Natasha Leighl, MD, FRCPC, FASCO:
The open-label phase III ALINA trial compared alectinib vs platinum-based CT in patients with resected stage IB (≥4 cm) to stage IIIA, ALK-positive NSCLC with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.^{[Solomon 2023]} Patients (N = 257) were postoperatively randomized 1:1 to receive either alectinib for 2 years at a standard dose of 600 mg twice daily or 4 cycles of platinum-based CT. The study was stratified by disease stage (IB vs II vs IIIA) and race (Asian vs non-Asian). The primary endpoint was disease-free survival (DFS) per investigator in a hierarchical manner: first in the stage II-IIIA subpopulation, then in the stage IB-IIIA intention-to-treat (ITT) population. Secondary endpoints included central nervous system (CNS) DFS, overall survival (OS), and safety.

Natasha Leighl, MD, FRCPC, FASCO:
The arms in this study were well balanced. Approximately one half of the patients were female, and the majority were never smokers.^{[Solomon 2023]} Approximately one half were Asian, one half had stage IIIA disease, and one half had N2 disease, and the vast majority underwent a lobectomy.
 

Natasha Leighl, MD, FRCPC, FASCO:
The primary endpoint of the study was met, with significantly improved median DFS with adjuvant alectinib treatment compared with platinum-based CT in patients with resected stage II and IIIA disease. The DFS was not reached in the alectinib arm vs 44.4 months with CT (HR: 0.24; 95% CI: 0.13-0.45; P <.0001).^{[Solomon 2023]} Within the ITT population, the HR was very similar (HR: 0.24; 95% CI: 0.13-0.43; P <.0001). Of note, the ITT population included patients with smaller tumors that were formerly known as stage IB but now classified as stage II. A DFS benefit was seen with alectinib across all subgroups of the ITT population, including age, sex, race, baseline ECOG PS, tobacco use history, tumor stage, and regional lymph node status.

Natasha Leighl, MD, FRCPC, FASCO:
In the ITT population, intracranial DFS was better with adjuvant alectinib compared with platinum-based CT, and after 3 years, only 4.5% of patients receiving adjuvant alectinib had developed recurrence in the brain vs 20.3% of those receiving adjuvant CT (HR: 0.22; 95% CI: 0.08-0.58).^{[Solomon 2023]} Overall, alectinib decreased recurrence rates throughout the body compared with platinum-based CT, whether the site was locoregional, distant, or both.

Natasha Leighl, MD, FRCPC, FASCO:
After recurrence, most patients (76%) in the adjuvant CT arm received an ALK TKI, and 40% of patients in the adjuvant alectinib arm went on to receive CT.^{[Solomon 2023]}

Natasha Leighl, MD, FRCPC, FASCO:
Adverse events (AEs) were similar to what we see in routine practice. The majority of patients completed the full 2 years of alectinib, with 20.3% remaining on therapy at data cutoff. In the platinum-based CT arm, patients received a median of 2.1 months of CT.^{[Solomon 2023]} Grade 3/4 AEs were observed in approximately 30% of patients in both arms, but only 5% of patients discontinued alectinib due to toxicity vs 13% of patients in the CT arm. Alectinib treatment resulted in increased rates of constipation and increases in creatine phosphokinase and bilirubin. 

Natasha Leighl, MD, FRCPC, FASCO:
Nivolumab is approved for treatment of adult patients with resectable (tumors ≥4 cm or node positive) NSCLC in the neoadjuvant setting in combination with platinum-doublet CT.^{[Nivolumab PI]} The phase III CheckMate 77T study addresses the question of whether adding adjuvant nivolumab after neoadjuvant nivolumab plus CT and resection improves outcomes.^{[Cascone 2023]}

The CheckMate 77T study randomized 461 patients with resectable stage II-IIIB NSCLC to receive 4 cycles of platinum-based CT with or without nivolumab, followed by surgery and adjuvant nivolumab (nivolumab arm) or placebo (CT arm) every 4 weeks for up to 1 year. The study was stratified by tumor histology (squamous vs nonsquamous), disease stage (II vs III), and PD-L1 expression (≥1% vs <1% vs not evaluable). The primary endpoint was event-free survival (EFS) by blinded independent central review (BICR), and secondary endpoints included pathologic complete response (pCR) and major pathologic response (mPR) by blinded independent pathologic review (BIPR).

