Abstract
Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non–small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion–mediated osimertinib resistance has not previously been published.
Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected.
Fourteen patients with EGFR-mutant and RET fusion–positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%–75%, n = 12], 83% (95% CI, 55%–95%), and 7.9 months (range, 0.8–25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4–ALK/STRN–ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms.
For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination.
These data provide a population-based estimate of the activity of concurrent third-generation EGFR and selective RET inhibitor therapy in RET fusion–mediated resistance to EGFR inhibition in EGFR-mutant lung cancers. Further treatment relapse can be mediated by competing clones harboring steric hindrance to EGFR/RET kinase engagement or non-EGFR/RET–mediated MAPK pathway reactivation.
Introduction
Clinical interrogation of the actionability of uncommon therapeutic resistance mechanisms is an unmet need. Unfortunately, increasing mechanism rarity may correlate with a decreasing likelihood of prospective resistance signature exploration. Although single-patient reports provide proof of concept that resistance-targeting strategies are potentially active, these reports typically do not provide denominators that allow adjudication of population-based efficacy estimates, albeit in small groups of patients.
Activating EGFR mutations are found in 15%–20% of metastatic lung adenocarcinomas (1). The current standard of care for treatment-naïve patients with metastatic EGFR-mutated lung cancer is the third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib (2). Unlike with earlier-generation TKIs (3), mechanisms of acquired resistance to osimertinib are more variable and include secondary driver gene mutations and fusions as well as histologic transformation (4). The rarity and heterogeneity of these mechanisms of acquired resistance make prospective study more challenging.
RET fusions are among these acquired rearrangements (5, 6). As de novo oncogenic drivers, activating RET fusions have been reported in approximately 1%–2% of lung adenocarcinomas (7) and predict for response to RET TKI therapy. Two selective RET inhibitors, selpercatinib and pralsetinib, are FDA-approved for treatment of RET fusion–positive lung cancers. A response rate of 84% and a median progression-free survival (PFS) of 22 months were reported for patients treated with first-line selpercatinib (8).
In EGFR-mutant lung cancers that acquire a RET fusion with osimertinib, small series of one or two patients have demonstrated that the combination of EGFR and RET TKIs is active (9–11). In one series, CCDC6-RET fusions were identified in 5% (n = 2/41) of EGFR-mutant cancers at osimertinib resistance. Both patients were treated with the combination of osimertinib and pralsetinib and experienced a radiographic response (9). Although these prior case reports of exceptional responders have been published, the probability of clinical benefit from the combination has yet to be established in a larger series.
Here, we describe the efficacy and safety outcomes of patients treated with osimertinib and selpercatinib for RET fusion-mediated osimertinib resistance in a combined analysis of patients prospectively treated on an expanded access clinical trial or single-patient compassionate use protocols. This comprises the largest series reported to date. In addition, we provide the first description of targeted therapy resistance patterns in patients who progress on the combination, exposing the likely influence of tumor clones competing in response to the in vivo pressures of concurrent EGFR and RET inhibition.
Patients and Methods
Patients
All patients treated with selpercatinib as part of a compassionate access protocol were evaluated retrospectively for eligibility for inclusion in this cohort, which included patients enrolled between June 2018 and July 2020. The compassionate access protocols included a prospective, multicenter expanded access clinical trial (NCT03906331) or agency-approved single-patient use trials. Institutional review board approval and appropriate written informed patient consent were obtained before patient enrollment in a compassionate access protocol. The study was conducted in accordance with the U.S. Common Rule or other geographically applicable ethical guidelines. Unifying criteria defined the population examined retrospectively in this integrated analysis.
To receive treatment, patients had to be 18 years of age or older and have adequate hematologic, renal, and hepatic function. A pathologic diagnosis of lung cancer and the presence of both a sensitizing EGFR mutation (L858R or exon 19 deletion), as well as a RET fusion (in-frame and kinase domain inclusive) detected at or after the onset of resistance to single-agent osimertinib therapy, were required. RET fusion had to be identified by plasma or tissue testing performed in a Clinical Laboratory Improvement Amendments (or equivalent) compliant laboratory (Supplementary Table S1). There were no limits on prior systemic therapy exposure.
