostly never smokers (68%).35 In total, 72.1% of patients had an Eastern Cooperative Oncology Group performance status of 1. The majority (59%) had EGFR ex19del, and 36% had L858R mutations. In addition, 64.8% of patients had received frontline osimertinib for >12 months.
INSIGHT 2: Efficacy in Patients With MET Amplification Detected by FISH Testing
Karen Reckamp, MD:
In 98 patients with MET amplification detected by tumor FISH testing, 43.9% had a partial response, and another 15.3% had stable disease.35 The responses usually occurred quickly (≤6 weeks), with a median DoR of 9.7 months (95% CI: 5.6-NE). Median PFS was 5.4 months (95% CI: 4.2-7.1), and OS was not yet reached.
INSIGHT 2: Efficacy in Patients With MET Amplification Detected by Blood Based NGS Testing
Karen Reckamp, MD:
In the 31 patients with MET amplification detected by blood based NGS testing, 51.6% had a partial response, and 9.7% had stable disease.35 Median DoR was 5.6 months, median PFS was 4.6 months, and OS was not yet reached. This outcome was similar to the FISH-positive analysis.
INSIGHT 2: Safety
Karen Reckamp, MD:
Looking at the safety signals for this study, 27.9% of patients had grade ≥3 toxicity, which led to dose reduction in 17%, discontinuation of treatment in 5.7%, and the death of 2 patients (1.6%).35 The most common treatment-related AEs (TRAEs) were low-grade diarrhea (46.7%), peripheral edema (34.4% any grade; 4.1% grade ≥3), paronychia (20.5% any grade; 0.8% grade ≥3), decreased appetite (18.0% any grade; 3.3% grade ≥3), and nausea (16.4% any grade; 1.6% grade ≥3). These are toxicities that we would expect with MET and EGFR inhibition.
In total, 4 patients received dose reductions of osimertinib and 19 patients received dose reductions of tepotinib because of TRAEs. Pneumonia/pneumonitis leading to the death of 2 patients was considered by the investigator to be potentially related to either tepotinib or osimertinib.
INSIGHT 2: Clinical Implications
Karen Reckamp, MD:
We know that up to 15% of patients with EGFR-mutant NSCLC will develop MET amplification as a mechanism of resistance to frontline EGFR-targeted therapy, particularly osimertinib. Thus, understanding the efficacy and toxicity of combination therapies is incredibly important. In INSIGHT 2, we saw efficacy with good response rates (in the 40% 50% range), and the toxicity was what we would expect from tepotinib and osimertinib without significant overlapping toxicity, so with proper management of side effects (especially edema), this may be an option for patients. We would like to see further evidence from a randomized study. Studying this population in a randomized trial is not likely to be feasible in the United States, however, because the numbers are small and generally, the preferred strategy is to continue targeted therapy as long as a targetable genomic alteration is present. If your patient has a MET alteration, you are going to be looking to give a MET-targeted therapy in combination with an EGFR inhibitor. I think the data tell us that we should look for alterations with NGS on tumor or liquid biopsy that have efficacious targeted treatments available at the time of the development of resistance, and that is what many physicians are doing in practice.
Ongoing trials are looking at the safety of combinations of MET inhibitors plus EGFR inhibitors. The phase III MARIPOSA study (NCT04487080) is comparing amivantamab-vmjw plus lazertinib vs osimertinib vs lazertinib in previously untreated, EGFR-mutated (ex19del or L858R) advanced NSCLC. Other ongoing phase II studies are evaluating osimertinib in combination with the MET inhibitor savolitinib (SAVANNAH, NCT03778229; ORCHARD, NCT03944772) in patients with EGFR-mutated advanced NSCLC who had progressed on prior osimertinib treatment.
Dr Wakelee, what do you currently do in clinical practice for patients with EGFR-mutated NSCLC after they have progressed from first-line EGFR TKI therapy? Are you repeating biomarker testing?
Heather Wakelee, MD, FASCO:
I have a high percentage of patients who have EGFR mutations or other driver mutations in their tumors. When a patient has progressed on first-line osimertinib, I routinely test for biomarkers of resistance. The reason for this is that occasionally we will find other alterations, such as MET overexpression, associated with development of osimertinib resistance. As I mentioned above, in such cases I have been using amivantamab-vmjw.
Occasionally, biomarker testing will find something that can change what we are able to do, but most of the time nothing actionable is found. In that case, I tend to transition to platinum CT and pemetrexed, and I think about giving bevacizumab, especially if the patient has a high disease burden or liver metastases. We have a phase II clinical trial (NCT03786692) that uses bevacizumab plus carboplatin and pemetrexed as a backbone with or without atezolizumab, but that is not something I am doing outside of a trial.