Natasha Leighl, MD, FRCPC, FASCO:
Baseline characteristics were similar between the 2 treatment arms.^{[Cascone 2023]} Two thirds of patients had stage IIIA or IIIB disease, and there were similar percentages with squamous (51%) or nonsquamous (49%) disease within and between the arms. Approximately 40% of patients had PD-L1–negative (<1%) disease, and approximately 20% had high (≥50%) PD-L1 expression. In the nivolumab plus CT arm, 24% of patients received cisplatin compared with 18% of patients in the control arm.

Natasha Leighl, MD, FRCPC, FASCO:
Similar percentages of patients in the nivolumab plus CT and placebo plus CT arms completed neoadjuvant treatment (85% vs 89%) and went on to receive surgery (78% vs 77%) and adjuvant treatment (62% vs 66%).^{[Cascone 2023]} This was very similar to what was seen in the CheckMate 816 trial of neoadjuvant therapy, in which 20% to 22% of patients did not receive definitive surgery.^{[Forde 2022]} The majority (60%) of patients in both arms completed all adjuvant therapy. Rates of lobectomy were somewhat higher in the nivolumab plus CT arm vs the placebo plus CT arm (80% vs 72%, respectively), with similar rates of R0 resection. 

Natasha Leighl, MD, FRCPC, FASCO:
Median EFS was not reached with neoadjuvant nivolumab plus CT and adjuvant nivolumab vs 18.4 months with placebo plus CT, which was significant (HR: 0.58; 95% CI: 0.42-0.81; P = .00025).^{[Cascone 2023]} The majority of the EFS benefit was seen in patients with stage III disease, with a median EFS of 30.2 months with nivolumab vs 13.4 months with CT (HR: 0.51; 95% CI: 0.36-0.72). The EFS difference among patients with stage II disease was not statistically significant, although nivolumab was favored with an HR of 0.81 (95% CI: 0.46-1.43). 

Natasha Leighl, MD, FRCPC, FASCO:
Patients with PD-L1–negative disease did not have a statistically significant benefit from nivolumab plus CT (HR: 0.73; 95% CI: 0.47-1.15).^{[Cascone 2023]} By contrast, patients with PD-L1–positive (≥1%) disease had a nearly 50% reduction in the risk of relapse, which was significant (HR: 0.52; 95% CI: 0.35-0.78). 

Patients with high (≥50%) PD-L1 expression levels had a higher median EFS benefit (HR: 0.26; 95% CI: 0.12-0.55), unlike those with low (1%-49%) PD-L1 expression (HR: 0.76; 95% CI: 0.46-1.25). Otherwise, the benefit for nivolumab plus CT vs placebo plus CT was seen across subgroups examined. 

Natasha Leighl, MD, FRCPC, FASCO:
Similar to other trials, 25.3% of patients achieved a pCR in the nivolumab plus CT arm, and 35.4% achieved mPR.^{[Cascone 2023]} This compared with the CT plus placebo arm, where only 4.7% of patients achieved pCR and 12.1% achieved mPR. This was a significant increase in pCR rate—at least 6.6-fold higher (95% CI: 3.40-12.97)—and as expected, higher pCR rate was closely associated with improved EFS. 

The team also performed an interesting analysis of EFS benefit in patients who received adjuvant therapy vs those who did not. Both groups had a significant improvement in EFS with nivolumab and similar HRs. Similarly, the EFS with nivolumab was significantly better in the subgroup of patients who achieved pCR and received adjuvant therapy (HR: 0.22; 95% CI: 0.04-1.08) and the group of patients who did not achieve pCR and received adjuvant therapy (HR: 0.63; 95% CI: 0.40-0.99). I do not think this slight improvement in HR for patients who achieve pCR vs those who do not helps us better understand who may not require further therapy. 