Patients were excluded from enrollment if they had (1) clinically significant active cardiovascular disease (including New York Heart Association class III/IV heart failure, stroke, severe valvular disease, or uncontrolled hypertension defined as blood pressure ≥140/80 mm Hg sustained over multiple readings) or history of myocardial infarction within 6 months before therapy (2), ongoing cardiomyopathy, or (3) prolongation (>470 msec) of the QT interval corrected for heart rate using Fridericia's formula.
Treatment
All patients received selpercatinib in combination with osimertinib in 28-day cycles. Selpercatinib was provided as a simple blend with excipients in a capsule in 40 and 80-mg dose strengths. A liquid suspension with a concentration of 20 mg/mL was provided to patients who could not swallow capsules. The recommended starting dose was 80-mg daily of osimertinib and 80-mg twice daily of selpercatinib; lower doses were allowed as deemed clinically appropriate by investigators and with sponsor approval. Dose modification was permitted on the basis of tolerability. Dose-modification levels included 40-mg twice daily of selpercatinib and 40-mg daily of osimertinib.
Safety and assessments
Serious adverse events were reported as per individual protocol requirements; however, as these were expanded access or compassionate use programs, full reporting of non-serious events was not required. Any reported adverse events were classified according to the Common Terminology Criteria for Adverse Events (version 4.0). Relatedness was adjudicated by individual investigators.
Although strict visit or scan timepoints were not mandated for every patient, whenever possible, assessment visits were conducted weekly for the first month, then approximately every 1–3 months or as needed for safety monitoring or standard-of-care needs. Patients underwent contrast-enhanced CT, or MRI on day 1 of cycle 3 then every 12 weeks. An end-of-treatment visit was completed approximately 7 days after last selpercatinib administration, followed by a safety follow-up visit within 28 days of the last dose of selpercatinib.
Statistical analysis
The primary objective of the integrated analysis was the determination of the response rate to osimertinib and selpercatinib following acquisition of a RET fusion while receiving EGFR TKI treatment. Responses were categorized per investigator evaluation by the RECIST version 1.1. Secondary objectives included an analysis of disease control rate, PFS, duration of therapy, and safety. Time-to-event outcomes were reported using the Kaplan–Meier estimate. Confidence intervals were estimated for proportions via the Wilson/Brown method. Descriptive statistics were used for the analysis of resistance to therapy.
Data availability
The data generated in this study are available within the article and its Supplementary Data Files.
Results
Clinicopathologic features
Fourteen patients across seven sites and five countries were identified for treatment with osimertinib and selpercatinib. Combination therapy was administered either on (1) a prospective, multicenter expanded access clinical trial (Clinicaltrials.gov: NCT03906331) or (2) a health agency-approved single-patient use trial. Patients were enrolled at centers in the United States (n = 10), Germany, Israel, India, and Taiwan (n = 1 each).
All patients had a pathologically confirmed diagnosis of advanced, EGFR-mutant lung cancer with progression on osimertinib that was accompanied by the identification of a RET fusion (Table 1). The median age was 61 years (range, 33–78 years). Seventy-one percent of patients were never smokers and 29% had a former history of tobacco use. Fifty percent of patients were male. All had stage IV non–small cell lung cancer; adenocarcinoma was the most common (93%) histology.
