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Key Studies in Lung Cancer: Independent Conference Coverage of the World Conference on Lung Cancer 2020

Shirish M. Gadgeel, MD
Nicolas Girard, MD, PhD
Released: March 31, 2021

NSCLC

CodeBreaK 100: Sotorasib in KRAS p.G12C–Mutated NSCLC: Study Design

Nicolas Girard, MD, PhD:
KRAS tumor–driving mutations are present in approximately 30% of patients with lung adenocarcinoma, and among those mutations KRAS pG12C represents approximately 13%, or approximately half of the KRAS mutations.1,2 The KRAS pG12C mutation has been considered untargetable until recently. During the past 20 years, many trials have investigated the use of drugs of various classes (eg, farnesyl transferase inhibitors, chemotherapy combinations, and MEK inhibitors) yet have failed to show clinical benefit when compared with standard of care chemotherapy.

At WCLC 2020, Li and colleagues3 presented follow-up results from the registrational phase II CodeBreaK 100 study evaluating sotorasib (previously AMG 510) in 124 patients with locally advanced or metastatic NSCLC with the KRAS pG12C mutation—confirmed by central testing—and who had previously received platinum-based chemotherapy. Patients had progressed on prior standard therapy and did not have active central nervous system metastases. In this study, patients received sotorasib 960 mg once-daily orally until disease progression. The primary endpoint was ORR by blinded independent central review. Key secondary endpoints included duration of response (DoR), disease control rate (DCR), time to response, PFS, OS, and safety.

CodeBreaK 100: Sotorasib in KRAS p.G12C–Mutated NSCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
The median age of patients enrolled on this study was approximately 64 years (range: 37-80) and >90% of patients were current or former smokers. Previous systemic therapies included platinum-based chemotherapy (89.7%), anti–PD-(L)1 inhibitor (91.3%), and platinum-based chemotherapy plus anti–PD-(L)1 inhibitor (81%).

CodeBreaK 100: Sotorasib in KRAS p.G12C–Mutated NSCLC: Efficacy

Nicolas Girard, MD, PhD:
After a median follow-up of 12.2 months, the ORR was 37% and the DCR was >80%, which is quite remarkable in the advanced, refractory disease setting. Moreover, 43% of patients achieved stable disease. The DoR is also very impressive in this phase II study, with patients achieving a median DoR of 10.0 months (range: 6.9-11.1 months). Responses to sotorasib were observed in key patient subgroups including across PD-L1 expression levels, and in patients with tumors harboring comutations, namely in STK11 and KEAP1, which are predictors of resistance to ICIs.

CodeBreaK 100: Sotorasib in KRAS p.G12C–Mutated NSCLC: Safety

Nicolas Girard, MD, PhD:
The drug, overall, was well tolerated. Most AEs with sotorasib were of low grade and manageable. As with other kinase inhibitors, we have to pay close attention to gastrointestinal and cutaneous AEs. The most common grade 3 treatment-related AEs (TRAEs) reported were alanine aminotransferase elevation (6.3%), aspartate aminotransferase elevation (5.6%), and diarrhea (4%). TRAEs led to dose modification in 22.2% of patients, and to discontinuation in 7.1% of patients. Of importance, there were no deaths on this study.

CodeBreaK 100: Sotorasib in KRAS p.G12C–Mutated NSCLC: Conclusions

Nicolas Girard, MD, PhD:
The CodeBreaK 100 study clearly shows that we now have a targeted therapy for KRAS pG12C–mutant NSCLC, which is wonderful news for patients for whom the only available treatment option had previously been chemotherapy (with or without immunotherapy). Ideally, going forward we should evaluate sotorasib earlier during the course of treatment—meaning moving from the late-line setting to the second-line setting, and then to the first-line setting.

Dr. Gadgeel, what are your thoughts on the efficacy of sotorasib in the CodeBreaK 100 study?

Shirish M. Gadgeel, MD:
A notable feature about this study design for me was the addition of exploratory endpoints, assessing efficacy of sotorasib in patients whose tumors had comutations in immunosuppressor and oxidative stress genes (STK11 and KEAP1) as well as using tumor PD-L1 expression as biomarker. Investigators did not find a substantial difference in efficacy based on the level of tumor PD-L1 expression. Of interest, when they assessed the response rate of sotorasib in tumors with STK11 and KEAP1 comutations, they found that patients whose tumors had mutations in STK11 had a higher ORR of 50% as compared with patients whose tumors did not have STK11 mutation. In addition, they did not find a similar difference in response in patients with STK11/KEAP1, or single KEAP1-mutant tumors. What is interesting to me is that another KRAS pG12C inhibitor, adagrasib (previously MRTX849), has also shown similar greater efficacy in patients with comutations in STK11, and this is particularly interesting since there are data to suggest that immunotherapy agents may not be effective or as efficacious in patients with STK11 mutations.4,5 Thus, it is possible that these drugs not only provide efficacy in patients with KRAS pG12C, but also may have a greater therapeutic benefit in patients whose tumors have KRAS pG12C mutation with the STK11 comutation.

CodeBreaK 200: Sotorasib vs Docetaxel in KRAS p.G12C–Mutated NSCLC: Study Design

Nicolas Girard, MD, PhD:
The confirmatory, multicenter, phase III CodeBreaK 200 study (NCT04303780) is comparing sotorasib with docetaxel in patients with locally advanced KRAS pG12C–mutant NSCLC as a second‑line treatment. In that patient population, docetaxel has historically shown a response rate of approximately 9% and a PFS of 2.9 months. Thus, given what we have learned from the CodeBreaK 100 study of sotorasib, I would expect to see a benefit for sotorasib vs docetaxel and subsequent integration of sotorasib into practice as a standard second-line treatment in patients with KRAS pG12C–mutant NSCLC.

Dr. Gadgeel, what are your thoughts on the CodeBreaK 100 clinical data to date? How should sotorasib be integrated in the second- or first-line setting: single agent, combination with chemotherapy, or with immunotherapy treatment?

Shirish M. Gadgeel, MD:
It is important to note that sotorasib is also being evaluated in phase I (NCT04185883) and phase II (NCT04625647) studies in combination with other agents, prominent among them being immunotherapy agents such as pembrolizumab, EGFR inhibitors, as well as SHP2 inhibitors. It is quite possible that one of those combinations may provide even greater benefit; in particular, it would be interesting to evaluate these combinations in specific patient subsets such as those with comutations in P53 or STK11.

I also believe the CodeBreaK 200 study will establish sotorasib as a second‑line treatment for patients with NSCLC and KRAS pG12C mutation. As far as its role as frontline therapy, including in combination, there is much work to be done. But my expectation is that the utility of this drug either in frontline or in recurrent KRAS G12C–mutant NSCLC is going to be in combination with other agents such as chemotherapy, checkpoint inhibitors, EGFR inhibitors, and SHP2 inhibitors.

EGFR Exon20ins vs Common EGFR Mutations Real-World Outcomes: Study Design

Nicolas Girard, MD, PhD:
Among the EGFR mutations in NSCLC, we have common EGFR mutations L858R and exon 19 deletions, and we have uncommon mutations, the most frequent of which are EGFR exon 20 insertions. Of importance, patients whose tumors harbor EGFR exon 20 insertions typically do not experience a meaningful benefit with available EGFR TKIs as do patients with EGFR L858R mutations or exon19 deletions, but these patients might benefit from EGFR exon 20 insertion–specific agents currently in development.

At WCLC 2020, I presented results from a retrospective real-world outcomes study comparing outcomes for patients with advanced NSCLC with EGFR exon 20 insertion vs common EGFR mutations using the Flatiron Health database.6 The key objectives of the study were to assess the prognostic value of EGFR exon 20 insertions as compared with common EGFR mutations, with the primary endpoint being differences in OS; the second objective was to look at the predictive value of EGFR exon 20 insertions for the efficacy of TKI treatments, with the primary endpoint of PFS; and the third objective was to discuss the patient characteristics and the treatment strategies delivered in those patients. Patients with advanced EGFR-mutant NSCLC diagnosed from 2011-2020 were included in the analysis, and those patients had to start treatment within 90 days after the diagnosis of advanced disease.

