CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 25, 2023
Expiration: August 24, 2024
Introduction to Adjuvant Therapy for EGFR-Positive Early-Stage NSCLC
Heather Wakelee, MD, FASCO:
Adjuvant osimertinib (an EGFR TKI) is approved by the FDA after tumor resection in patients with NSCLC harboring EGFR ex19del or exon 21 L858R mutations.1 This approval was based on the strongly positive DFS outcomes for osimertinib vs placebo in the phase III ADAURA trial, performed in 682 patients with completely resected, primary, nonsquamous, EGFR-positive NSCLC.2 Despite these positive results, which led to approvals in the US and many other areas of the world, osimertinib is not globally approved because it was unclear whether the DFS benefit would translate to an OS benefit, a problem that has been seen in previous adjuvant studies of EGFR TKIs such as gefitinib.3 In the RADIANT trial, adjuvant erlotinib was compared with placebo in patients with elevated EGFR expression.4 DFS results trended toward a benefit to erlotinib treatment, but the difference in median DFS (46.4 months vs 28.5 months; HR: 0.61; 95% CI: 0.38-0.98; P = .039) was not statistically significant based on the trial’s statistical plan, and no OS benefit was noted. This study did not have a large number of patients with known EGFR-activating mutations
ADAURA: Adjuvant Osimertinib vs Placebo After Complete Resection in Stage IB-IIIA EGFR-Positive NSCLC
Heather Wakelee, MD, FASCO:
OS data from the phase III ADAURA trial were presented at ASCO 2023. Enrollment was restricted to patients with stage IB (≥4 cm) to stage IIIA NSCLC with the 2 most common EGFR mutations: ex19del and L858R.2,5,7 Patients with stage II or III disease were encouraged to receive adjuvant CT, but it was not mandated. All enrolled patients were randomized 1:1 to receive osimertinib or placebo for 3 years. The primary endpoint was investigator-assessed DFS in patients with stage II-IIIA NSCLC. Key secondary endpoints included DFS in the overall population; landmark DFS rates at 2, 3, 4, and 5 years; OS; quality of life (QoL); and safety.
ADAURA: Updated DFS (Overall Population)
Heather Wakelee, MD, FASCO:
The primary endpoint of DFS in stage II-IIIA disease was met in the first interim analysis,6 and the updated data show a continued significant DFS benefit for the overall population of patients who received osimertinib compared with placebo (HR: 0.27; 95% CI: 0.21-0.34).2 There is some concern that the curves start to come together after 3 years when the adjuvant osimertinib is stopped.
ADAURA: DFS by Disease Stage
Heather Wakelee, MD, FASCO:
Differences were evident when analyzing DFS by disease stage. Patients with stage IIIA disease had the most favorable HR (0.20) compared with stage II (0.34) and stage IB (0.41) disease.2
ADAURA: OS in Patients With Stage IB-IIIA NSCLC (Overall Population)
Heather Wakelee, MD, FASCO:
There was a profound OS benefit across the overall population for osimertinib (HR: 0.49; 95.03% CI: 0.34-0.70; P <.001) compared with placebo.5,7 You can see the separation in OS curves by year 2, indicating a very strong benefit. The 5-year OS rate was greater for osimertinib (88%; 95% CI: 83%-91%) compared with placebo (78%; 95% CI: 73%-82%).
ADAURA: OS by Disease Stage
Heather Wakelee, MD, FASCO:
I think it is particularly important that the OS benefit was seen across the disease stages. The biggest survival benefit with osimertinib was seen for patients with stage IIIA disease (HR for death: 0.37; 95% CI: 0.20-0.64), but we still see a benefit for those with stage IB (HR: 0.44; 95% CI: 0.17-1.02) and stage II (HR: 0.63; 95% CI: 0.34-1.12) disease.5,7
ADAURA: OS by Subgroup in Overall Population
Heather Wakelee, MD, FASCO:
Looking at the subgroup analysis for OS in ADAURA, there really are no subsets where osimertinib is not helpful.5,7 Thus, adjuvant osimertinib is even more strongly a standard approach—and something that we will need to discuss with our patients with resected EGFR-mutated NSCLC, regardless of stage.