Feature . | . | %, (n) . |
---|---|---|
Age | Median (range) | 61 years (33–78 years) |
Sex | Male | 50% (7) |
Female | 50% (7) | |
Country | United States | 71% (10) |
Germany | 7% (1) | |
Israel | 7% (1) | |
Taiwan | 7% (1) | |
India | 7% (1) | |
Smoking history | Never smoker | 71% (10) |
Former smoker | 29% (4) | |
Histology | Adenocarcinoma | 93% (13) |
Not otherwise specified | 7% (1) | |
EGFR mutation | Exon 19 deletion | 57% (8) |
Exon 19 deletion + T790M | 29% (4) | |
L858R + L747S + T790M | 7% (1) | |
L858R + T790M | 7% (1) | |
RET fusion | CCDC6–RET | 43% (6) |
NCOA4–RET | 36% (5) | |
KIF5B–RET | 14% (2) | |
RUFY2–RET | 7% (1) | |
Prior systemic therapy | Median (range) | 2 (1–5) |
Prior chemotherapy for metastatic disease | Platinum doublet naïve | 57% (8) |
Platinum doublet pretreated | 36% (5) | |
Unknown | 7% (1) | |
Prior EGFR TKI therapy | Median (range) | 2 (1–3) |
Therapy immediately before osimertinib + selpercatinib | Osimertinib | 64% (9) |
Osimertinib + cabozantinib | 7% (1) | |
Osimertinib + alectinib | 7% (1) | |
Osimertinib + selumetinib | 7% (1) | |
Carboplatin/abraxane | 7% (1) | |
Carboplatin/pemetrexed/nivolumab/veliparib | 7% (1) |
Feature . | . | %, (n) . |
---|---|---|
Age | Median (range) | 61 years (33–78 years) |
Sex | Male | 50% (7) |
Female | 50% (7) | |
Country | United States | 71% (10) |
Germany | 7% (1) | |
Israel | 7% (1) | |
Taiwan | 7% (1) | |
India | 7% (1) | |
Smoking history | Never smoker | 71% (10) |
Former smoker | 29% (4) | |
Histology | Adenocarcinoma | 93% (13) |
Not otherwise specified | 7% (1) | |
EGFR mutation | Exon 19 deletion | 57% (8) |
Exon 19 deletion + T790M | 29% (4) | |
L858R + L747S + T790M | 7% (1) | |
L858R + T790M | 7% (1) | |
RET fusion | CCDC6–RET | 43% (6) |
NCOA4–RET | 36% (5) | |
KIF5B–RET | 14% (2) | |
RUFY2–RET | 7% (1) | |
Prior systemic therapy | Median (range) | 2 (1–5) |
Prior chemotherapy for metastatic disease | Platinum doublet naïve | 57% (8) |
Platinum doublet pretreated | 36% (5) | |
Unknown | 7% (1) | |
Prior EGFR TKI therapy | Median (range) | 2 (1–3) |
Therapy immediately before osimertinib + selpercatinib | Osimertinib | 64% (9) |
Osimertinib + cabozantinib | 7% (1) | |
Osimertinib + alectinib | 7% (1) | |
Osimertinib + selumetinib | 7% (1) | |
Carboplatin/abraxane | 7% (1) | |
Carboplatin/pemetrexed/nivolumab/veliparib | 7% (1) |
Note: Patients with RET fusion–positive lung cancers were treated on a prospective extended access protocol or single-patient use programs. The demographics, pathologic features, molecular features, and prior treatment of patients retrospectively identified as treated with osimertinib and selpercatinib in combination for acquired RET fusions at osimertinib resistance are summarized.
The median number of prior systemic (targeted or cytotoxic) lines of therapy was 2 (range, 1–5). The median number of prior EGFR TKIs was 2 (range, 1–3). Additional details regarding EGFR TKI sequencing are shown in Supplementary Table S2. The treatment administered immediately before enrollment was most commonly osimertinib (86%, n = 12; 3 of 12 received osimertinib with cabozantinib, alectinib, or selumetinib), followed by chemotherapy (14%, n = 2; 1 received carboplatin and abraxane, 1 received carboplatin, pemetetrexed, nivolumab, and veliparib).
Molecular features
Testing for molecular mechanisms of acquired osimertinib resistance identified a RET fusion in all patients who were identified for inclusion in this patient cohort. This was performed using tumor next-generation sequencing (NGS) in 8 patients (57%) and plasma cell-free (cf)DNA sequencing in 6 patients (Supplementary Table S1). The EGFR mutation was present at the time of RET fusion identification in all but one patient (in whom plasma cfDNA did not concurrently identify the original EGFR mutation).
Most tumors (86%, n = 12) harbored an EGFR exon 19 deletion (4 of which harbored a concurrent EGFR T790M mutation); the remaining cancers (n = 2) both harbored EGFR L858R and EGFR T790M mutations, one of which harbored a concurrent EGFR L747S mutation. The spectrum of observed RET fusions was compelling in that non-KIF5B fusions predominated: CCDC6-RET (43%, n = 6), NCOA4-RET (36%, n = 5), KIF5B-RET (14%, n = 2), and RUFY2-RET (7%, n = 1).