Natasha Leighl, MD, FRCPC, FASCO:
Toxicities were similar to what we observe in clinical practice and the known AE profile for these agents.^{[Cascone 2023]} There were more AEs leading to treatment discontinuation in the nivolumab plus CT arm vs CT plus placebo arm (25% vs 11%) and more treatment-related AEs (TRAEs) leading to discontinuation. Of note, there were 2 treatment-related deaths during the neoadjuvant period in the nivolumab plus CT arm: 1 each from grade 4 and grade 5 pneumonitis. Surgical AEs were similar in both arms.

Natasha Leighl, MD, FRCPC, FASCO:
In terms of immune-mediated AEs, these were in line with other chemoimmunotherapy studies.^{[Cascone 2023; Nivolumab PI]}

Natasha Leighl, MD, FRCPC, FASCO:
A number of really exciting updates in advanced disease were presented at ESMO 2023, particularly for targeted agents. RET gene fusions present targetable alterations in patients with advanced NSCLC, and TKIs such as selpercatinib have shown potent RET inhibition. Based on the efficacy demonstrated in frontline treatment in the registrational phase I/II LIBRETTO-001 trial,^{[Drilon 2023]} selpercatinib was approved for treatment of adult patients with locally advanced or metastatic NSCLC with a RET gene fusion.^{[Selpercatinib PI]}

The open-label phase III LIBRETTO-431 study enrolled 261 patients with stage IIIB/IIIC/IV nonsquamous, RET fusion‒positive lung cancer who were randomized 2:1 to receive selpercatinib 160 mg twice daily or platinum-based CT with or without pembrolizumab based on the center’s SoC.^{[Loong 2023; Zhou 2023]} Patients receiving CT plus pembrolizumab were permitted to cross over to receive selpercatinib upon BICR-confirmed progressive disease. The ITT-pembrolizumab cohort (n = 212) was stratified by investigator intent to administer pembrolizumab with CT and had to comprise ≥80% of the ITT population per protocol.

The sequential primary endpoints were progression-free survival (PFS) by BICR in the ITT-pembrolizumab population and then the ITT population. Secondary endpoints included OS, objective response rate (ORR), duration of response (DoR), CNS ORR, CNS DoR, CNS time to progression, safety, and patient-reported outcomes.

Natasha Leighl, MD, FRCPC, FASCO:
Patient characteristics were similar between the 2 arms.^{[Loong 2023; Zhou 2023]} Approximately one half of patients were Asian, and 20% had known brain metastasis. Approximately 45% had PD-L1–positive (≥1%) disease, and most of those with a defined fusion partner had a KIF5B-RET fusion, as we see in clinical practice.

Natasha Leighl, MD, FRCPC, FASCO:
The study met both its primary endpoints, showing a dramatic improvement in median PFS with selpercatinib (24.8 months) vs pembrolizumab plus CT (11.2 months) in the ITT-pembrolizumab population (HR: 0.46; 95% CI: 0.31-0.70; P <.001).^{[Loong 2023; Zhou 2023]} Similarly, median PFS was significantly longer with selpercatinib (24.8 months) vs pembrolizumab plus CT (11.2 months) in the ITT population (HR: 0.48; 95% CI: 0.33-0.70; P <.001). The PFS benefit was seen across all preplanned subgroups.

Natasha Leighl, MD, FRCPC, FASCO:
The ORR was higher with selpercatinib vs CT plus pembrolizumab (84% vs 65%), with a longer DoR.^{[Loong 2023; Zhou 2023]} There was also a dramatic difference in intracranial ORR at 82.4% with selpercatinib vs 58.3% with pembrolizumab plus CT. The median intracranial PFS also was higher for selpercatinib vs pembrolizumab plus CT (16.1 vs 10.4 months). Among patients receiving selpercatinib, 35.3% achieved a complete response (CR) in the brain vs 16.7% in the pembrolizumab plus CT arm. The OS data are immature and confounded by a very high rate of crossover.

Natasha Leighl, MD, FRCPC, FASCO:
Although toxicity rates were similar, the selpercatinib arm had more patients who had dose reductions (51.3%) vs pembrolizumab plus CT (28.6%). Rates of discontinuation also were higher with selpercatinib (10.1%) vs pembrolizumab plus CT (2.0%).^{[Loong 2023; Zhou 2023]} However, this is probably a reflection of the fact that median time receiving treatment was 70% longer with selpercatinib vs pembrolizumab plus CT. Common toxicities were similar to those seen in earlier studies, including transaminitis and hypertension, among others. 