In this study, baseline patient characteristics were well balanced except for a slightly higher proportion of patients of male gender in the EGFR exon 20 insertion cohort (43%) compared with patients with common EGFR mutations (33%).

EGFR Exon20ins vs Common EGFR Mutations (Real-World Outcomes): Efficacy

Nicolas Girard, MD, PhD:
In this study, as expected, we were able to show that patients with NSCLC and EGFR exon 20 insertions have a worse prognosis—and worse OS overall— compared with patients with NSCLC harboring common EGFR mutations. The median OS was 16.2 months with EGFR exon 20 insertions vs 25.5 months for common EGFR mutations. The 5-year OS for patients with EGFR exon 20 insertions was only 8% vs 19% for patients with NSCLC and common EGFR mutations.

In addition, if we look at the PFS of patients with EGFR exon 20 insertions, receiving treatment with available anti-EGFR TKI, we confirm a substantial absence of efficacy for currently available TKIs not designed specifically to target EGFR exon 20 insertions with a PFS of only 2.9 months vs 10.5 months in patients with common EGFR mutations. Of importance, compared with patients whose tumors harbor common EGFR mutations, patients whose tumors harbor EGFR exon 20 insertion are 154% more likely to have a shorter time to next treatment, and 170% more likely to die from their lung cancer. These findings agree with other worldwide studies and clinical trials that have evaluated the efficacy of those TKIs in this setting. The takeaways are, clearly, spontaneously worse OS and limited efficacy of available EGFR TKIs in patients with NSCLC carrying EGFR exon 20 insertions.

EGFR Exon20ins vs Common EGFR Mutations Real-World Outcomes: Treatment Patterns

Nicolas Girard, MD, PhD:
When looking at the treatment patterns for patients with EGFR exon 20 insertions, most patients received platinum-based chemotherapy as first-line treatment, which yielded a median PFS of 6.6 months and an OS of 17.4 months. Some patients were treated in the first-line setting with EGFR TKIs, but as mentioned previously, this strategy had limited efficacy as demonstrated by a median PFS of 2.9 months and median OS of only 9.5 months—which is much lower than platinum-based chemotherapy.

And if we look at the global strategy in the second-line setting, patients treated in first line with TKIs went on to receive platinum-based chemotherapy in second line, and patients who did receive platinum-based chemotherapy probably moved to ICIs or a combination of chemotherapy plus VEGF inhibitors. Thus, here we have the treatment patterns from a real-world-evidence perspective. Ultimately what we can say, from a predictor standpoint, is that those patients with tumors harboring EGFR exon 20 insertions should not receive the currently available EGFR TKIs in any line of treatment and should receive platinum-based chemotherapy instead, which is associated with the best outcomes in terms of PFS and OS.

EGFR Exon20ins vs Common EGFR Mutations Real-World Outcomes: Conclusions

Nicolas Girard, MD, PhD:
Data from this retrospective real-world outcomes study suggest that patients with NSCLC and EGFR exon 20 insertions have a worse prognosis than those with common EGFR mutations—namely, L858R and exon 19 deletions. Moreover, currently available TKIs yield substandard PFS and OS when compared with platinum-based chemotherapy and should not be used as first-line treatment of patients with NSCLC and EGFR exon 20 insertions. Ultimately, these data show that we need targeted agents specific for EGFR exon 20 insertions. At WCLC 2020, exciting new data were reported for 2 EGFR exon 20 insertion–specific agents—amivantamab and mobocertinib—which we discuss next.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Study Design

Nicolas Girard, MD, PhD:
At WCLC 2020, Sabari and colleagues7 reported updated results from the phase I dose-escalation/expansion CHRYSALIS study of amivantamab, an EGFR-MET bispecific antibody, in patients with unresectable/metastatic NSCLC and EGFR exon 20 insertions who had progressed on previous platinum-based chemotherapy. The study had a dose-escalation cohort and a dose-expansion cohort focusing on NSCLC with EGFR exon 20 insertions. The safety population consisted of 114 patients and an efficacy population of 81 patients. The primary endpoint was ORR, and secondary endpoints included clinical benefit rate, DoR, PFS, and OS.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Baseline Characteristics

Nicolas Girard, MD, PhD:
In this efficacy population, the median age was 62 years; 22% had previous history of brain metastases; the median previous lines of therapy was 2 (range: 1-7); all patients had received previous platinum-doublet chemotherapy, 46% had received previous immune-oncology treatment, and 25% had previously received anti-EGFR TKI (first generation 9%; second generation 7%; third generation 7%) or the multikinase inhibitor poziotinib (1%).

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Patient Disposition

Nicolas Girard, MD, PhD:
Treatment with amivantamab was relatively well tolerated. Grade ≥3 TRAEs were reported in 16% of patients. TRAEs leading to dose interruptions, dose reductions, and treatment discontinuation were reported in 21%, 13%, and 4% of patients, respectively. Of importance, there were no treatment-related deaths on this study.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Safety Summary

Nicolas Girard, MD, PhD:
The safety profile of amivantamab was consistent with EGFR and MET pathway inhibition. TRAEs reported were mostly cutaneous and gastrointestinal in nature. EGFR inhibition–related all-grade AEs of rash, paronychia, stomatitis, and pruritus were reported in 86%, 42%, 18%, and 17% of patients, respectively; only 2% of patients discontinued amivantamab treatment due to rash. MET inhibition–related all-grade AEs of hypoalbuminemia and peripheral edema were reported in 15% and 10% of patients, respectively. Infusion-related reactions were reported in 66% of patients, primarily occurring during the first infusion (94%), but this did not affect patients’ ability to receive subsequent treatments.

Dr. Gadgeel, is there anything else you would like to highlight about the safety profile of amivantamab?

Shirish M. Gadgeel, MD:
It is important to reiterate that this drug is associated with infusion‑related reactions usually occurring during the first dose. It is for this reason that the initial dose is divided over 2 days, where approximately 350 mg of the dose is infused on the first day and the remaining portion is infused on Day 2. This approach has led to a significant reduction in infusion‑related reactions in patients receiving amivantamab. In addition, all patients receive premedications prior to infusion on Day 1. However, infusion reactions can still occur but usually they are manageable by initially holding the infusion and then resuming the infusion once the patient has recovered. An extremely small minority of patients do develop infusion‑related reactions during the second infusion the following week. However, it is with these measures that the drug can be delivered quite safely.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: BICR Responses

Nicolas Girard, MD, PhD:
In CHRYSALIS, amivantamab yielded an ORR of 40% (complete response: 4%) and a clinical benefit rate of 74%, which is very high for this patient population with refractory disease and in which the available treatments have limited efficacy. The ORR benefit was observed across all key subgroups of patients, including in patients with ≥3 previous lines of therapy (58%). The median duration of response in this cohort of patients was 11.1 months.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Response Over Time

Nicolas Girard, MD, PhD:
Something I thought was promising from this study was that 63% of patients achieved a prolonged response of more than 6 months. The median PFS reported was 8.3 months and the median OS was 22.8 months, and at the time of data cutoff, 47% of patients remained on treatment.

CHRYSALIS Study of Amivantamab in NSCLC With EGFR Exon20ins: Conclusions

Nicolas Girard, MD, PhD:
Overall, the efficacy of amivantamab in EGFR exon 20 insertion NSCLC is very promising. An ORR of 40%, and up to 58% in patients with ≥3 previous lines of therapy, is quite impressive. Amivantamab exhibited a manageable safety profile consistent with on-target EGFR and MET pathway inhibition. The CHRYSALIS study is still ongoing and I am interested to see results for the other cohorts, particularly in patients who previously failed an EGFR TKI in the context of common EGFR mutations—namely, EGFR L858R mutations or exon 19 deletions. Amivantamab is also being studied as frontline therapy in combination with carboplatin-pemetrexed chemotherapy in patients with metastatic NSCLC and EGFR exon 20 insertions in the phase III PAPILLON study (NCT04538664).