All patients were on osimertinib when the acquired RET fusion was identified; 64% (9 patients) were known to have received additional EGFR-directed therapy before osimertinib with an earlier generation EGFR TKI (e.g., erlotinib, afatinib). Of the 9 patients with known prior earlier generation EGFR TKI treatment, 6 had an EGFR T790M mutation detectable at time of study enrollment. One patient received combination treatment with osimertinib and an investigational MEK inhibitor on a clinical trial before disease progression.
Dosing
The most common starting dose (osimertinib 80-mg daily and selpercatinib 80-mg twice daily, Supplementary Table S3) was chosen considering single-agent pharmacokinetics and the potential for overlapping toxicities. Although the selpercatinib dose of 80-mg twice daily is half of the approved dose of 160-mg twice daily, substantial RET target coverage is achieved with the former dose and activity is comparable with higher doses (120-mg twice daily and 160-mg twice daily; refs. 12, 13). Notably, the majority (79%, n = 11) of patients were successfully maintained at this dose or higher doses (two patients escalated the dose of osimertinib or selpercatinib at combination therapy progression) during the course of their therapy.
Safety
All 14 patients were eligible for safety analysis (Supplementary Fig. S1). Standard adverse event reporting as performed for non-compassionate use trials was not mandated, though reporting of dose modifications and of serious adverse events was required. Reported treatment-emergent and treatment-related adverse events are summarized in Supplementary Table S4. Most reported adverse events were low grade in nature and unrelated to treatment, though the true rate of adverse events is predicted to be higher given the voluntary nature of low-grade adverse event reporting. Reported treatment-related adverse events were consistent with the prior safety profile of osimertinib or selpercatinib and included rash, paronychia, hypertension, dry mouth, transaminitis, QTc prolongation, and hypersensitivity. Serious adverse events were reported in five patients, all of which were unrelated to therapy.
Dose reductions were reported in 14% (n = 2) of patients (Supplementary Table S5). One patient required an osimertinib dose reduction (80 to 40-mg daily) due to QTc interval prolongation. Another patient required a selpercatinib dose reduction (80 to 40 mg twice daily) for a hypersensitivity reaction (rash, fever, neutropenia/leukopenia; later resolved). Of note, this patient had prior exposure to an immune checkpoint inhibitor, with atezolizumab given as part of a regimen received until approximately 4 months before the initiation of combination therapy. Only one patient (7%) discontinued therapy (Supplementary Table S6) due to a treatment-related toxicity (grade 2 pneumonitis). One death occurred due to an unrelated pneumonia.
Efficacy
Thirteen of the 14 patients were evaluable for response to therapy (12 with measurable disease); the fourteenth patient was deemed unevaluable due to withdrawal of therapy after 18 days (0.6 months) secondary to unrelated oropharyngeal candidiasis. A partial response was achieved in six of 12 patients with measurable disease (50%; 95% CI, 25%–75%), one of which was not confirmed. Stable disease was observed in four patients (33%), and primary progressive disease was seen in two (17%) of 12 patients. The disease control rate was 83% (95% CI, 55%–95%, Supplementary Table S7). One patient with an unconfirmed partial response demonstrated an 80% decrease in target lesion size at initial scans, with progression of non-target lesions at subsequent scans at 3 months treatment.
A waterfall plot of best objective response to combination therapy is shown in Fig. 1A for the 11 patients with measurable disease per RECIST 1.1 at baseline and at least one follow-up scan. One patient with measurable disease is not displayed on the plot as the patient came off treatment before radiographic assessment was repeated. The median depth of response, measured as best percentage of change in target lesions, was −35%.
A swimmer's plot of the duration of combination osimertinib and selpercatinib is shown for all 13 evaluable patients in Fig. 1B. Of note, the patient without measurable disease also experienced clinical benefit; a reduction in non-target disease burden was ongoing at 16 months into combination therapy at the time of the data cutoff. The median duration of treatment in evaluable patients (n = 13) was 7.9 months [95% CI, 3.5–NR). In patients with an objective response to treatment (n = 6), the median duration of treatment was 10.6 months (95% CI, 7.9–NR).
All but one patient evaluable for response had been treated with an osimertinib-containing regimen immediately before trial participation. In one patient, there was a several year gap between exposure to osimertinib and the initiation of combination therapy. This patient lacked measurable disease and was not included in the response rate calculation but did experience clinical benefit as noted above; if this patient were excluded from analysis, the median duration of treatment would be 7.4 months (95% CI, 3.5–NR).