Natasha Leighl, MD, FRCPC, FASCO:
In terms of patient-reported outcomes, selpercatinib delayed the time to worsening of pulmonary symptoms and overall physical function compared with CT plus pembrolizumab.^{[Loong 2023; Zhou 2023]} 

Natasha Leighl, MD, FRCPC, FASCO:
At ESMO 2023, numerous studies using antibody‒drug conjugates (ADCs) were presented, aiming to improve outcomes for patients with previously treated advanced or metastatic NSCLC—and the TROPION-Lung01 study was probably the most impactful.

Datopotamab deruxtecan (Dato-DXd) is a humanized anti–TROP-2 IgG1 monoclonal antibody (mAb) connected to the topoisomerase I inhibitor deruxtecan via an enzymatically cleavable tetrapeptide linker.^{[Okajima 2021]} In the phase I TROPION-PanTumor01 trial, Dato-DXd monotherapy suggested antitumor activity in metastatic NSCLC.^{[Shimizu 2023]}

In the open-label phase III TROPION-Lung01 trial, 604 patients with stage IIIB/IIIC/IV NSCLC whose disease had progressed on prior systemic therapy were randomized 1:1 to receive Dato-DXd at a dose of 6 mg/kg every 3 weeks or docetaxel 75 mg/m² every 3 weeks.^{[Lisberg 2023]} The study was stratified by tumor histology (squamous vs nonsquamous), actionable genomic alterations, geography (United States vs Japan vs Western Europe vs rest of world), and anti–PD-1/PD-L1 mAb used in most recent prior therapy. The primary endpoints were PFS by BICR and OS, with secondary endpoints including ORR and DoR by BICR, and safety.

Natasha Leighl, MD, FRCPC, FASCO:
Patient characteristics were well balanced; approximately 78% of patients had nonsquamous NSCLC, and 17% had actionable genomic alterations (mostly EGFR mutations). Approximately 43% of patients had received multiple lines of prior therapy.^{[Lisberg 2023]}  

Natasha Leighl, MD, FRCPC, FASCO:
In terms of efficacy, a significantly better median PFS was seen with Dato-DXd vs docetaxel (4.4 vs 3.7 months; HR: 0.75; 95% CI: 0.62-0.91; P = .004) in the ITT population.^{[Lisberg 2023]} However, the difference in median OS between the 2 arms was not statistically significant at 12.4 months for Dato-DXd vs 11.0 months for docetaxel (HR: 0.90; 95% CI: 0.72-1.13). ORR was higher at 26% with Dato-DXd vs 13% with docetaxel, and median DoR was slightly longer with Dato-DXd vs docetaxel.

Natasha Leighl, MD, FRCPC, FASCO:
Subgroup analysis revealed a difference in patients who benefit from Dato-DXd, particularly by tumor histology.^{[Lisberg 2023]} The greatest benefit with Dato-DXd was seen in patients with nonsquamous NSCLC, with a clear improvement in PFS and a trend toward better OS. In patients with squamous NSCLC, PFS was longer with docetaxel, and OS also favored docetaxel. With respect to ORR, in the nonsquamous population there was a dramatically higher ORR of 31.2% with Dato-DXd vs 12.8% with docetaxel. In the population with squamous tumors, there was no ORR benefit with Dato-DXd, but the ORR with docetaxel was 12.7%, just as in the nonsquamous population. It was interesting that the PFS benefit also was greater in patients with actionable genetic alterations vs those without.

Natasha Leighl, MD, FRCPC, FASCO:
In terms of toxicities, all-grade TRAEs were similar between the arms, but grade ≥3 TRAEs were lower with Dato-DXd (25%) vs docetaxel (41%).^{[Lisberg 2023]} More patients had TRAEs associated with dose delay with Dato-DXd vs docetaxel (17% vs 11%), but those leading to treatment discontinuation (8% vs 12%) and death (1% vs 1%) were very similar. The most common TRAES with Dato-DXd were stomatitis and nausea. Of note, a similar number of patients had pneumonitis and sepsis/septic shock in both arms.