Some questions remain about the importance of CT, and I still recommend CT for my patients with stage II and III disease. For stage IB disease, it is a bit more controversial, and I think that is something we are still talking through. I also think it will be important to continue to follow these patients for an extended period of time. It will be important to understand the magnitude of ongoing benefit after osimertinib is stopped at 3 years and whether the DFS and OS curves shift after osimertinib is stopped.
Neoadjuvant Osimertinib in EGFR-Mutated NSCLC: Study Design
Heather Wakelee, MD, FASCO:
Now, we will look at the use of neoadjuvant osimertinib in EGFR-mutated NSCLC. A single-arm phase II trial is evaluating neoadjuvant osimertinib treatment in 27 patients with resectable stage I-IIIA NSCLC harboring EGFR ex19del or L858R mutations.8 The primary endpoint was major pathologic response (MPR) rate (≤10% residual viable tumor), with key secondary endpoints including pathologic response rate (≤50% residual viable tumor) and pathologic complete response (pCR; no detectable residual tumor).
Neoadjuvant Osimertinib in EGFR-Mutated NSCLC: Efficacy in ITT Population
Heather Wakelee, MD, FASCO:
This study did not meet its primary endpoint, with an MPR rate of 15% in patients receiving osimertinib prior to surgery.8 The MPR was lower than we expected, bringing a bit into question whether neoadjuvant osimertinib would become a new standard. So, at this point, we still are using only adjuvant osimertinib.
Clinical Implications: Adjuvant and Neoadjuvant Osimertinib for Early-Stage EGFR-Positive NSCLC
Karen Reckamp, MD:
The significantly positive OS results from the ADAURA trial confirm osimertinib as the standard approach for a patient with EGFR-mutated lung cancer who has undergone a surgical resection.
A big question remains about the duration of treatment—should we be treating for longer?
Heather Wakelee, MD, FASCO:
The standard would be to stop after 3 years. The ADAURA trial lasted 3 years, and the DFS curves do start to come together after that 3-year mark, but not completely. This does not take away from the excellent OS benefit, but it remains an open question for the future.
I have a few patients who have been receiving treatment for longer than 3 years, but some patients were happy to stop treatment after 3 years. For patients who choose to stop therapy, I discuss with them that there is some uncertainty on whether recurrence will occur and that if disease does recur, we do not know that they are going to have that dramatic benefit we see from the ADAURA study.
Do you have other thoughts on this study, Dr Reckamp?
Karen Reckamp, MD:
I think most of us have discussed osimertinib and used it based on the previous data on improved DFS and intracranial DFS. The additional DFS data and early OS data presented at ASCO 2023 show that there are prolonged benefits. Fortunately, the number of patients who have had events is still very small, but the 10% improvement in 5-year OS for osimertinib compared with placebo is highly impactful. We have not seen that with anything in the adjuvant setting in NSCLC and only minimally with CT. Osimertinib is reasonably well tolerated compared with some of the agents used to treat other tumor types, such as breast cancer, which are much more toxic for often less percentage benefit. I think this really does push adjuvant osimertinib as SoC for eligible patients (resectable stage IB-IIIA NSCLC with EGFR mutation), and it is a big step forward for our patients to see a targeted therapy provide a survival benefit.
Dr Wakelee, are there any patients with early-stage EGFR-mutated lung cancer whom you would not give adjuvant osimertinib?
Heather Wakelee, MD, FASCO:
There are some patients for whom adjuvant osimertinib may not be the best approach. One would be a patient with stage IB disease with a chance of recurrence who is not comfortable with the idea of receiving a 3-year regimen from a QoL standpoint. As you said, osimertinib is generally well tolerated, but not perfectly so, and there are patients who experience gastrointestinal and skin toxicities. QT prolongation is something we need to be mindful of as well, with EKG follow-up.