Frontline IO for Advanced NSCLC Without Actionable Mutations
Karen Reckamp, MD:
The current frontline SoC for advanced NSCLC without actionable mutations is IO, alone or with CT.
Pembrolizumab in combination with pemetrexed and platinum CT is approved by the FDA as first-line treatment of patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations.12 It also is approved in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of patients with metastatic squamous NSCLC. Pembrolizumab also is approved by the FDA as a single agent for the first-line treatment of patients with NSCLC expressing PD-L1 (TPS ≥1%) with no EGFR or ALK genomic tumor aberrations.
Atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin is approved for the first-line treatment of adult patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations.10 It is also approved in combination with nab-paclitaxel and carboplatin for the first-line treatment of adult patients with metastatic nonsquamous NSCLC with no EGFR or ALK genomic tumor aberrations. As monotherapy, atezolizumab also is approved by the FDA for the first-line treatment of adult patients with metastatic NSCLC whose tumors have high PD-L1 expression (≥50% of tumor cells or ≥10% stained tumor-infiltrating immune cells) with no EGFR or ALK genomic tumor aberrations.
Cemiplimab (anti‒PD-1 antibody) in combination with platinum-based CT is approved for the first-line treatment of adult patients with locally advanced (for patients who are not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC with no EGFR, ALK, or ROS1 aberrations.36 It also is approved as a single agent for the first-line treatment of adult patients with locally advanced (for patients who are not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC whose tumors have high PD-L1 expression (≥50%) with no EGFR, ALK, or ROS1 aberrations.
Durvalumab (anti‒PD-L1 antibody) in combination with tremelimumab-actl (anti‒CTLA-4 antibody) and platinum-based CT is approved for the treatment of adult patients with metastatic NSCLC with no sensitizing EGFR mutations or ALK genomic tumor aberrations.37
Finally, nivolumab in combination with ipilimumab (anti‒CTLA-4 antibody) is approved for the first-line treatment of adult patients with metastatic NSCLC expressing PD-L1 (≥1%) with no EGFR or ALK genomic tumor aberrations.14 Nivolumab also is approved by the FDA for adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations as first-line treatment in combination with ipilimumab and 2 cycles of platinum-doublet CT.
CheckMate 9LA 4 Year Update : Study Design
Karen Reckamp, MD:
The approval of nivolumab for first-line treatment of metastatic or recurrent NSCLC with no EGFR or ALK alterations was based on the results of the phase III CheckMate 9LA study.38 At ASCO 2023, we saw the 4-year update of this study.39 This randomized phase III study compared the combination of nivolumab and ipilimumab plus 2 cycles of platinum-doublet CT vs the standard 4 cycles of platinum doublet CT for frontline treatment of patients with stage IV recurrent NSCLC with no sensitizing EGFR or ALK alterations (N = 719). IO continued for up to 2 years or until disease progression or unacceptable toxicity. The primary endpoint was OS, and secondary endpoints included PFS and ORR by BICR and efficacy by PD L1 expression. OS by histologic subtype was included as an exploratory endpoint.
CheckMate 9LA 4-Year Update: ORR, DoR, and PFS
Karen Reckamp, MD:
Patients who received the IO combination plus CT had a higher ORR (38.0% vs 25.1%) and 4-year PFS rate (12% vs 5%) compared with CT alone.39
Subgroup analysis showed similar improvement in patients with PD-L1 ≥1% (ORR: 42.6% vs 27.5%; 4-year PFS: 12% vs 6%), PD-L1 <1% (ORR: 31.1% vs 20.2%; 4-year PFS: 12% vs 3%), and nonsquamous histology (ORR: 33% vs 22%; 4-year PFS: 13% vs 5%).
Patients with squamous histology showed similar improvement in ORR (49% vs 31%) and slightly lower improvement in 4-year PFS (8% vs 4%).
CheckMate 9LA 4-Year Update: OS
Karen Reckamp, MD:
At the 4 year update, median OS was significantly improved in all patients who received 2 cycles of CT plus nivolumab and ipilimumab (15.8 months vs 11.0 months; HR: 0.74; 95% CI: 0.63-0.87) compared with 4 cycles of CT alone.39 Subgroup analysis showed similar median OS improvement in patients with PD L1 ≥1% (15.8 months vs 10.9 months; HR: 0.74; 95% CI: 0.60-0.92) or PD L1 <1% (17.7 months vs 9.8 months; HR: 0.66; 95% CI: 0.50-0.86) and with nonsquamous (17.8 months vs 12.0 months; HR: 0.80; 95% CI: 0.66-0.97) or squamous (14.5 months vs 9.1 months; HR: 0.64; 95% CI: 0.48-0.84) histology.