Disease control was durable and exceeded 6 months in 70% (n = 7/10) of evaluable patients without primary progression on the combination. The longest response was ongoing at 25 months; this exceptional responder's course is detailed in Supplementary Fig. S2. Notably, in two of the three patients who received prior combination osimertinib therapy (with a MEK or multikinase RET inhibitor), the duration of combination osimertinib and selpercatinib therapy exceeded 6 months (Fig. 1B). In an exploratory analysis, there was no significant difference in median duration of response for patients with RET fusions identified via NGS versus plasma cfDNA testing. At the time of the data cutoff, five patients remained on therapy, one had discontinued treatment for toxicity (pneumonitis), and eight patients had discontinued treatment for disease progression.
Resistance
Acquired resistance to osimertinib plus selpercatinib was interrogated in pre-combination and post-progression samples (Fig. 2A). Of the eight patients who progressed on the combination, paired samples were available in six patients, of whom one or more putative resistance mechanisms were identified in five patients (83%). Individual patient identification numbers (see Supplementary Table S8 for corresponding patient-level combination efficacy data) and the sample types (plasma/tumor) sequenced are shown in Fig. 2B.
Resistance mutations that impart steric hindrance to therapeutic EGFR or RET kinase engagement were observed in four of six cases (67%). For EGFR on-target resistance, EGFR C797S was acquired in one patient, and EGFR T790M and C797S were acquired in a second patient. It is unclear for the second patient if the T790M mutation pre-existed; the mutation was not detected by prior sequencing. For RET on-target resistance, gatekeeper mutations (RET V804M/E) were identified in two patients and a solvent front mutation (RET G810S) was identified in a third patient. Interestingly, EGFR and RET on-target resistance co-occurred in one of these cases (Fig. 3A).
Presumed loss of the enrolling RET fusion in one or more post-combination therapy progression samples was noted in four of six cases (67%, Fig. 2A). In three of these cases, post-progression genomics were limited to a single analysis of plasma cfDNA; loss of CCDC6–RET (n = 2) or KIF5B–RET (n = 1) was observed. An acquired RET mutation was not identified in these three cases, supporting the potential loss of the RET fusion. To this point, the fourth patient (the only one of the four that had post-progression tumor and plasma analyzed) had CCDC6-RET loss in a tumor biopsy but CCDC6-RET retention in plasma (along with an acquired RET G810S mutation; Fig. 2B).
Off-target resistance involving receptor tyrosine kinase or MAPK pathway activation was observed in three of six cases (50%). Hotspot mutations were found in two of these cases: BRAF V600E (n = 1) and KRAS G12S (n = 1). Acquired gene fusion targeting a non-RET gene was observed in the remaining patient for whom two different ALK fusions (STRN–ALK and EML4–ALK, Fig. 3B) were detected. In this case, the original NCOA4–RET fusion was retained and detected alongside the emergent ALK fusions.
Finally, these individual resistance mechanisms commonly co-occurred (Fig. 3). In a third of evaluable paired cases, on-target and off-target resistance coexisted: RET V804E + EML4-ALK + STRN-ALK (n = 1) and RET V804M + KRAS G12S (n = 1). Concurrent dual EGFR and RET on-target resistance was observed in one case (EGFR C797S and RET G810S). Potential RET fusion loss co-occurred with on-target (EGFR C797S) and off-target (BRAF V600E) mechanisms.
Discussion
This multicenter dataset underscores the utility of concatenating data across prospective expanded access trials and compassionate use programs to generate therapeutic efficacy, safety, and resistance outcomes in underserved populations defined by a rare genomic signature. This analysis of patients with EGFR-mutant and RET fusion-positive lung cancers that were prospectively treated with osimertinib and selpercatinib revealed clinical benefit. A response rate of 50%, disease control rate of 83%, and median treatment duration of 7.9 months were observed. Notably, several patients were pretreated with an osimertinib and RET/MET inhibitor combination. In some patients, durability extended beyond 1 to 2 years in the face of exceptional sensitivity. These data confirm the actionability of this “double hit” signature in the clinic.