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Study Design

Nicolas Girard, MD, PhD:
Another option for patients with NSCLC and EGFR exon 20 insertions is mobocertinib, a potent first-in-class TKI targeting EGFR exon 20 insertion mutations. Mobocertinib was initially evaluated in a phase I study, with a dose-expansion phase II with several different cohorts in NSCLC, including with EGFR exon 20 insertions.8

At WCLC 2020, Zhou and colleagues9 presented data from a phase I/II study of mobocertinib, with first results from the EXCLAIM extension cohort and including results for patients who received previous platinum-based chemotherapy from the dose-escalation/expansion cohorts. The primary endpoint was ORR by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints included safety, tolerability, pharmacokinetics, and efficacy.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Baseline Characteristics

Nicolas Girard, MD, PhD:
Baseline characteristics in the 2 cohorts were relatively well balanced. The median age of patients enrolled in this study was 60 and 59 years in the platinum-pretreated patient (PPP) cohort and in the EXCLAIM cohort, respectively; 90% of patients in the EXCLAIM cohort and 100% in the PPP cohort had received previous platinum-based chemotherapy, and at least a quarter of patients in either cohort had received previous TKI or immunotherapy.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Efficacy

Nicolas Girard, MD, PhD:
In the 96 patients from the EXCLAIM extension cohort, the response rate by independent review committee was 25% at the updated analysis, similar to what was previously reported at the first analysis. Response per investigator in the EXCLAIM extension cohort was 32%, median PFS was 7.3 months, and median DoR had not been reached. In the PPP cohort, response rate by independent review committee was 28% at the updated analysis, which is also similar to what was previously reported at the first analysis (26%). Response per investigator in the PPP cohort was 35% at both analyses, and the median PFS was also 7.3 months, and similar to the EXCLAIM cohort, median DoR had not been reached. In 78% of patients in the PPP cohort and 84% in the EXCLAIM cohort who had response, the DoR per independent review committee extended beyond 6 months.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Response

Nicolas Girard, MD, PhD:
Of interest, and similar to what we had previously seen with amivantamab, patients who do not achieve an overall response are presenting with stable disease. Overall, 82% of patients in the PPP cohort and 80% in the EXCLAIM cohort had reductions in target lesion volume.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: PFS and DoR in Platinum-Pretreated Patients

Nicolas Girard, MD, PhD:
In the PPP cohort, the median PFS and DoR were 7.3 months and 17.5 months, respectively, which compares favorably with the historical PFS expected for this heavily pretreated patient population.6 In the EXCLAIM cohort, the median PFS and DoR were 7.3 months and not reached, respectively, which also compares favorably with the historical PFS expected for this patient population.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Safety

Nicolas Girard, MD, PhD:
For me, one of the key differences, so far, between amivantamab and mobocertinib is probably the safety profile of these novel agents. Grade 3 treatment-related AEs were observed in approximately 40% of the patients treated with mobocertinib.

In the PPP cohort, TRAEs leading to dose reductions, treatment discontinuations, or death were reported in 25%, 17%, and 1% of patients, respectively. In the EXCLAIM cohort, TRAEs leading to dose reductions, treatment discontinuations, or death were reported in 21%, 10%, and 1% of patients, respectively. The most common AEs leading to drug discontinuations in both PPP and EXCLAIM cohorts were nausea (4% and 2%) and diarrhea (4% and 2%).

Of note, investigators also reported 1 treatment-related death due to cardiac failure—potentially related to the kinase inhibition or mechanism of action of mobocertinib. Thus, cardiac-related toxicity is something that may need to be explored further in this study. However, the frequency and the severity of cardiac side effects seem to be a little bit lower than what we have seen with amivantamab—but then again, the efficacy with mobocertinib appears to be a bit lower than what we have seen with amivantamab in a similar patient population.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Safety by Patient Cohort

Nicolas Girard, MD, PhD:
Similar to amivantamab, the safety profile of mobocertinib is associated with cutaneous and gastrointestinal AEs mainly. However, the incidence of diarrhea seems to be more of a concern with mobocertinib. In the PPP and EXCLAIM cohorts, the incidence of diarrhea was quite high, and was reported in 90% of patients receiving mobocertinib; grade 3/4 diarrhea occurred in 21% and 16% of patients in the PPP cohort and EXCLAIM cohorts, respectively. Of interest, evident changes in symptoms scores were observed after cycle 2 and this was maintained throughout treatment.

Dr, Gadgeel, would you like to comment on the AE profile of mobocertinib and how to manage its potential toxicities?

Shirish M. Gadgeel, MD:
Mobocertinib is associated with gastrointestinal toxicities, primarily diarrhea and nausea, and vomiting. In these patients, diarrhea can be managed with standard antidiarrheals, or with drug hold, and drug dose reduction. Despite its AE profile, mobocertinib led to improvement in lung cancer–related symptoms such as shortness of breath, coughing, and chest pain. In other words, patients experienced improvement in symptoms related to their lung cancer with this drug.

Phase I/II of Mobocertinib in NSCLC With EGFR Exon20ins: Conclusions

Nicolas Girard, MD, PhD:
Data for mobocertinib in NSCLC with EGFR exon 20 insertions is promising. Patients in the PPP and EXCLAIM cohorts achieved an ORR between 23% and 26%, and a median PFS of 7.3 months in both cohorts by independent review committee, which compares favorably with the historical median PFS in previously treated NSCLC with EGFR exon 20 insertions.6

However, gastrointestinal AEs are a concern with mobocertinib. In this study, diarrhea was reported in ≥90% of patients, and it led to treatment discontinuation in up to 4% of patients at the first analysis.

To better understand the roles of these 2 novel EGFR exon 20 insertion–specific targeted therapies, we will need longer-term follow-up data for the CHRYSALIS study of amivantamab and the various cohorts of the phase I/II study of mobocertinib. We eagerly await these results, and what I think will also be key are the results of the randomized studies in the first‑line setting with amivantamab (NCT04538664) and in the first/second‑line setting with mobocertinib (NCT04129502; NCT04535557).

Dr. Gadgeel, what do you think of the data for these 2 inhibitors specific for EGFR exon 20 insertions? How would you differentiate between amivantamab and mobocertinib if available for this patient population?

Shirish M. Gadgeel, MD:
I think that both amivantamab and mobocertinib have demonstrated efficacy and, based on the results presented at WCLC 2020, there is a very good chance, in my opinion, that these drugs will be approved in the United States. My suspicion is that both drugs will get utilized and whether one drug is used before the other will really be individualized based on a patient’s status and a patient’s needs and preferences. Amivantamab is given intravenously and is associated with infusion‑related reactions but, in my opinion, appears to be generally better tolerated over time, whereas mobocertinib is an orally administered drug and so is clearly more convenient and has none of the infusion‑related AEs observed with amivantamab. On the other hand, diarrhea can be a significant challenge with mobocertinib both for the patient as well as for the healthcare provider—in terms of maintaining the patient on the drug, and because the AEs may lead to discontinuations or dose reduction, which may limit its efficacy. In general, my prediction is that both agents will be utilized and physicians will choose based on individual patient situation and preferences.

Antibody–Drug Conjugates: Mechanism of Action

Nicolas Girard, MD, PhD:
Antibody–drug conjugates (ADCs) are a novel class of drugs currently being evaluated in several different tumor types, including in NSCLC. ADCs typically consist of a humanized IgG1 monoclonal antibody with a tetrapeptide-based cleavable linker and a cytotoxic agent payload (eg, topoisomerase I inhibitor). Some of the advantages of these novel compounds include a high antibody–drug ratio, tumor-selectivity with intratumor cleavable linker, high potency, and short systemic half-life to reduce off-target toxicity.

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: Study Design

Nicolas Girard, MD, PhD:
DESTINY-Lung01 is a multicenter, open label phase II study evaluating trastuzumab deruxtecan (formerly DS-8201), a HER2-directed ADC with a protease-cleavable linker to a topoisomerase I inhibitor, in patients with unresectable/metastatic nonsquamous NSCLC that is HER2-overexpressing or with a HER2-activating mutation (NCT03505710).10 At the 2020 ASCO annual meeting, we saw results of trastuzumab deruxtecan in HER2-mutant NSCLC (cohort 2) reporting an ORR of approximately 62%, DCR of 90.5%, and median PFS of 14.0 months, which was really impressive, and obviously this requires further follow-up and assessment in those patients.