The 4-year OS rate was similar across the subgroups, showing that approximately 20% of patients will see a long-term benefit with 2 cycles of CT plus nivolumab and ipilimumab.
CheckMate 9LA 4-Year Update: OS by Tumor Histologic Subtype (Exploratory Analysis)
Karen Reckamp, MD:
The exploratory analysis of OS by tumor histologic subtype in patients with nonsquamous NSCLC suggested a benefit for combination IO plus CT in solid tumors (median OS: 17.9 months vs 9.5 months, HR: 0.70, 95% CI: 0.49-0.99; 4-year OS rate: 26% vs 19%) and acinar tumors (median OS: 18.7 months vs 12.7 months, HR: 0.77, 95% CI: 0.51-1.15; 4-year OS rate: 20% vs 20%) compared with CT alone.39
CheckMate 9LA 4-Year Update: Efficacy in Patients Discontinuing Due to TRAEs (Post Hoc Analysis)
Karen Reckamp, MD:
When giving combination CTLA-4 and PD 1 inhibitor therapy, we are concerned about increased immune related AEs. A post hoc analysis looking at patients who discontinued the IO plus CT therapy due to TRAEs (n = 61) showed a higher median OS (27.5 months vs 15.8 months), 4-year OS rate (41% vs 21%), ORR (51% vs 38%), and treatment-free interval (10.6 months vs 2.2 months) compared with all patients receiving IO plus CT (n = 361).39 In total, 11% of all patients receiving combination IO plus CT were alive and treatment free 4 years after stopping treatment vs 27% of those who discontinued treatment due to TRAEs. The presence of TRAEs can indicate that patients are having an immune response that may be significantly beneficial to the antitumor response.
CheckMate 9LA 4-Year Update: Clinical Implications
Karen Reckamp, MD:
This report is another confirmation of the long term benefit from frontline nivolumab plus ipilimumab and 2 cycles of CT, which we know is better than CT in all comers. It is nice to see a similar benefit for patients with PD-L1–negative disease because we have fewer options and expectations that IO will be beneficial. The response and 4-year OS for this patient population were similar to the patients with PD-L1 positive disease.
Putting this in the clinical context, where we are dealing with shortages of platinum CT, this may be a real option to try to save some of those medications, with only 2 cycles compared with the standard 4 cycles in other regimens.
ADCs for Treatment of Advanced NSCLC
Heather Wakelee, MD, FASCO:
Some exciting new options are on the horizon for patients with advanced NSCLC.
Antibody‒drug conjugates (ADCs) are antibodies linked to a drug to deliver CT more precisely to cancer cells. As a result, they avoid broad toxicity to the normal tissue. Typically, ADC therapy uses a humanized monoclonal antibody that attaches to an antigen that is preferentially expressed on the cancer cell surface and not on normal tissue.40 A linker attaches the antibody to the “warhead” payload, which is a very potent CT agent with cytotoxic activity.
ADCs are an established class of agents in oncology, but they are new to lung cancer. One ADC that we use in lung cancer is fam-trastuzumab deruxtecan-nxki, which was granted accelerated approval for adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations and who have received a prior systemic therapy.41
Fam-trastuzumab deruxtecan-nxki is a HER2-targeted antibody conjugated to the camptothecin analogue deruxtecan (topoisomerase I inhibitor), and it really acts as a targeted agent. Some other ADCs are not so narrowly targeted; for example, datopotamab deruxtecan and sacituzumab govitecan-hziy are ADCs that target TROP2, which is overexpressed in the majority of NSCLC.42,43
TROPION-Lung02 : Datopotamab Deruxtecan + Pembrolizumab With or Without Platinum CT in Advanced NSCLC
Heather Wakelee, MD, FASCO:
In one cohort of the phase I TROPION-PanTumor01 trial (NCT03401385), datopotamab deruxtecan monotherapy suggested antitumor activity in 180 patients with heavily pretreated advanced/metastatic NSCLC (ORR: 22%-26%, depending on dose).44
The phase Ib TROPION-Lung02 trial looked to improve efficacy by combining different doses of datopotamab deruxtecan with pembrolizumab with or without platinum CT.45 This was a complex trial design looking at different doses of datopotamab deruxtecan and different platinum CT agents (carboplatin or cisplatin). The study enrolled patients with advanced or metastatic NSCLC without actionable genomic alterations (N = 136), a subset of whom were treatment naive (n = 91). The primary objective was to assess safety and tolerability, with secondary objectives of efficacy, pharmacokinetics, and antidrug antibody determination.