Natasha Leighl, MD, FRCPC, FASCO:
AEs of special interest for Dato-DXd included stomatitis; ocular events including dry eye, tearing, and keratitis; and interstitial lung disease adjudicated to be drug related.^{[Lisberg 2023]} As lung cancer healthcare professionals, we will need to learn how to manage some of these new toxicities.

Natasha Leighl, MD, FRCPC, FASCO:
The phase II HERTHENA-Lung01 study examined the HER3-directed ADC patritumab deruxtecan given at 5.6 mg/kg IV every 3 weeks in patients with EGFR-mutated (ex19del or exon 21 L858R mutations) NSCLC who had received prior EGFR TKI therapy and platinum-based CT.^{[Yu 2023; Johnson 2023]} The primary endpoint of this study was confirmed ORR by BICR, with a key secondary endpoint of DoR by BICR.

In the initial results of HERTHENA-Lung01, patritumab deruxtecan demonstrated durable antitumor activity with a confirmed ORR of 29.8%.^{[Yu 2023]} At ESMO 2023, an analysis of intracranial efficacy in the HERTHENA-Lung01 trial was presented.^{[Johnson 2023]}

Natasha Leighl, MD, FRCPC, FASCO:
In patients with brain metastases at baseline (n = 95), the confirmed ORR was 20%, including 15.8% CR, and the median DoR was 9.2 months.^{[Johnson 2023]} In patients who had not received prior radiation (n = 30), confirmed ORR was 33% (30% CR), with a median DoR of 8.4 months.

Natasha Leighl, MD, FRCPC, FASCO:
The brain was the site of first progression in 21% of patients with a history of brain metastases and 3% of patients without a history of brain metastases.^{[Johnson 2023]}

Natasha Leighl, MD, FRCPC, FASCO:
When they looked at cumulative incidence rates of CNS progression, non-CNS progression, and death, non-CNS progression was the main contributor to morbidity in this study.^{[Johnson 2023]}

Natasha Leighl, MD, FRCPC, FASCO:
Turning now to ADCs in extensive-stage small-cell lung cancer (ES-SCLC), data from the single arm, multicohort phase II TROPiCS-03 basket trial of sacituzumab govitecan were presented at ESMO 2023.^{[Dowlati 2023]} Sacituzumab govitecan is a TROP-2‒directed ADC composed of a humanized IgG1 antibody connected to SN-38, the active metabolite of irinotecan (topoisomerase I inhibitor), via a pH-sensitive linker.^{[Goldenberg 2019]} Sacituzumab govitecan has regulatory approval for some types of advanced breast cancer and metastatic urothelial carcinoma.

The TROPiCS-03 trial enrolled patients with ES-SCLC (n = 40) who had progressed after 1 prior line of platinum-based CT and anti–PD-1/PD-L1 therapy with no known active CNS metastases and/or carcinomatous meningitis. Patients received sacituzumab govitecan at 10 mg/kg until disease progression or unacceptable toxicity. The primary endpoint was ORR by investigator, with key secondary endpoints including DoR, clinical benefit rate, PFS, OS, and safety.

Natasha Leighl, MD, FRCPC, FASCO:
Nearly all patients had stage IV disease at initial diagnosis, and one half had had a prior response to previous therapy.^{[Dowlati 2023]} The median duration of treatment was 3.9 months, and 37% of patients were receiving treatment as of data cutoff.

Natasha Leighl, MD, FRCPC, FASCO:
The ORR for sacituzumab govitecan was 37%, and all were partial responses.^{[Dowlati 2023]} The median DoR was 6.3 months. Of patients with postbaseline tumor assessments, 77% had some reduction in tumor size.

Natasha Leighl, MD, FRCPC, FASCO:
In terms of safety, the leading causes of toxicity were gastrointestinal related, including diarrhea, constipation, and nausea; most were grade 1-2.^{[Dowlati 2023]} Grade ≥3 neutropenia was observed in 33% of patients.