Both osimertinib and selpercatinib are highly selective kinase inhibitors that independently avoid off-target toxicity. There were no treatment-related serious adverse events and the combination of these agents was well tolerated, with only one patient discontinuing treatment for toxicity, consistent with the generally favorable side effect profiles of both drugs as monotherapy (2, 8). Toxicities that drove dose modification or discontinuation were likewise aligned with prior reports, and a regimen of 80 mg of osimertinib daily and 80 mg of selpercatinib twice daily was most commonly administered. No unexpected emergent adverse events were observed, even in patients who were exposed to therapy the longest.
Importantly, this series provides the first analysis of resistance to combination EGFR and RET inhibition. Distinct resistance patterns were observed. The first pattern was characterized by retained EGFR and/or RET dependence with the acquisition of a second site resistance mutation that abrogated drug binding. EGFR C797S mutations have previously been implicated in osimertinib resistance, as have RET G810S solvent front mutations in selpercatinib resistance (14). RET V804M/E gatekeeper mutations may have been observed due to the lower dose of selpercatinib used in the combination, recognizing that the full dose of the drug (160-mg twice daily) is predicted to cover gatekeeper substitutions effectively. The second pattern was characterized by the potential loss of a detectable RET fusion, perhaps corroborated by the absence of a second site RET mutation in most cases. The third pattern involved the acquisition of non-EGFR/RET mitogenic drivers such as hotspot mutations or fusions. Although the acquisition of KRAS or BRAF mutations has been reported in the context of EGFR/RET TKI resistance (4, 15), this first report of an acquired ALK fusion superimposed on an EGFR mutation and a RET fusion with a gatekeeper mutation is notable. Although the co-existence of on-target and off-target resistance mechanisms was observed, it is unclear how many mitogenic drivers a single tumor cell can tolerate and these alterations may be present in competing clones. In support of this, a recent report describes the potential emergence of KRAS-mutant and RET wild-type clones in response to selpercatinib use in patients with RET fusion-positive lung cancers (16). The small size of this cohort and the variable nature of genomic testing performed at baseline and acquired resistance may impact our ability to differentiate acquired genomic alterations versus tumor heterogeneity, or to detect uncommon mechanisms of resistance.
Characterizing optimal treatment approaches beyond the combination of osimertinib and selpercatinib will require continued investigation. The heterogenous nature of acquired combination therapy resistance exposes challenges with next-line targeted therapy options. EGFR second-site (EGFR C797S) and RET second-site substitutions (RET G810X) would require the use of next-generation EGFR and RET TKIs (e.g., BLU-945 for EGFR C797S; LOXO-260 or HM06 for RET G810X) that have not been tested in combination. Furthermore, the acquisition of off-target and polyclonal resistance suggests the need for more broadly active therapeutic options, such as emerging antibody–drug conjugates (ADC; e.g., patritumab–deruxtecan). These ADCs target proteins on the tumor cell surface and may retain activity in cancers with complex genomic profiles.
There are several limitations to these data. The compassionate access programs enrolled a more variable patient population and permitted greater treating physician discretion in drug dosing and efficacy assessments than would a prospective therapeutic trial. Formal adverse effect reporting was not mandated, limiting the capture of adverse events that did not result in dose modification or discontinuation. Prospective study will be necessary to more definitively establish the efficacy and safety of this combination. In the interim, the research community and regulatory agencies should consider developing standardized methods of capturing information on aggregated and limited datasets such as this to circumvent the limitations noted here.
In summary, this integrated analysis improves our understanding of the probability of clinical benefit and resistance to the combination of osimertinib and selpercatinib in EGFR-mutant lung cancers with RET fusion-mediated osimertinib resistance. Our results provide a model for exploring combinatorial therapies in EGFR-mutant and RET fusion-positive cancers, or similar resistance states (17, 18). The ongoing multi-arm ORCHARD study (NCT03944772) opened an osimertinib and selpercatinib cohort following the treatment of the seminal cases on this program; this trial will further evaluate the safety and efficacy of this personalized combination. It would be ideal to establish sufficient evidence to support the inclusion of this therapeutic strategy in clinical guidelines and the approval of the combination by one or more health care agencies in the future.