I would really like to see the field moving toward the ability to customize treatment based on a biomarker, probably circulating tumor DNA (ctDNA), where if we see positivity, we know the patient absolutely needs to receive additional treatment, and osimertinib is the definitive best option for that.
Right now, I do not think any of the commercial assays can be used to say a patient does not need treatment. For now, it is a very personal decision; for stage IB, we can discuss and customize therapy, but I would be very hesitant to not give adjuvant osimertinib to patients with stage II or III disease.
Karen Reckamp, MD:
Osimertinib is currently approved for patients with stage IB or higher disease, but ongoing studies are looking at osimertinib in earlier-stage disease. The phase III ADAURA2 trial (NCT05120349) is evaluating adjuvant osimertinib in patients with stage IA NSCLC, but it is powered only for DFS. Although we do not have data to support giving osimertinib for stage IA disease, now that we have seen its efficacy across stages IB-IIIA, I think the harm is small. This is an oral agent, so if a toxicity occurs, we can stop treatment. If an improvement in DFS is seen in the earlier stage studies, I think it would be easy to extrapolate and give osimertinib to most patients.
Heather Wakelee, MD, FASCO:
How do you approach tumor testing or biomarker testing in patients with early stage disease?
Karen Reckamp, MD:
Broad genomic testing is recommended for patients with advanced NSCLC, and for patients with resectable stage IB-IIIA NSCLC we should be testing for EGFR mutations to determine eligibility for adjuvant osimertinib.9 Plasma-based ctDNA testing can be useful for biomarker detection despite its limitations for use as a diagnostic tool.
In addition, ctDNA may have some utility in helping us determine how best to treat patients with early-stage disease and to know who might need more therapy after resection. In the early stage setting, however, when we are looking for measurable residual disease, we generally want to look at a tumor-informed ctDNA assay (looking for ctDNA based on results of the biopsy). The markers we are looking for in standard ctDNA assays—which we would do for metastatic NSCLC—are not seen at high enough levels to detect or guide treatment in early-stage disease. Measurable residual disease still has a ways to go to help us understand patients most suited for additional therapy.
Adjuvant IO in NSCLC
Heather Wakelee, MD, FASCO:
If you do not find an EGFR mutation in your patient’s tumor, we now have lots of other options with immunotherapy (IO).
In the adjuvant setting, atezolizumab (anti‒PD-L1 antibody) is approved by the FDA following resection and platinum-based CT for adult patients with stage II-IIIA NSCLC whose tumors have PD-L1 expression on ≥1% of tumor cells.10 This approval was based on the positive DFS outcomes for atezolizumab compared with best supportive care in the phase III IMpower010 trial.11
Adjuvant pembrolizumab (anti‒PD-1 antibody) is approved by the FDA following resection and platinum-based CT for adult patients with stage IB, II, or IIIA NSCLC.12 The approval was based on positive DFS outcomes for pembrolizumab compared with placebo in the phase III PEARLS/KEYNOTE-091 study.13
Neoadjuvant IO in NSCLC
Heather Wakelee, MD, FASCO:
In the neoadjuvant setting, nivolumab (anti‒PD-1 antibody) is approved by the FDA for adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in combination with platinum-doublet CT.14 This approval was based on the positive EFS and pCR for nivolumab plus platinum-based CT vs platinum-based CT alone in the phase III CheckMate 816 trial.15
More recently, we have been hearing about perioperative studies, which give an anti‒PD-1/PD-L1 ICI before surgery with CT and then continue after surgery. The phase III AEGEAN trial looked at neoadjuvant durvalumab (anti‒PD-L1 antibody) plus platinum-based CT followed by surgery and adjuvant durvalumab compared with placebo plus platinum-based CT in 802 patients with resectable NSCLC.16 This trial met both primary endpoints of higher pCR rate (17.2% vs 4.3%; difference: 13.0%; 95% CI: 8.7%-17.6%; P = .000036) and prolonged EFS (median EFS not reached vs 25.9 months; HR: 0.68; 95% CI: 0.53-0.88; P = .0039) for perioperative durvalumab plus CT vs placebo plus CT.