At WCLC 2020, Nakagawa and colleagues11 reported interim efficacy and safety results from the cohort 1 of DESTINY-Lung01, in 49 patients with HER2-overexpressing metastatic NSCLC. In this study, HER2 overexpression (IHC2+ or IHC3+ status) was evaluated with archived tissue and confirmed centrally. At data cutoff, 11 patients remained on treatment and 38 patients had discontinued treatment (22 due to progressive disease, 9 due to AEs, and 7 for other reasons).

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
Baseline characteristics of patients enrolled in cohort 1 of DESTINY-Lung01 included a median age of 63 years (range: 37-85) and a median of 3 previous lines therapy (range: 1-8). Approximately 80% of patients had HER2 IHC2+ status and 20% had IHC3+ status. Approximately 35% of patients in cohort 1 were reported to have central nervous system involvement.

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: Efficacy Summary

Nicolas Girard, MD, PhD:
The results show an ORR of 24.5% overall. Of note, ORR was comparable between patients with IHC2+ status (25.6%) and those with IHC3+ status (20.0%). For all patients, the DCR was 69% (95% CI: 54.6-81.8) and the median duration of response was 6.0 months (95% CI: 3.2-not estimable). In patients with IHC3+ status, the DCR was 80.0% (95% CI: 44.4-97.5). To me, these data appear a bit lower than what we had previously seen in the HER2-mutant cohort.10 However, these data are clinically significant in a population of patients with heavily pretreated or refractory tumors, who had received several different treatments including chemotherapy, ICIs, and other HER2-targeted treatments.

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: Safety Summary

Nicolas Girard, MD, PhD:
The safety profile of trastuzumab deruxtecan was consistent with previous reports in patients with other solid tumors.12 Median treatment duration was 18 weeks (range: 3.0-57.1 weeks). Overall and drug-related grade ≥3 AEs were reported in 73.5% and 55.1% of patients, respectively. Treatment-emergent AEs (TEAEs) leading to dose reduction, dose interruption, and treatment discontinuation were reported in 32.7%, 34.4%, and 12.2%, respectively. AEs of neutropenia (10.2%), fatigue (8.2%), and nausea (6.1) were associated with dose reductions, and AE of pneumonitis (10.2%) was associated with drug discontinuation.

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: AEs of Special Interest

Nicolas Girard, MD, PhD:
With regard to safety, one key concern with ADCs is the occurrence of interstitial lung disease (ILD), which was observed in approximately 16% of patients on this study. It is often challenging, in a patient with NSCLC, especially HER2-mutant NSCLC which may present with interstitial carcinomatosis, to make the distinction between tumor progression, infection, and toxicity of the treatment itself. In DESTINY-Lung01, there were 3 events of grade 5 ILD—this may be a concern and this should lead to better education of investigators and healthcare providers on this potentially deadly AE. And even more so now that trastuzumab deruxtecan is becoming available in many more countries for advanced tumors like HER2-positive breast cancer, I think additional education on how to closely monitor patients is clearly needed to help prevent cases of severe ILD. We also must pay close attention to the lung parenchyma during the follow-up of those patients receiving trastuzumab deruxtecan.

Dr, Gadgeel, do you have any comments on the AEs of interest with trastuzumab deruxtecan or any advice on how to manage events of ILD?

Shirish M. Gadgeel, MD:
Overall, the drug was reasonably well tolerated, and toxicities observed were no different than what has been previously reported with this drug. One of the important AEs to be aware of is pneumonitis, which occurred in approximately 10% of the patients. Typically, this AE of ILD [pneumonitis] is managed with steroids. Previous data have shown that the rate of ILD is higher at the higher dose, and because of this, the dose in the subsequent cohort is going to be 5.4 mg as compared with 6.4 mg, which was the dose used for the interim cohort that was presented at WCLC 2020—hopefully maintaining efficacy. Another important finding worth highlighting is that 4 of the 8 patients who did experience ILD had received prior ICIs, and it remains to be determined whether prior treatment with ICIs may be a risk factor for patients developing ILD with trastuzumab deruxtecan.

Phase II DESTINY-Lung01 of Trastuzumab Deruxtecan in HER2-Overexpressing NSCLC: Conclusions

Nicolas Girard, MD, PhD:
I think that in patients with HER2‑overexpressing NSCLC, trastuzumab deruxtecan appears to exhibit lower efficacy than in patients with HER2‑mutant NSCLC. Nonetheless, an ORR of 25% is clinically significant in the refractory disease setting. I also think we probably need more data and longer follow-up from the DESTINY-Lung01 study. Moreover, we probably need to assess trastuzumab deruxtecan earlier during the course of treatment—and I would also say an ORR of 25% is much better than what we currently have with docetaxel. I think we need to continue to evaluate the role of trastuzumab deruxtecan in NSCLC, both in HER2‑mutant and HER2‑overexpressing tumors.

Dr, Gadgeel, what do you think?

Shirish M. Gadgeel, MD:
These results show that trastuzumab deruxtecan does have promising efficacy in patients with HER2-overexpressing NSCLC. What is remarkable to me is that this clinical activity was observed in patients who were heavily pretreated. Also, potentially this drug could be used in combination with other drugs, such as other chemotherapy drugs as another possible option for patients whose tumors overexpress HER2. Of course, we will need to await the results of the expansion cohort 1 to confirm these findings before this drug is further evaluated.

Phase I TROPION-PanTumor01 Study of Datopotamab Deruxtecan in Advanced NSCLC: Study Design

Shirish M. Gadgeel, MD:
At WCLC 2020, Spira and colleagues13 presented results from the dose-expansion phase of the TROPION-PanTumor01 study evaluating datopotamab deruxtecan in patients with advanced NSCLC. Important to note is that this study also evaluates this agent in other tumor types as well. Datopotamab deruxtecan has a similar structure to trastuzumab deruxtecan, which we previously discussed, except that the antibody moiety targets TROP-2. TROP-2 is a molecule that is expressed on several tumor types, including NSCLC, and it is preferentially expressed in tumor cells as compared with normal cells, which makes it ideal as a therapeutic target and improves the therapeutic window of this payload. Patients enrolled on this study had relapsed or refractory NSCLC, and were not selected based on TROP-2 expression. The initial dose-escalation portion of the study evaluated datopotamab deruxtecan in 63 patients at doses ranging from 0.27 mg/kg to 10 mg/kg every 3 weeks, and in dose-expansion, patients with NSCLC received either 1 of 3 dose levels: 4 mg/kg, 6 mg/kg, or 8 mg/kg, also given every 3 weeks. In total, 175 patients with NSCLC were treated in the dose-expansion and the data for these patients was presented at WCLC 2020. The primary endpoints for the dose-escalation part was identifying the maximum tolerated dose and safety, whereas for the dose-expansion cohort, the endpoints were efficacy and pharmacokinetics.

Phase I TROPION-PanTumor01 Study of Datopotamab Deruxtecan in Advanced NSCLC: Safety/Disposition

Shirish M. Gadgeel, MD:
The median follow-up at this meeting was 7.4 months (range: 0.1-21.7 months). Regarding safety, the toxicities observed with this drug were primarily nonhematologic, including nausea, vomiting, stomatitis, fatigue, and constipation. Grade ≥3 stomatitis was observed at a higher rate with the 8-mg/kg dose, compared with the 6-mg/kg or the 4-mg/kg dose. Moreover, similar to that seen with trastuzumab deruxtecan, treatment-related ILD was observed with this drug and was reported in 8% of patients—the rate was higher with the higher dose of 8 mg/kg as compared with 6 mg/kg, or 4 mg/kg. Thus, this appears to be a drug class–related AE with these novel agents. Grade ≥3 TEAEs occurred in 56%, 38%, and 22% of patients at the 8-mg/kg, 6-mg/kg, and 4-mg/kg doses, respectively. Drug discontinuation due to an AE was reported in 15%, 7%, and 4% of patients at the 8-mg/kg, 6-mg/kg, and 4-mg/kg doses, respectively. Of importance, treatment-emergent or treatment-related deaths were reported in 3%, 0%, and 2% of patients at the 8-mg/kg, 6-mg/kg, and 4-mg/kg doses, respectively.