TROPION-Lung02: Best Overall Tumor Change From Baseline
Heather Wakelee, MD, FASCO:
The response rates for doublet datopotamab plus pembrolizumab or the triplet with added platinum CT were similar in all-comers (confirmed plus pending ORR: 38% vs 49%) and in the first-line cohort (50% vs 57%).45 The waterfall plots of best overall tumor change do not look much different when comparing the all-comers and first-line cohort, so there is not a clear advantage to adding the platinum CT.
TROPION-Lung02: Depth and Duration of Response
Heather Wakelee, MD, FASCO:
When looking at the depth and duration of response to therapy, you see that doublet ADC plus IO is working very well,45 so perhaps we do not always need the platinum CT, which is important to keep in mind given the current shortages. Median DoR was not estimable in all-comers and the first-line cohort for patients receiving either the doublet or triplet therapy. The CT may just add toxicity without necessarily improving efficacy.
TROPION-Lung02: Treatment-Emergent AEs Occurring in ≥20% of Patients
Heather Wakelee, MD, FASCO:
In general, the triplet therapy had a higher rate of severe treatment-emergent AEs. Looking at individual toxicities, doublet ADC plus IO therapy had a bit more stomatitis, but the triplet therapy with added platinum CT had more thrombocytopenia, anemia, and neutropenia.45 It is important to be aware that some AEs seen with ADCs are unique to the linker and, in this case, the deruxtecan warhead, which can result in some toxicities that we have not seen as much. As these drugs become more available, we want to be mindful that it is not the same as CT alone. Looking at this list, many of the toxicities are very specific to CT.
TROPION-Lung02: Clinical Implications
Heather Wakelee, MD, FASCO:
My main highlight is that although datopotamab deruxtecan is not being heavily used yet, there are some very good studies designed based on the data from TROPION-Lung02. The randomized phase III TROPION-Lung07 trial (NCT05555732) is a comparison of datopotamab deruxtecan plus pembrolizumab with or without platinum CT vs pembrolizumab plus pemetrexed and platinum CT in patients with newly diagnosed advanced/metastatic NSCLC with no actionable genomic alterations and low tumor PD-L1 expression (<50%). The phase III TROPION-Lung08 trial (NCT05215340) is a comparison of datopotamab deruxtecan plus pembrolizumab vs pembrolizumab alone (SoC) in patients with newly diagnosed advanced/metastatic NSCLC with no actionable genomic alterations who have high tumor PD-L1 expression (≥50%). So, we will see more to come on this agent.
Karen Reckamp, MD:
The TROPION Lung02 study showed some interesting data, and we are still awaiting the final outcomes. To move ADCs into the frontline setting in NSCLC, the main hurdle will be the increase in toxicity, because the current SoC sets such a high bar. We have seen activity for unselected TROP2-directed ADCs in smaller trials but do not yet have an approval in lung cancer for an ADC outside of fam-trastuzumab deruxtecan-nxki (specific for activating HER2 mutations). We do see responses—and that is helpful—but there are more long-term data with SoC CT and IO, so we would need to see improvements at 4- and 5 year follow-up on those studies. Considering that there is a clear increase in toxicity for TROP2-directed ADCs when used in the frontline setting along with CT and IO, we must be sure that the efficacy is meeting what we expect.
TTFields Therapy
Heather Wakelee, MD, FASCO:
A novel idea in the lung cancer field—TTFields—was presented at ASCO 2023.
TTFields devices work by applying alternating current electrical fields with low intensity (1-3 V/cm) and intermediate frequency (100-300 kHz), resulting in cellular stress that disrupts cancer cell growth with no systemic toxicity.46,47 Healthcare professionals who treat primary brain tumors are probably familiar with this technology—where patients wear the TTFields device on their head—which can significantly improve efficacy of antitumoral therapy.