KEYNOTE-671 : Neoadjuvant Platinum CT Plus Pembrolizumab or Placebo Followed by Resection and Adjuvant Pembrolizumab or Placebo in Early-Stage NSCLC
Heather Wakelee, MD, FASCO:
I was fortunate to present the phase III KEYNOTE-671 study at ASCO 2023.17,18 The trial design was very similar to the AEGEAN study, randomizing patients with resectable stage II or III NSCLC (N = 797) to receive 4 cycles of platinum CT (cisplatin plus gemcitabine or pemetrexed) with either pembrolizumab or placebo prior to surgery and then continuing with pembrolizumab or placebo for up to 1 year after the surgery. We stratified by disease stage, histology, geographic region, and PD-L1 TPS. The primary endpoints were EFS per investigator and OS, with key secondary endpoints of MPR, pCR (by blinded independent pathology review [BIPR]) and safety.
KEYNOTE-671: Baseline Characteristics
Heather Wakelee, MD, FASCO:
Looking at who went on the trial, 30% of patients had stage II disease, and 70% had stage III disease.17,18 The majority of patients had nonsquamous disease (56.8%), and a very small number of patients had known EGFR mutations (4.1%) or ALK translocations (2.6%), although because testing was not required, it is likely that some patients had mutations that we do not know about. In some of the other perioperative trials, patients with tumors with EGFR mutations and ALK translocations were excluded.
KEYNOTE-671: Treatment Disposition
Heather Wakelee, MD, FASCO:
Nearly 1400 patients were screened, and 797 were enrolled.17,18 The main reason patients did not pass the screening was the very strict criteria for knowing disease stage and PD-L1 level. So, patients who did not have adequate tissue or nodal sampling prior to enrollment were not eligible for this trial. Of the patients who went on to receive treatment, approximately 20% did not go on to receive the trial-specified surgery. This seems consistent with other perioperative and neoadjuvant trials, in which 15% to 20% of patients do not get to the point of having surgery. Some of that may be due to the selection of patients who are not really surgical candidates to begin with, but it is an issue we need to investigate further as we debate neoadjuvant approaches vs surgery upfront. There is also a debate about whether patients should get just neoadjuvant IO or just adjuvant IO and which patients should get both. In KEYNOTE-671, 70% of patients on the trial continued on to adjuvant therapy—a bit higher for those receiving pembrolizumab vs the placebo—which reflects the fact that slightly more patients actually underwent surgery on the pembrolizumab arm (82.1% vs 79.4%).
KEYNOTE-671: EFS (Primary Endpoint)
Heather Wakelee, MD, FASCO:
Looking at the first of the 2 primary endpoints, improvement in EFS at the first interim analysis was statistically significant for perioperative pembrolizumab (HR: 0.58; 95% CI: 0.46-0.72; P <.00001) compared with placebo.17,18
KEYNOTE-671: EFS by Subgroup
Heather Wakelee, MD, FASCO:
When looking at EFS by subgroup, the benefit of pembrolizumab vs placebo was evident across all assessed subgroups, including pathologic stage and histology. When looking at PD-L1 TPS, benefit was also seen across all expression levels (<1%, 1%-49%, and ≥50%). However, the patients with higher PD-L1 TPS attained more benefit (HR for <1%: 0.77; HR for 1%-49%: 0.51; HR for ≥50%: 0.42).