Phase I TROPION-PanTumor01 Study of Datopotamab Deruxtecan in Advanced NSCLC: Efficacy

Shirish M. Gadgeel, MD:
The ORR in this heavily pretreated patient population was 21% to 25%, with a disease control rate ranging between 67% and 80%. The median PFS ranged from 4.3 to 8.2 months. However, these data have to be viewed with a level of caution as the numbers are relatively small. Investigators also report there was consistent pharmacokinetics, and this was observed throughout the 3 treatment cycles at each dose and, based on the efficacy data and the toxicity data, the drug is going to be further evaluated at the 6-mg/kg dose.

Phase I TROPION-PanTumor01 Study of Datopotamab Deruxtecan in Advanced NSCLC: Conclusion

Shirish M. Gadgeel, MD:
Data from the expansion cohort of this phase I study of datopotamab deruxtecan in patients with heavily pretreated NSCLC show similar safety and efficacy to that of trastuzumab deruxtecan. Events of ILD continue to be of concern with this class of agents, and they were reported in 8% of patients in this study. The ORR also was similar to that of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC, and it was 21% at the 6-mg/kg dose and 25% at the 8-mg/kg dose.

I think it would be interesting to see efficacy analyses based on the level of TROP-2 expression in the TROPION-PanTumor01 study. Tissue has been collected from these patients and there will be a retrospective assessment of efficacy based on TROP-2 expression, which I am looking forward to seeing presented. It is possible that patients with tumors with high TROP-2 expression may derive even greater benefit from this drug, and it is also possible for this drug to have a role in the treatment of patients with NSCLC in the future.

KRAS and TP53 Mutations in Predicting Response to ICIs in NSCLC: Study Design

Shirish M. Gadgeel, MD:
In recent years, a major step forward in the management of advanced NSCLC was the use of immunotherapy agents. Of importance, the main reason immunotherapy for the treatment of patients with NSCLC has created a high level of interest is because of the sustained benefit observed in a minority of patients with this disease. Thus, there’s a great deal of interest in identifying additional subgroups of patients who could derive a sustained benefit with immunotherapy treatment.

At WCLC 2020, Li and colleagues14 presented data on a meta-analysis conducted in 1129 patients with EGFR/ALKWT nonsquamous NSCLC with the goal of evaluating the relevance of KRAS mutations and TP53 mutations, particularly comutations in these 2 genes, and responses to ICIs. There were 8 cohorts, which included patients treated in a clinical trial setting or a real-world setting; patients had received either PD-1 or PD-L1 inhibitors with or without a CTLA-4 inhibitor (ipilimumab). Investigators assessed 3 key variables of efficacy—ORR, PFS, and OS—and they evaluated this cohort based on whether the patients’ tumors had a TP53-mutated or wild-type gene, a KRAS-mutated or wild-type gene, or comutations in both KRAS and TP53.

KRAS and TP53 Mutations in Predicting Response to ICIs in NSCLC: Efficacy Analysis

Shirish M. Gadgeel, MD:
In patients whose tumors had TP53 mutations without or with KRAS mutations, ORR was significantly higher (P = .001 and P = .011, respectively) and PFS was significantly improved compared with patients whose tumors were TP53 wild-type (P = .019 and P = .017, respectively), but there was no significant difference in OS (P = .071 and P = .078, respectively).

Similarly, in patients with KRAS mutation–positive NSCLC, ORR with ICIs was significantly higher vs KRAS wild‑type NSCLC (P = .040) but with no significant difference found for PFS (P = .295) or OS (P = .947). In patients with KRAS-mutated and TP53-comutated tumors, ORR was significantly higher (P = .011), almost twice the response rate for patients with KRAS wild-type and TP53 mutated tumors (relative risk: 1.98; 95% CI: 1.17-3.35). Moreover, the HR for PFS in TP53- and KRAS-mutated was 0.66—showing significant improvement relative to patients with TP53-mutated/KRAS wild-type tumors. Similarly, the HR for OS in the same group was 0.73—which did not meet statistical significance but suggested that these patients did survive longer with the checkpoint inhibitors than patients who did not have TP53 and KRAS comutations. When compared with patients without TP53 and KRAS comutations, patients with TP53 and KRAS comutations had an approximately 2.5-fold higher ORR (P <.001), a 42% reduced risk of progression or death (HR: 0.58; P <.001), and a nonsignificant 14% reduced risk of death (HR: 0.86).

KRAS and TP53 Mutations in Predicting Response to ICIs in NSCLC: PFS

Shirish M. Gadgeel, MD:
Of interest, benefit was not observed in this data set when investigators assessed efficacy with chemotherapy. They also conducted a similar analysis from a combined cohort of the POPLAR and OAK trials, which evaluated atezolizumab in patients with recurrent NSCLC vs docetaxel, and they found that patients who had both TP53 and KRAS mutations in the meta-analysis had an ORR of 50% with atezolizumab vs 7.7% with docetaxel in the POPLAR/OAK trials.

KRAS and TP53 Mutations in Predicting Response to ICIs in NSCLC: Conclusion

Shirish M. Gadgeel, MD:
Taken together, data suggest TP53/KRAS comutations are associated with better ORR and PFS with immunotherapy vs chemotherapy. Moreover, patients whose tumors have both KRAS and TP53 mutations have a much greater benefit with atezolizumab both in terms of ORR and PFS. Further study of these biomarkers and efficacy of immunotherapy agents is warranted, particularly in the context of emerging KRAS mutation–directed targeted agents.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: Study Design

Shirish M. Gadgeel, MD:
The KEYNOTE-598 trial is an ongoing double-blind randomized, phase III study evaluating pembrolizumab plus ipilimumab vs pembrolizumab plus placebo in 600 patients with high tumor cell expression of PD-L1 (≥50%) and no actionable EGFR or ALK genetic alterations.15 In this population of patients, the standard of care is single-agent pembrolizumab, which has demonstrated an OS benefit compared with chemotherapy.16 The key objective of the KEYNOTE-598 study was to improve the outcomes of patients with PD-L1–high metastatic NSCLC from the standard-of-care pembrolizumab. Patients received standard-dose pembrolizumab at 200 mg every 3 weeks and ipilimumab at a dose of 1 mg/kg every 6 weeks. The primary endpoints were OS and PFS per RECIST v1.1 by blinded independent central review.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: Baseline Characteristics

Nicolas Girard, MD, PhD:
In KEYNOTE-598, treatment arms were well balanced overall. The median age was 64 years for pembrolizumab plus ipilimumab (range: 35-85) and 65 years (range: 35-85) for pembrolizumab plus placebo. Most patients (89.8% and 91.2%) were current or former smokers with predominantly nonsquamous tumor histology (72.9% and 71.5%) in the pembrolizumab plus ipilimumab or pembrolizumab plus placebo arms, respectively.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: Responses

Nicolas Girard, MD, PhD:
ORR was not different between the 2 arms (45% vs 45%), and it is similar to what was reported in the landmark KEYNOTE-024 trial.16 Thus, the addition of ipilimumab to pembrolizumab did not improve ORR in the KEYNOTE-598 study.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: OS and PFS

