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Associate Attending Physician
Thoracic Oncology Service
Memorial Sloan Kettering Cancer Center
New York, New York
Jamie E. Chaft, MD, has disclosed that she has received consulting fees and funds for research support (paid to her institution) from AstraZeneca, Bristol-Myers Squibb, Flame Biosciences, Genentech, Janssen, Merck, and Novartis.
Head of the Thorax Institute Curie-Montsouris
Nicolas Girard, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, PharmaMar, Roche, Sanofi, and Teva, and funds for research support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, and Roche.
In this commentary, Jamie E. Chaft, MD, and Nicolas Girard, MD, PhD, discuss some of their top picks of abstracts presented during the virtual 2020 World Congress on Lung Cancers (WCLC) annual meeting, sharing their perspectives on how the new data may affect clinical practice.
Nicolas Girard, MD, PhD: Advanced NSCLC
CodeBreaK 100: Sotorasib in KRAS pG12–Mutated NSCLC
KRAS tumor-driving mutations are present in approximately 25% to 30% of patients with lung adenocarcinoma, and among those mutations, KRAS pG12C represents approximately 13%. The KRAS pG12C mutation has been associated with poor prognosis, and until recently, it had been considered untargetable. During the past 20 years, many trials have investigated the use of drugs of various classes (eg, farnesyl inhibitors, chemotherapy combinations, and MEK inhibitors), yet have failed to show clinical benefit in this setting when compared with standard-of-care chemotherapy.
At WCLC 2020, Li and colleagues 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 non-small-cell lung cancer (NSCLC) with the KRAS pG12C mutation—confirmed by central testing—and who had previously received platinum-based chemotherapy. In this study, patients received sotorasib 960 mg once-daily orally until disease progression. The primary endpoint was ORR by blinded independent central review. Secondary endpoints included duration of response (DoR), disease control rate, time to response, PFS, OS, and safety.
After a median follow-up of just more than 1 year, the ORR was 37% and disease control rate was > 80%, which is quite remarkable in the advanced disease setting. DoR is also very impressive in this phase II study, with patients achieving a median DoR of 10 months. Responses to sotorasib were observed in key patient subgroups including across PD-L1 expression levels and in patients with tumors harboring comutations in STK11 and KEAP1, which are predictors of resistance to immune checkpoint inhibitors.
Most adverse events (AEs) with sotorasib were low grade and manageable. As with kinase inhibitors, we have to pay close attention to gastrointestinal and cutaneous AEs. The most common grade 3 treatment-related AEs reported were alanine aminotransferase elevation (6.3%), aspartate aminotransferase elevation (5.6%), and diarrhea (4%). Treatment-related AEs led to dose modification in approximately 1 in 5 of patients and to discontinuation in approximately 7% of patients. Of importance, there were no deaths in this study.
The CodeBreaK 100 study clearly shows that we have now a targeted therapy for KRAS pG12C–mutant NSCLC, which is wonderful news for these patients for whom the only available treatment option had previously been chemotherapy. The confirmatory, multicenter phase III CodeBreaK 200 study (NCT04303780) is comparing sotorasib with docetaxel in patients with advanced KRAS pG12C–mutant NSCLC in the second‑line setting. In this 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.
But what about integrating sotorasib in the first-line setting where chemotherapy in combination with a checkpoint inhibitor shows some efficacy? Will sotorasib be used in combination? Will it be a replacement for chemotherapy plus immunotherapy? Those are the key outstanding questions right now. Based on the response rates we have seen with sotorasib to date, my guess is that combination therapy may be the best way to assess sotorasib in the first‑line setting.
CHRYSALIS: Amivantamab in Postplatinum NSCLC With EGFR Exon 20 Insertions
Patients with NSCLC and EGFR exon 20 insertions do not experience a meaningful benefit with available EGFR tyrosine kinase inhibitors (TKI) as do patients with EGFR exon 19 deletions or L858R mutations, but might benefit from EGFR exon 20 insertion–specific agents currently in development. At WCLC 2020, Sabari and colleagues reported updated results from the phase I dose-escalation/dose-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 EGFR exon 20 insertions NSCLC. The safety population consisted of 114 patients and an efficacy population of 81 patients. The primary endpoint was ORR. Secondary endpoints included clinical benefit rate, DoR, PFS, and OS.
The safety profile of amivantamab was consistent with EGFR and MET pathway inhibition. Treatment-related AEs 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. 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%) and did not affect patients’ ability to receive subsequent treatments. Only 2% of patients discontinued amivantamab treatment due to rash.
In CHRYSALIS, amivantamab yielded an ORR of 40% 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, particularly in patients with ≥ 3 previous lines of therapy (58%). In addition, most patients achieved a prolonged response for more than 6 months. The median PFS reported was 8.3 months and the median OS was 22.8 months. At the time of data cutoff, 47% of patients remained on treatment.
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 inhibition. The CHRYSALIS study is 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).
EMPOWER‑Lung 1: Cemiplimab in Advanced NSCLC With PD-L1 ≥ 50%
Kilickap and colleagues presented results for the exploratory analyses of the randomized phase III EMPOWER-Lung 1 study, comparing cemiplimab vs chemotherapy in patients with advanced NSCLC with PD-L1 ≥ 50% and no EGFR/ALK/ROS1 mutation. The study design of EMPOWER-Lung 1 is very similar to that of the KEYNOTE‑024 study, which compared pembrolizumab vs chemotherapy. A key difference between the 2 studies is that patients in the cemiplimab arm who are experiencing disease progression may continue cemiplimab in combination with 4 cycles of platinum‑based chemotherapy.