KEYNOTE-671: OS (Primary Endpoint)
Heather Wakelee, MD, FASCO:
For OS—the other primary endpoint—although there is a strong trend toward a benefit for pembrolizumab vs placebo (HR: 0.73; 95% CI: 0.54-0.99; P = .02124), the prespecified boundary for statistical significance was not met. There were not enough events at the time of the first interim analysis for a definitive call one way or the other.17,18
KEYNOTE-671: Pathologic Response
Heather Wakelee, MD, FASCO:
Other topics discussed in the neoadjuvant setting are MPR and pCR, which are scored slightly differently across trials despite efforts to standardize them by the International Association for the Study of Lung Cancer. For this reason, we must be careful when making cross-trial comparisons.
In KEYNOTE-671, pembrolizumab treatment resulted in a significantly higher MPR rate (30.2% vs 11.0%; difference: 19.2%; 95% CI: 13.9%-24.7%; P <.00001) and pCR rate (18.1% vs 4.0%; difference: 14.2%; 95% CI: 10.1%-18.7%; P <.00001) vs placebo.17,18 These results were very strongly in favor of pembrolizumab in this study.
NEOTORCH: Perioperative Toripalimab Plus Platinum CT vs Platinum CT in Resectable Stage II/III NSCLC
Heather Wakelee, MD, FASCO:
The other perioperative IO trial that was discussed at ASCO 2023 was the randomized phase III NEOTORCH trial, which was conducted exclusively in China.19 This study compared perioperative toripalimab (anti‒PD-1 antibody) plus platinum-based CT vs placebo plus platinum-based CT in patients with resectable stage II/III NSCLC. Three cycles of platinum-based CT were given with or without toripalimab before surgery and then, 1 cycle after, followed by up to 13 cycles of maintenance toripalimab or placebo. This plan varied slightly from KEYNOTE-671 and AEGEAN (4 cycles neoadjuvant IO plus CT) and CheckMate 816 (3 cycles neoadjuvant IO plus CT only). This trial also excluded patients whose tumors had EGFR or ALK alterations. The primary endpoints were EFS (by investigator) and MPR rate (by BIPR), with secondary endpoints of OS, pCR(by BIPR), EFS (by independent review committee [IRC]), DFS, and safety. In China, a high population of patients with lung cancer have tumors that harbor EGFR mutations,20 so they ended up excluding a lot of patients who had EGFR-driven lung cancer in this trial which led to a very high proportion of patients with squamous histology.
NEOTORCH: Baseline Characteristics of Patients With Stage III NSCLC
Heather Wakelee, MD, FASCO:
Although this trial did enroll patients with stage II and III disease, only data from stage III were reported at this first interim analysis.19 The study included mostly patients with stage IIIA disease (67.3%) and fewer women (8.4%). Approximately 78% of patients had squamous histology, making NEOTORCH the only perioperative IO trial with a majority squamous population.
NEOTORCH: EFS and MPR (Primary Endpoints)
Heather Wakelee, MD, FASCO:
The EFS data for toripalimab plus CT vs placebo plus CT in patients with stage III disease were impressive (HR: 0.40; 95% CI: 0.277-0.565; P <.0001).19 Similarly, EFS by IRC was also 0.40.
Clinical Implications: Perioperative IO for Early-Stage NSCLC
Heather Wakelee, MD, FASCO:
When looking at outcomes from trials, it is important to keep in mind the difference between DFS and EFS. In the adjuvant trials, we talk about DFS because all patients complete surgical excision before going on the trial; they are theoretically disease free, so any evidence of disease would be a DFS event. EFS is different, as it not only includes DFS after the surgery, but anything (such as disease progression) that prevents a patient from going to surgery or definitive therapy would count as an event. These are slightly different outcomes, with variations in what counts as an event across the trial. For this reason, one must be careful with cross-trial comparisons.
All 3 of the perioperative IO studies discussed above had very positive EFS results. We are still waiting for OS data, and then we will figure out how to distinguish between them.