Nicolas Girard, MD, PhD:
PFS and OS analyses also showed no difference between the treatment arms in this study. To me, this was an interesting study because it showed that ipilimumab is probably not the way to improve the outcomes of patients who can potentially achieve a good efficacy outcome with single-agent pembrolizumab—namely, patients with PD-L1 ≥50%—and in whom the addition of a CTLA-4 inhibitor may not be needed. These data agree with what the CheckMate 227 study showed,17 which was exploring the combination of nivolumab plus ipilimumab vs nivolumab alone. On the other hand, we also have data from the CheckMate 9LA trial evaluating chemotherapy plus nivolumab and ipilimumab vs chemotherapy alone as first-line treatment of patients with advanced NSCLC.18 In that study, the combination arm showed ORR/PFS/OS improvement compared with chemotherapy. The lack of improvement seen in the KEYNOTE-598 trial, by adding ipilimumab to pembrolizumab, potentially suggests that in patients with high PD-L1 tumor expression we may not need the combination of 2 checkpoint inhibitors—potentially the combination of anti–PD-1 plus anti–CTLA-4 should be reserved for patients with low or no PD-L1 expression.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: Safety

Nicolas Girard, MD, PhD:
As expected, the combination of pembrolizumab and ipilimumab resulted in numerically higher immune-mediated toxicity. The median number of treatment cycles with pembrolizumab plus ipilimumab was 10 months vs 15 months with pembrolizumab plus placebo. Treatment-related grade 3-5 AEs were reported in 35.1% of patients treated in the combination vs 19.6% of patients treated with pembrolizumab plus placebo; immune-mediated grade 3-5 AEs were reported in 20.2% of patients treated in the combination arm vs 7.8% of patients who received pembrolizumab plus placebo. Similarly, serious treatment-related (27.7 vs 13.9%) and immune-related (19.1% vs 7.1%) AEs were higher with pembrolizumab and ipilimumab vs pembrolizumab plus placebo.

KEYNOTE-598 Study of Pembro Plus Ipi as 1L in NSCLC With PD-L1 TPS ≥50%: Conclusions

Nicolas Girard, MD, PhD:
In summary, KEYNOTE 598 is a phase III study evaluating dual checkpoint inhibition in patients without an actionable EGFR/ALK molecular alteration and PD-L1 expression of ≥50% in tumor cells. In this population of patients, the standard of care is pembrolizumab alone, which demonstrated a benefit in terms of survival as compared with chemotherapy. And in this study the combination of pembrolizumab plus ipilimumab did not improve outcomes in these patients. I think these are very important data even if it’s a negative trial, and perhaps it will also be helpful to integrate nivolumab plus ipilimumab and chemotherapy (CheckMate 9LA) into our treatment algorithm.

Nivo Plus Ipi vs Nivo in Previously Treated Metastatic EGFR-Mutant NSCLC: Study Design

Shirish M. Gadgeel, MD:
There has been a great deal of interest in utilizing ICIs in patients with genetically altered NSCLC, specifically in EGFR mutation–positive patients. At WCLC 2020, Lai and colleagues19 presented the results of a randomized phase II study of nivolumab plus ipilimumab vs nivolumab in previously treated metastatic EGFR-mutant NSCLC. The study was terminated early due to futility with only 31 patients enrolled. Patients in that study received either nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, or single-agent nivolumab 3 mg/kg every 2 weeks. Patients were stratified according to PD-L1 tumor proportion status (<1% vs ≥1%) and presence of brain metastases (yes vs no). The primary endpoint was ORR and secondary endpoints included PFS, OS, DoR, and safety.

Nivo Plus Ipi vs Nivo in Previously Treated Metastatic EGFR-Mutant NSCLC: Efficacy

Shirish M. Gadgeel, MD:
What this study showed is that the response rate was quite low. There were no complete responses, and only 1 partial response (PR) (6.3%) was observed in the nivolumab plus ipilimumab arm. Compared with nivolumab alone, the combination of nivolumab plus ipilimumab yielded numerically similar median PFS (1.22 vs 1.33 months) and 6-month PFS (8.9% vs 8.3%). At 6 months, 5 patients had attained clinical benefit (PR or ongoing PR/stable disease); 5 with EGFR exon 19 deletion and 1 was positive for the T790M mutation. There were 3 patients who crossed over from the nivolumab monotherapy arm to the nivolumab plus ipilimumab arm, but none achieved a response after crossover.

Nivo Plus Ipi vs Nivo in Previously Treated Metastatic EGFR-Mutant NSCLC: Biomarker Analyses

Shirish M. Gadgeel, MD:
Regarding biomarker analyses, the study showed that there was no correlation between PD-L1 status, tumor mutation burden status, or gene expression profiling status with response in patients with EGFR-mutant NSCLC. Of note, no patients with clinical benefit had tumor mutation burden with ≥10 mutations/megabase.

Nivo Plus Ipi vs Nivo in Previously Treated Metastatic EGFR-Mutant NSCLC: Safety

Shirish M. Gadgeel, MD:
Unlike the KEYNOTE-598 study discussed previously, investigators reported the addition of ipilimumab to nivolumab did not result in increased incidence of any-grade TRAEs compared with nivolumab alone (80% vs 75%). Grade 3 AE of type 1 diabetes mellitus and myositis were reported in the nivolumab plus ipilimumab arm, and there was 1 event of grade 1 pneumonitis reported in the nivolumab monotherapy arm.

Nivo Plus Ipi vs Nivo in Previously Treated Metastatic EGFR-Mutant NSCLC: Conclusions

Shirish M. Gadgeel, MD:
The results from this study of nivolumab plus ipilimumab vs nivolumab in EGFR-mutant NSCLC are consistent with previous reports of checkpoint inhibitors in this patient population,20 and they also suggest that only a small proportion of patients with EGFR-mutant NSCLC derive benefit from checkpoint inhibitors—and that generally checkpoint inhibitors should not be considered in the management of EGFR-mutant NSCLC until these patients have been treated with the appropriate TKIs as well as chemotherapy.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Study Design

Nicolas Girard, MD, PhD:
Kilickap and colleagues21 presented results for the exploratory analyses of the randomized phase III EMPOWER-Lung 1 study of cemiplimab, an anti–PD-1 monoclonal antibody, vs chemotherapy in patients with advanced NSCLC with PD-L1 ≥50% and no EGFR/ALK/ROS1 mutation. Patients received either cemiplimab 350 mg every 3 weeks or 4-6 cycles of investigator’s choice chemotherapy. The coprimary endpoints in this study were OS and PFS, and secondary endpoints included ORR, DoR, health-related quality of life (HRQoL), and safety. The study design of EMPOWER-Lung 1 is very similar to that of the KEYNOTE‑024 study, which compared pembrolizumab vs chemotherapy in patients with high PD-L1 expression in tumors.16 A key difference between the 2 studies is that patients in the cemiplimab arm who are experiencing disease progression may continue cemiplimab plus 4 cycles of platinum‑based chemotherapy—meaning there is a double crossover allowed in this study.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Baseline Characteristics

Nicolas Girard, MD, PhD:
The median age of patients enrolled on the EMPOWER-Lung 1 study was 64 years, and most patients enrolled were men (>81%). Otherwise, baseline characteristics were relatively well balanced for the different cohorts.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Response by PD-L1 Expression

Nicolas Girard, MD, PhD:
Of note, Sezer and colleagues22 presented a previous report from EMPOWER-Lung 1 at European Society for Medical Oncology (ESMO) 2020, which led to the FDA approval of cemiplimab as a first-line therapy for patients with advanced NSCLC and high PD-L1 expression. What is unique about the data presented at WCLC 2020 for EMPOWER-Lung 1 is that efficacy was analyzed in clusters of patients defined by PD-L1 expression ≥50%. Data presented at the meeting also showed that increasing PD-L1 expression levels in tumor cells correlated with better response vs chemotherapy (ORR: 35.3% vs 17.7%) and increasing tumor size reduction as well.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Efficacy

Nicolas Girard, MD, PhD:
We also saw that patients with higher PD-L1 levels had prolonged efficacy vs chemotherapy, which suggests that increasing responses may translate into survival benefit.