In the glioblastoma setting, the FDA-approved TTFields device is the NovoTTF-100A system. This system is intended as a treatment for adult patients (22 years of age and older) with histologically confirmed glioblastoma multiforme (GBM).48 The NovoTTF-100A system with temozolomide is indicated for the treatment of adult patients with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy (RT) together with concomitant SoC CT. For the treatment of recurrent GBM, the NovoTTF-100A system is indicated following histologically or radiologically confirmed recurrence in the supratentorial region of the brain after receiving CT. The device is intended to be used as monotherapy and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.
TTFields also is approved by the FDA for MPM. In this setting, the NovoTTF-100L system is indicated for the treatment of adult patients with unresectable, locally advanced, or metastatic MPM to be used concurrently with pemetrexed and platinum-based CT.49
Patients who use TTFields devices may experience rash, and the patient must deal with wearing the device. Some patients like having an active role in their treatment, however, so it is not necessarily a negative.
LUNAR : Study Design
Heather Wakelee, MD, FASCO:
The randomized phase III LUNAR trial was a test of TTFields (NovoTTF-200T device) in combination with SoC therapy vs SoC alone in 276 adult patients with metastatic NSCLC who had progressed on prior platinum-based CT.50 Of note, the trials was mostly conducted before ICI was a standard approach in combination with chemotherapy, so these patients were pretreated with CT alone as first-line therapy. SoC for second-line therapy was defined as investigator’s choice of docetaxel or ICI (pembrolizumab, atezolizumab, or nivolumab). The primary endpoint was OS, with secondary endpoints including OS by SoC subgroup (ICI vs CT), PFS, ORR, QoL, safety, and PFS/OS by histology.
LUNAR: OS (Primary Endpoint)
Heather Wakelee, MD, FASCO:
The trial met its primary endpoint, with significant improvement in median OS (13.2 months vs 9.9 months; HR: 0.74; 95% CI: 0.56-0.98; P = .035) for TTFields plus SoC vs SoC alone.50 Of interest, the type of SoC received greatly affected the outcome; patients who received ICI as SoC along with TTFields had significantly improved median OS (18.5 months vs 10.8 months; HR: 0.63; 95% CI: 0.41-0.96; P = .03) compared with SoC alone, whereas the patients who received docetaxel as SoC had no significant improvement (median OS: 11.1 months vs 8.7 months; HR: 0.81; 95% CI: 0.55-1.19; P = .28).
LUNAR: Response and PFS in ITT Population
Heather Wakelee, MD, FASCO:
There were not significant differences in ORR (20% vs 17%) or median PFS (4.8 months vs 4.1 months; HR: 0.85; 95% CI: 0.67-1.11; P = .23) with TTFields plus SoC vs SoC alone.50
LUNAR: Safety
Heather Wakelee, MD, FASCO:
Toxicity was minimal, and the most frequent AE with TTFields was grade 1-2 dermatitis; 87% of cases were resolved, with a median duration of 3 weeks.50
LUNAR: Adverse Device Effects With TTFields
Heather Wakelee, MD, FASCO:
Median device usage was similar among patients receiving an ICI (15 weeks) vs docetaxel (13 weeks). There were no grade 4 adverse device effects and no deaths due to TTFields.
LUNAR: Clinical Implications
Karen Reckamp, MD:
I think the LUNAR study with TTFields is an interesting move forward, and people are looking for therapies that can target a physical location as much as driver mutation–targeted therapies. There is some question about how applicable these results are to current clinical practice because the study was done in patients who had not received frontline IO.
Heather Wakelee, MD, FASCO:
When studies are designed, they are designed with whatever the SoC is at the moment, which sometimes has evolved by the time the trial is completed. Second-line docetaxel is still very much a standard; often, it is given with ramucirumab, and there are discussions around whether it should be given with continuation of IO. Now that single-agent IO has moved into the first line, giving it as a single agent in the second line is no longer a standard.
I do not think that at this time providers will give single-agent ICI plus TTFields in the second line, but the trial is a proof of concept that can lead to further studies. TTFields had a positive survival benefit for patients and is a proven technology that is used for patients with GBM—and somewhat for MPM, as well. I imagine that this device could be used in regimens that are using ICIs, probably in the first line once those trials are completed.
Karen Reckamp, MD:
It is very good to see that patients receiving TTFields along with either docetaxel or IO in the second line had improved outcomes, but this is not how we treat patients currently. Patients in this study did receive prior IO, so it is difficult to extrapolate to an understanding of who is benefiting. How much benefit is the TTFields adding to the IO benefit, and what is the impact of PD-L1 expression on response and outcome? We do not have that answer, so we need to see some of these subsets, and we need to understand how TTFields work in patients who have received prior IO, or in the frontline setting if that is where it is going.
Back