Karen Reckamp, MD:
It is exciting to see IO move into the perioperative setting. We already know the benefit of neoadjuvant therapy for our patients with stage II and III disease, with improvement in DFS or EFS, and the KEYNOTE 671 trial really adds to the CheckMate 816 and AEGEAN studies. The data are coming out rapidly, but many unanswered questions remain. It is clear that patients who achieve pCR do best long term, but how many patients are being overtreated or potentially exposed to greater toxicity by being given both neoadjuvant and adjuvant therapy? Some patients will not need both, and we do not have a way to know whom those patients are at this time. On the other hand, some patients do need more therapy, and we do not know how to identify them, but some trials are asking that question. It is great that we can use IO in the neoadjuvant and then adjuvant setting, but how can we further refine our process to decrease toxicity and provide the optimal amount of treatment to our patients?
Heather Wakelee, MD, FASCO:
Going back to the idea of ctDNA assays, I can envision a patient going through CT and IO, then having surgery, and if they have no evidence of additional disease and they have had a complete response, then maybe those are patients who can stop therapy. Other patients who still have evidence of disease by ctDNA would need to continue treatment. There also would be some patients with stage IB and II disease who could go straight to surgery and of course others who would need additional adjuvant treatment. Having good enough testing would prevent us from overtreating. We are probably some years away from this being a reality.
For now, the standard approach is if a patient comes in with stage III disease, I would think about a perioperative strategy including both adjuvant and neoadjuvant treatment. Neoadjuvant nivolumab plus platinum CT without adjuvant therapy is certainly a reasonable strategy, too. This is an ongoing question, and I think practice patterns are going to continue to evolve. We only have hints right now to tell us that the use of both adjuvant and neoadjuvant therapy makes a huge difference.
Clinical Implications: Perioperative IO vs Neoadjuvant IO
Karen Reckamp, MD:
How do you see perioperative IO shaping up against neoadjuvant IO currently used in practice?
Heather Wakelee, MD, FASCO:
We now have positive data for ICIs given with CT before surgery plus the addition of adjuvant ICI, as well as adjuvant ICIs alone. How do we choose the right approach for each patient? We do not have clear answers for that question. In our analysis of KEYNOTE-671, it was difficult to know how much additional benefit the adjuvant component gave for patients who had a strong neoadjuvant response. In the melanoma setting, a combined analysis of the OpACIN-neo and PRADO trials evaluated how much additional benefit was gained with the addition of adjuvant ICI in patients with melanoma who had not achieved a pCR with neoadjuvant nivolumab plus ipilimumab.21 For patients with a pathologic nonresponse to neoadjuvant therapy, adjuvant therapy resulted in an improved relapse-free survival and distant metastasis‒free survival. Of course, this study was not in lung cancer, but it is intriguing—although it is not a definitive answer. The question remains if a patient has a very strong response with the combination of CT plus ICI in the neoadjuvant setting, do they need that additional treatment? That is an important question. However, if they do not have a great response to neoadjuvant therapy, I look at the data we have in the melanoma setting21 and at an exploratory analysis of the KEYNOTE-671 trial that shows EFS benefit for perioperative IO even in patients who did not achieve a pCR or MPR18, and the data sway me towards considering adjuvant therapy.
We need to configure analyses to clearly determine the benefit of the adjuvant therapy, and we need to do different trials to be able to answer this question clearly. If I have a patient who has received neoadjuvant CT plus IO and has not had a pCR, in my practice I am tempted to continue with the adjuvant strategy.
Karen Reckamp, MD:
There are several challenges facing the neoadjuvant setting, both for IO and EGFR TKI therapy. Patients need to be tested for actionable mutations before neoadjuvant therapy or surgery. There are implications for patients who are EGFR positive receiving neoadjuvant IO, who might be harmed if they go on to receive adjuvant osimertinib several months after surgery. Patient testing is going to be important to avoid exposing our patients who are EGFR positive to IO.
Heather Wakelee, MD, FASCO:
Yes, the trials are all strongly telling us that we need to know about the EGFR mutation status for a patient with early-stage lung cancer, because otherwise you are not going to pick the right treatment approach.
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