We need a longer follow-up to better interpret the data from the EMPOWER-Lung 1 study—because long-term outcomes are a more relevant measure of efficacy with ICIs. For the KEYNOTE-024 study of pembrolizumab vs chemotherapy, we have at least 5 years of follow-up data.16 In that study, even after crossover from the chemotherapy arm to the pembrolizumab arm, the 5-year OS rate with pembrolizumab is double of that for patients treated in the chemotherapy arm (32% vs 16%). Thus, it will be very interesting to see what the long‑term outcomes will be for the EMPOWER-Lung 1 study.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Safety

Nicolas Girard, MD, PhD:
Regarding safety, cemiplimab exhibited a safety profile consistent with what we have come to expect with ICIs. Grade ≥3 immune-related AEs led to discontinuation in 1.4% of patients treated with cemiplimab vs none treated with chemotherapy. Median duration of exposure was 27.3 weeks with cemiplimab vs 17.7 weeks with chemotherapy. Thus, we do not have any unexpected side effects in this study.

Exploratory Analyses of EMPOWER-Lung 1 Study by PD-L1 Expression: Conclusions

Nicolas Girard, MD, PhD:
An outstanding question is how the continuation of cemiplimab at the time of progression, and the addition of 4 cycles of chemotherapy, could affect the OS of the experimental arm of EMPOWER-Lung 1. Moreover, to me, it would be interesting to see data for second PFS, to better understand what the best sequencing of treatments might be in patients with NSCLC with PD-L1 ≥50% who progressed after immunotherapy.

Dr. Gadgeel what are your thoughts on the continuation of cemiplimab after progression? Do you think there is some logic/merit to this strategy?

Shirish M. Gadgeel, MD:
In general, in select patients who progress during checkpoint inhibitors therapy, for example, if they have oligoprogression, I have continued them on checkpoint inhibitors. Therefore, I do see a role for checkpoint inhibitors beyond progression. However, in most cases, my strategy is to add chemotherapy in patients with high tumor PD-L1 expression who progress during treatment with a checkpoint inhibitor.

Comutations in DDR Pathways and Response to Atezolizumab in NSCLC (POPLAR/OAK): Study Design

Shirish M. Gadgeel, MD:
As previously mentioned, there is clearly an interest in identifying additional patients who could derive a sustained clinical benefit with ICIs. Previously, PD-L1 expression as well as tumor mutational burden have been evaluated as biomarkers to help identify patient populations that could derive sustained benefit from checkpoint inhibitors. Although high expression of PD-L1 in tumor tissue has been useful, the predictive utility in patients with mid to low expression of PD-L1 in tumors is quite limited. At WCLC 2020, Nie and colleagues23 presented an exploratory analysis utilizing the POPLAR/OAK data set assessing the relevance of mutations in DNA damage repair (DDR) pathway genes and response to atezolizumab. The POPLAR and OAK studies evaluated atezolizumab vs docetaxel in patients with previously treated advanced NSCLC.24 In this analysis, there were a total 853 patients, including 49 patients who had tumors with at least 2 DDR gene pathway alterations.

Comutations in DDR Pathways and Response to Atezolizumab in NSCLC (POPLAR/OAK): Baseline Characteristics

Shirish M. Gadgeel, MD:
When you looked at the baseline characteristics between the patients who had mutations in DDR genes as compared with the patients who did not have mutations in DDR genes, the baseline characteristics were very similar except that there was a slightly higher proportion of patients with mutations in the DDR gene pathway population who were treated with atezolizumab as compared with the negative cohort. The median blood tumor mutational burden was higher in this cohort of patients, which is not surprising since having mutations in the DDR gene pathway is likely to lead to a higher number of mutations in these tumors, resulting in higher tumor mutational burden.

Comutations in DDR Pathways and Response to Atezolizumab in NSCLC (POPLAR/OAK): Efficacy Summary

Shirish M. Gadgeel, MD:
The analysis by Nie and colleagues showed that the ORR with atezolizumab was significantly higher in patients whose tumors had mutations in DDR genes, at 26.7% vs 14.8% in patients who did not have DDR pathway mutations in their tumor. Of interest, when assessing the efficacy of docetaxel using this data set, there did not appear to be any significant difference, and patients who had mutations in their DDR pathway genes exhibited a lower response rate (11.8 vs 15.6%). Of importance, the higher ORR with atezolizumab in patients with DDR pathway mutations was associated with improvement in survival. Patients treated with atezolizumab who had DDR comutations achieved a significantly higher median PFS of 6.9 months vs 2.7 months, and median OS of 14.9 months vs 12.5 months when compared with those also receiving atezolizumab but without DDR mutations. Important to note, the interaction P value for these factors was statistically significant.

Comutations in DDR Pathways and Response to Atezolizumab in NSCLC (POPLAR/OAK): Conclusions

Shirish M. Gadgeel, MD:
Investigators concluded that atezolizumab monotherapy was associated with better response, PFS, and OS, in patients with comutation status in DDR pathway genes.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Study Design

Nicolas Girard, MD, PhD:
ADAURA is a global phase III study of adjuvant osimertinib, a third-generation EGFR TKI, vs placebo in 682 patients with EGFR‑driven NSCLC.25 This study enrolled patients 18 years of age or older with completely resected stage IB-IIIA NSCLC and either an EGFR exon 19 deletion or an EGFR L858R point mutation. Previous adjuvant chemotherapy was permitted, but previous radiotherapy was not. Patients in this study were randomized to receive either osimertinib 80 mg orally daily or placebo for up to 3 years or until disease progression. The primary endpoint of investigator‑assessed disease‑free survival (DFS) was previously reported and demonstrated a dramatic improvement favoring osimertinib vs placebo, with a reduction in the risk of disease progression or disease recurrence above 80%. At WCLC 2020, Wu and colleagues26 and Majem and colleagues27 reported subanalyses for DFS outcomes with or without postoperative chemotherapy and HRQoL outcomes from the ADAURA study, respectively. Postoperative chemotherapy was allowed based on current guidelines, but an outstanding question is whether this postoperative chemotherapy is needed in patients receiving osimertinib.

Evaluating the effect of osimertinib treatment in the adjuvant setting on the quality of life of patients is of great interest because of the prolonged duration of treatment in those patients who may have been potentially cured in the adjuvant setting.

The ADAURA study represents a paradigm shift, because this is the first time it has been demonstrated that precision medicine for lung cancer can move from metastatic disease to the early stage disease setting.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
As expected for a large, randomized clinical trial, baseline patient characteristics were well balanced for the osimertinib arm vs the placebo arm.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Prior Adj Chemotherapy

Nicolas Girard, MD, PhD:
In this study, 60% of patients in the total study population had received adjuvant chemotherapy prior to enrollment for a median of 4 cycles. And this varied by stage: 26% of patients with stage IB disease vs 80% of patients with stage IIIA disease, which is consistent with guideline recommendations. Moreover, patients younger than 70 years of age were more likely to receive chemotherapy than patients older than 70 years (66% vs 42%).

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: DFS by Previous Adj Chemotherapy/Stage

Nicolas Girard, MD, PhD:
Looking at outcomes with or without adjuvant chemotherapy, a similar magnitude of DFS benefit was observed across patients who had previously received adjuvant chemotherapy and patients who did not. To me this is very interesting, and it also leads to the obvious question about the need for adjuvant chemotherapy in patients with resected stage IB-IIIA disease. At the ASCO 2020 annual meeting, we had results for another study evaluating adjuvant use of an EGFR TKI—the ADJUVANT-CTONG 1104 trial.[28] That study compared gefitinib vs platinum-based chemotherapy in the adjuvant setting and also reported positive results in terms of DFS, but it failed to show an OS improvement in the intention-to-treat population.28

To me, even if we have a similar benefit in patients with or without adjuvant chemotherapy, we should continue to follow the design of ADAURA within routine practice setting—meaning that patients eligible and for whom chemotherapy is recommended should receive adjuvant chemotherapy before receiving treatment with osimertinib. At this time, we lack prospective randomized studies to better inform the actual need of adjuvant chemotherapy in those patients.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: SF-36 Compliance/Baseline Scores

Nicolas Girard, MD, PhD:
To evaluate any potential negative impact of prolonged osimertinib use in the adjuvant setting, investigators employed the SF‑36 health survey, which looks at general physical and mental HRQoL irrespective of a cancer diagnosis. The SF-36 surveys were completed at baseline, Week 12, Week 24, and then every 24 weeks until treatment completion. Results presented at WCLC 2020 showed that compliance with completing the SF‑36 survey was quite good for both treatment arms (≥85%). Moreover, SF-36 questionnaire results show that there was no clinically meaningful difference between the 2 arms in either the physical or mental scores at baseline. Except for Role-Physical, Social Functioning, and Role-Emotional scores, baseline health domain T-scores were comparable between arms and most were comparable with the general population mean (± 0.3 standard deviation of normative mean).