Of note, a previous report from EMPOWER-Lung 1 was presented at ESMO 2020 by Sezer and colleagues led to the FDA approval of this agent as first-line therapy for patients with advanced NSCLC and high PD-L1 expression. What is unique about the data presented at WCLC 2020 is that efficacy was analyzed in clusters of patients defined by PD-L1 expression ≥ 50%. Overall, data presented at the meeting showed that increasing PD-L1 expression levels in tumor cells correlated with better ORR and 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 immune checkpoint inhibitors. For the KEYNOTE‑024 study of pembrolizumab vs chemotherapy, we have at least 5 years of follow-up data. 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.
Regarding safety, cemiplimab exhibited a safety profile consistent with what we have come to expect with immune checkpoint inhibitors. Grade ≥ 3 immune-related AEs led to discontinuation in 1.4% of patients treated with cemiplimab vs 0 % with chemotherapy. Median duration of exposure was 27.3 weeks with cemiplimab vs 17.7 weeks with chemotherapy.
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, it would be interesting to see data for second PFS, to better understand what would be the best sequencing of treatments in patients with NSCLC with PD-L1 ≥ 50% who progressed after immunotherapy.
Jamie E. Chaft: Early-Stage NSCLC
ADAURA: Updated Results for Osimertinib vs Placebo in Resected, EGFR-Mutated NSCLC
ADAURA is a global phase III study of adjuvant osimertinib, a third-generation EGFR TKI, vs placebo in 682 patients with EGFR‑driven NSCLC. 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 were stratified by stage, mutation, and race (Asian or non‑Asian) and randomized to receive osimertinib 80 mg once daily for up to 3 years vs placebo. The primary endpoint of this study, investigator‑assessed DFS, has previously been presented and demonstrated a dramatic improvement with osimertinib vs placebo. Although this is not surprising, it was certainly reassuring to see. The OS data, however, are many years away, and the study was unblinded early based on overwhelming efficacy. Therefore, subset analyses can help establish confidence in prescribing this intervention in the adjuvant setting.
In ADAURA, 60% of patients in the total study population had received adjuvant chemotherapy prior to enrollment—and this varied by stage: 26% with stage IB disease vs 80% of patients with stage IIIA. As expected, patients younger than 70 years were more likely to receive chemotherapy than older patients (66% vs 42%). In the results presented at WCLC 2020, the previously noted DFS advantage of osimertinib was seen across disease stages with impressive HRs, regardless of receipt of previous adjuvant chemotherapy.
In the adjuvant setting, patients should not have residual symptoms of disease, which is why the investigators selected the 36-Item Short Form Survey (SF‑36) health survey, which looks at general physical and mental health-related quality of life regardless of a cancer diagnosis. The SF-36 surveys were completed at baseline and throughout follow-up in both the osimertinib and placebo groups. Results presented at WCLC 2020 showed that compliance with completing the SF‑36 survey was quite good across both arms—approximately 80%. Of note, these data were not collected after recurrence, but it would be interesting to see data from follow-up beyond recurrence. In the absence of OS data, we have to make educated guesses as to how well patients will tolerate this intervention. Of importance, the health-related quality-of-life results showed no clinically meaningful changes in either physical or mental SF-36 scores in either arm across the duration of the study. This finding suggests adjuvant osimertinib did not appear to result in a meaningful deterioration in quality of life. At this time, I find it reassuring that we are not harming patients while improving DFS—but again, we eagerly await the OS data.
ITACA: Tailored vs Standard Adjuvant Chemotherapy in Resected NSCLC
The ITACA study, conducted in centers across Italy, Germany, and Poland, was designed to determine if predictive biomarkers could be associated with benefit from matched chemotherapy regimens. ITACA was a randomized phase III study comparing investigators’ choice of a cisplatin doublet to one of 4 standard chemotherapy approaches in 690 patients with resected stage II-IIIA NSCLC. Patients were randomized to one 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. Treatment compliance was good, with patients in the tailored-therapy and standard-therapy arms receiving a median of 4 cycles of chemotherapy (range: 1-4).
At WCLC 2020, Novello and colleagues presented an intention-to-treat analysis from ITACA, showing a positive trend toward improvement in OS, but which did not reach statistical significance. Moreover, recurrence-free survival at a median follow-up of longer than 2 years was not significantly different whether patients received tailored or standard chemotherapy (HR: 0.94). The results also reaffirmed that when cisplatin is removed from adjuvant therapy—here, in the subset of patients who previously received a personalized regimen—lower toxicity occurs. Overall, personalizing chemotherapy based on ERCC1 or TS mRNA expression did not lead to a statistically significant improvement in survival.
More WCLC 2020 Conference Coverage on the CCO Web Site!
These are just a few of the top abstracts selected by our expert faculty from WCLC 2020. Remember to download a highlights slideset of these studies and listen to a Podcast with additional studies in early-stage NSCLC presented at the virtual WCLC 2020.
Online Treatment Decision Tool for Unresectable Stage III or Metastatic NSCLC
Click here to use CCO’s “Interactive Decision Support Tool: Expert Insight on Therapy Selection for Unresectable Stage III and Metastatic NSCLC” to receive management recommendations from a panel of 5 lung cancer experts for a wide variety of patient presentations.
Which presentations did you find most compelling from WCLC 2020? Answer the polling question and share your thoughts and questions in the discussion section below.