Natasha Leighl, MD, FRCPC, FASCO:
Similar to advanced NSCLC, RET alterations are also an important targetable oncogenic driver in thyroid cancer. At ESMO 2023, an exciting advance in RET-mutated medullary thyroid cancer (MTC) was presented. MTC is a rare neuroendocrine thyroid tumor derived from neuroendocrine parafollicular C-cells.^{[Locati 2020]} RET mutations are present in almost all hereditary cases of multiple endocrine neoplasia type 2A and 2B and 25% to 50% of sporadic cases.^{[Romei 2016; Ciampi 2019]} The SoC for advanced MTC includes the multikinase inhibitors cabozantinib and vandetanib.^{[NCCN Thyroid]} 

Selpercatinib, a selective and potent RET kinase inhibitor, suggested durable antitumor activity in patients with advanced or metastatic RET-mutant MTC in the phase I/II LIBRETTO-001 trial.[Wirth 2020] Selpercatinib is approved by the FDA for adult and pediatric patients 12 years of age and older with advanced or metastatic MTC with a RET mutation who require systemic therapy and for adult and pediatric patients 12 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate).^{[Selpercatinib PI]}

In the open-label phase III LIBRETTO-531 study, 291 patients with advanced, TKI-naive, RET-mutant MTC were randomized 2:1 to receive selpercatinib or physician’s choice of cabozantinib or vandetanib.^{[Hadoux 2023a; Hadoux 2023b]} The study was stratified by mutation status (M918T vs other) and physician’s choice in control arm. The primary endpoint was PFS by BICR, with key secondary endpoints including treatment failure–free survival (TFFS), ORR, OS, and safety.

Natasha Leighl, MD, FRCPC, FASCO:
Most patients had the M918T mutation (63%), and the median time from diagnosis to starting treatment was 42.7 months for patients receiving selpercatinib and 61.6 months for patients receiving cabozantinib or vandetanib.^{[Hadoux 2023a; Hadoux 2023b]} This actually favored the control arm of cabozantinib or vandetanib, as these patients had more indolent disease. 

Natasha Leighl, MD, FRCPC, FASCO:
Median PFS by BICR was significantly better with selpercatinib vs cabozantinib or vandetanib (not estimable [NE] vs 16.8 months; HR: 0.28; 95% CI: 0.16-0.48; P <.001).^{[Hadoux 2023a; Hadoux 2023b]} 

Natasha Leighl, MD, FRCPC, FASCO:
A similar benefit was observed for investigator-assessed PFS (HR: 0.19; 95% CI: 0.11-0.32; P <.0001) and across all the different subgroups and mutation subtypes.

Natasha Leighl, MD, FRCPC, FASCO:
Median TFFS by BICR was also significantly prolonged (NE vs 13.9 months; HR: 0.25; 95% CI: 0.15-0.42; P <.001) in the selpercatinib arm vs the cabozantinib or vandetanib arm.^{[Hadoux 2023a; Hadoux 2023b]} 

Natasha Leighl, MD, FRCPC, FASCO:
Similarly, the ORR was higher in the selpercatinib arm (69.4%) vs the cabozantinib or vandetanib arm (38.8%), including a higher percentage of CR.^{[Hadoux 2023a; Hadoux 2023b]} Median DoR also was prolonged in patients receiving selpercatinib vs the older generation multitargeted kinase inhibitors (NE vs 16.6 months).

Natasha Leighl, MD, FRCPC, FASCO:
There also was an early signal of improved OS (HR: 0.37; 95% CI: 0.15-0.95; P = .0312), but the data are not yet mature. The majority of patients eligible to cross over to selpercatinib did so (77%).^{[Hadoux 2023a; Hadoux 2023b]} 

Natasha Leighl, MD, FRCPC, FASCO:
Safety signals were similar to what we have seen with previous studies. In particular, selpercatinib was better tolerated than the older-generation kinase inhibitors cabozantinib or vandetanib, with grade ≥3 TRAEs of 52.8% vs 76.3%.^{[Hadoux 2023a; Hadoux 2023b]} Rates of permanent discontinuation also were lower with selpercatinib (4.7%) vs cabozantinib or vandetanib (26.8%). There were no treatment-related deaths.