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Adjusted Mean Change in SF-36 T-Scores

Nicolas Girard, MD, PhD:
The HRQoL analysis of ADAURA showed there were no meaningful changes in SF-36 T-score components over time for osimertinib vs placebo. It is important to note however that these data were not collected after recurrence, but it would be interesting to see data from follow-up beyond recurrence as well.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Deterioration of SF-36 Components

Nicolas Girard, MD, PhD:
Investigators report that most patients in both arms did not experience clinically meaningful deterioration in Physical Component Summary or Mental Component Summary scores, and there was also no difference in time to deterioration between osimertinib and placebo in patients who did experienced deterioration.

ADAURA Subanalyses in Resected EGFR-Mutated NSCLC: Conclusions

Nicolas Girard, MD, PhD:
Overall, the reported subanalyses of ADAURA to date demonstrated comparable DFS benefit with or without previous adjuvant chemotherapy and showed that delivering osimertinib in the adjuvant setting, even for prolonged duration of treatment, does not appear to have a detrimental effect on the quality of life of patients treated in the adjuvant setting, which is very important given the need for daily treatment in those patients.

ITACA Study of Tailored vs Standard Adjuvant Chemotherapy in Resected Stage II-IIIA NSCLC: Study Design

Nicolas Girard, MD, PhD:
Another key study in the adjuvant setting presented at WCLC 2020 was the randomized, multinational, open-label ITACA trial evaluating tailored vs standard adjuvant chemotherapy in 690 patients with completely resected stage II-IIIA NSCLC.29 Patients were randomized to 1 of 4 profiles based on levels of mRNA expression: high excision repair cross-complementation 1 (ERCC1; predicted to confer resistance to platinum‑based therapy) and high thymidylate synthase (TS; likely to confer resistance to pemetrexed) to paclitaxel; high ERCC1 and low TS to pemetrexed; low ERCC1 and high TS to cisplatin/gemcitabine; and low ERCC1 and low TS to cisplatin/pemetrexed. The primary endpoint of the study was OS. Secondary endpoints included recurrence-free survival, toxicity, treatment compliance, and correlation of ECCR1 and TS mRNA levels with protein levels.

ITACA Study of Tailored vs Standard Adjuvant Chemotherapy in Resected Stage II-IIIA NSCLC: Baseline Characteristics

Nicolas Girard, MD, PhD:
Baseline characteristics were fairly similar in the ITACA study for the tailored and standard adjuvant chemotherapy arms. The median age was 65 and 64 years for patients in the tailored and standard adjuvant chemotherapy arms, respectively; most patients were male (70% and 68%), had adenocarcinoma histology (59% and 59%), and had undergone either previous lobectomy (83% and 76%) or pneumonectomy (17% and 14%).

ITACA Study of Tailored vs Standard Adjuvant Chemotherapy in Resected Stage II-IIIA NSCLC: RFS and OS

Nicolas Girard, MD, PhD:
After a median follow-up of 28.2 months, recurrence-free survival and OS curves showed a trend toward improvement in patients who had received tailored vs standard adjuvant chemotherapy. However, the difference was not statistically significant (HR: 0.94). Investigators also noted the study was not powered for assessing OS, and some expected events in this analysis were missed.

ITACA Study of Tailored vs Standard Adjuvant Chemotherapy in Resected Stage II-IIIA NSCLC: Safety

Nicolas Girard, MD, PhD:
In the ITACA study, tailored adjuvant chemotherapy was associated with lower rates of any-grade 3/4 AEs vs standard adjuvant chemotherapy (32.6% vs 45.9%); grade 3/4 AEs of neutropenia (13.4% vs 18.9%), leukopenia (3.9% vs 13.3%), and thrombocytopenia (3.3% vs 7.7%) were numerically lower with tailored vs standard adjuvant chemotherapy. Overall, grade 3/4 toxicities were likely to be significantly reduced by 43% with the use of tailored chemotherapy vs standard adjuvant chemotherapy.

ITACA Study of Tailored vs Standard Adjuvant Chemotherapy in Resected Stage II-IIIA NSCLC: Conclusions

Nicolas Girard, MD, PhD:
My takeaway from the ITACA study was that this study could benefit from a longer follow-up to better assess differences in OS. Also, it would be important to assess the feasibility of incorporating ERCC1 and TS mRNA testing into a routine practice setting.

Midtreatment PET/CT-Guided Adaptive RT in Locally Advanced NSCLC: Study Design

Shirish M. Gadgeel, MD:
Kong and colleagues30 presented the final report from the multicenter, randomized phase II RTOG 1106 study of midtreatment FDG-PET/CT-guided adaptive radiotherapy (RT) in 132 patients with inoperable stage III NSCLC who were medically fit for concurrent chemoradiotherapy. The study objective was to evaluate whether escalating RT based on midtreatment FDG-PET/CT scans could confer an improvement in locoregional control for these patients. All patients had a midtreatment FDG-PET/CT scan at approximately 50 Gy, after which adaptive planning was undertaken to guide the remaining concurrent chemoradiation dosing. At this point, patients in the experimental group received adaptive chemoradiation escalated to the residual tumor up to 20 Gy in 10 fractions of 2.4-3.5 Gy/fraction for a total of 66-100 Gy, whereas the standard therapy group continued receiving the same concurrent chemoradiation dose up to a total of 60 Gy (or mean lung dose of 20 Gy). The primary endpoint of the study was a 2-year local-regional control rate per central review, and key exploratory endpoints included reduction in tumor volume, adaptive RT dose, local regional PFS, OS, and safety.

Midtreatment PET/CT-Guided Adaptive RT in Locally Advanced NSCLC: Efficacy Summary

Shirish M. Gadgeel, MD:
Compared with standard RT, the 2-year local-regional control rate in the adaptive RT arm was 54.6% vs 59.5%. The study also showed similar median local-regional tumor progression-free (28.4 vs 27.5 months; P = .6585), median PFS (13.2 vs 12.2 months; P = .5896), and median OS (31.2 vs 35.5 months; P = .7950) for the adaptive RT arm vs the standard RT arm, respectively.

The expectation was that the adaptive radiation dosing, based on the results of midtreatment PET/CT, would result in better local control as well as improved overall efficacy. What this randomized phase II demonstrated was there was no difference between patients who had adaptive radiation dosing based on midtreatment PET/CT vs those who received standard radiation therapy.

Midtreatment PET/CT-Guided Adaptive RT in Locally Advanced NSCLC: Safety Summary

Shirish M. Gadgeel, MD:
Toxicity was also comparable between the 2 treatment arms. Grade 5 AEs were reported in 6.3% and 4.8% of patients in the adaptive RT and standard RT arms, respectively. Grade 3/4 anemia was higher in the adaptive RT arm vs the standard RT arm, and it was reported in 10.1% vs 4.8% of patients, respectively. Thoracic AEs were similar between the 2 treatment arms. Grade ≥2 esophagitis was numerically higher in the adaptive RT arm vs the standard therapy arm, and it was reported in 42.5% vs 31.0% of patients in the adaptive RT arm vs standard RT, respectively.

There was a slightly higher rate of anemia and esophagitis in patients who received adaptive radiation, but overall both treatment arm toxicity rates were very similar.

Midtreatment PET/CT-Guided Adaptive RT in Locally Advanced NSCLC: Conclusions

Shirish M. Gadgeel, MD:
Although an interesting study, results showed escalated RT alone based on radiographic mid-treatment FDG-PET/CT scan using gross tumor volume as a biomarker was not sufficient to improve local-regional control.

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