Authors' Disclosures
J. Rotow reports grants, personal fees, and nonfinancial support from Loxo/Lilly, AstraZeneca, and BioAtla; personal fees and nonfinancial support from Takeda and G1 Therapeutics; personal fees from Chiatai Tianqing, Gritstone Bio, Janssen, Sanofi Genzyme, Genentech, Guardant Health, and Summit Therapeutics; grants and personal fees from AbbVie; and grants from Daiichi Sankyo, Blueprint Medicines, Red Cloud, EpimAb, and Bicycle Therapeutics outside the submitted work. J.D. Patel reports other support from AstraZeneca, AnHearth, Takeda, and Genentech during the conduct of the study. M.P. Hanley reports personal fees from Eli Lilly and Company outside the submitted work. H. Yu reports other support from AstraZeneca, Daiichi, Cullinan, Novartis, Black Diamond, Blueprint Medicine, Janssen, Amgen, and Takeda during the conduct of the study. M. Awad reports grants and personal fees from Genentech, Bristol-Myers Squibb, and AstraZeneca; personal fees from Merck, Blueprint Medicine, Gritstone, ArcherDx, and Mirati; and grants from Lilly and Amgen outside the submitted work. J.W. Goldman reports grants from AstraZeneca during the conduct of the study as well as grants and personal fees from AstraZeneca and Eli Lilly outside the submitted work. H. Nechushtan reports other support from AstraZeneca and Loxo/Lilly during the conduct of the study; in addition, H. Nechushtan obtained compassionate use of selpercatinib for some patients and has served as a local principal investigator for research with selpercatinib. M. Scheffler reports personal fees from AstraZeneca during the conduct of the study as well as personal fees from Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, Takeda, and BMS outside the submitted work. C.-H.S. Kuo reports personal fees from AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Eli Lilly, Novartis, Ono Pharma, Chugai, Merck, Janssen Pharma, Takeda, and Guardant Health outside the submitted work. G. Harada reports personal fees from Lilly, AstraZeneca, MSD, Bayer, and Merck outside the submitted work. S. Clifford reports employment with Foundation Medicine since July 2020. L. Silva reports personal fees from Eli Lilly & Company outside the submitted work. R. Tupper reports personal fees from Eli Lilly & Company outside the submitted work. G.R. Oxnard reports personal fees from Foundation Medicine and Roche outside the submitted work. J. Kherani reports other support from Eli Lilly during the conduct of the study as well as other support from Loxo Oncology outside the submitted work; in addition, J. Kherani reports employment with Loxo Oncology, the company responsible for the development of selpercatinib and the sponsor of all clinical trials for this compound. During the course of development, Loxo Oncology was acquired by Eli Lilly and the development and commercialization of selpercatinib became a joint endeavor. Loxo Oncology became a wholly owned subsidiary of Eli Lilly. A. Drilon reports personal fees from Loxo/Lilly during the conduct of the study as well as personal fees from Ignyta/Genentech/Roche, Bayer, Takeda/Ariad/Millenium, TP Therapeutics/BMS, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, AbbVie, 14ner/Elevation Oncology, ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Repare RX, Nuvalent, Merus, Chugai Pharmaceutical, Remedica Ltd., AXIS, EPG Health, Harborside, Nexus, LiberumRV, More Ology, Amgen, TouchIME, Janssen, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc., AiCME, I3 Health, MonteRosa, and EcoR1 outside the submitted work; in addition, A. Drilon reports a patent for selpercatinib/osimertinib pending; associated research to institution: Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, and PharmaMar; equity: Treeline Bio and mBrace; royalties: Wolters Kluwer; and other/food/beverages: Boehringer Ingelheim, Merck, Puma, and Merus. No disclosures were reported by the other authors.
Authors' Contributions
J. Rotow: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. J.D. Patel: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. M.P. Hanley: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. H. Yu: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. M. Awad: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. J.W. Goldman: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. H. Nechushtan: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. M. Scheffler: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. C.-H.S. Kuo: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. S. Rajappa: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. G. Harada: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. S. Clifford: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. A. Santucci: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. L. Silva: Conceptualization, formal analysis, validation, writing–original draft, writing–review and editing. R. Tupper: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. G.R. Oxnard: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. J. Kherani: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing. A. Drilon: Conceptualization, formal analysis, investigation, writing–original draft, writing–review and editing.
Acknowledgments
This article was supported in part by funding from the National Cancer Institute of the National Institute of Health: R01CA251591–01A1 and P30CA008748. Partial support was likewise provided by LUNGevity.
The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).