Following outcomes of multiple landmark clinical trials reported for the first time in late-breaking presentations at the annual meeting of the European Society for Medical Oncology (ESMO Congress 2023) – some with practice changing updates – more patients diagnosed with non-small cell lung cancer (NSCLC) are likely to benefit from novel treatment options designed to target molecular alterations in tumor cells, with less need for chemotherapy. 
Today, the vast majority of lung cancers (85%) is NSCLC (the remaining percentage (15%) is known as small cell lung cancer (SCLC). Although NSCLC progresses more slowly than SCLC, 40% of NSCLCs will have spread beyond the lungs by the time the disease is diagnosed. Generally, treatments for NSCLC include surgery, chemotherapy, radiation therapy and targeted therapy. While advances over the last 5 years have changed treatment options for patients, the advances presented at the ESMO 2023 Congress are expected to again further advance treatment options, creating more and real hope for patients. These presented treatment advances highlight the importance of tumor testing at diagnosis and sets the potential for major changes in first-line treatment for patients with NSCLC with targetable tumor cell mutations.
These better outcomes were achieved with combinations of experimental new drugs targeting common and rare tumor mutations than with standard treatments, with improvements seen in both early and late-stage NSCLC – the type of lung cancer responsible for approximately eight out of 10 cases of the disease. 
“The results are very impressive and mean that we can expect major changes in first-line treatment for patients with NSCLC with these targetable tumor cell alterations, and in the way we care for patients whose previous treatment has stopped working,” explained Professor Alessandra Curioni-Fontecedro, University of Fribourg, Switzerland.
“As a result, it will be more important than ever that lung cancer is diagnosed and treated by lung cancer specialists with access and understanding of molecular testing and findings,” added Alessandra.
“We are entering an era of personalized medicine in NSCLC where we are using combinations of novel, targeted agents, and it will be essential to know the whole mutational burden of each patient at diagnosis so we can properly plan the most effective and least toxic approach. The future of lung cancer care lies in finding the right combination of targeted treatment, or chemotherapy with immunotherapy for each patient,” Dr Elene Mariamidze, Todua Clinic, Tbilisi, Georgia, agreed.
Both Curioni-Fontecedro and Mariamidze highlighted data from studies using a new combination of targeted drugs in patients with advanced or metastatic NSCLC who had an EGFR mutation – one of the most common tumor mutations. 
When people were given the combination as first-line treatment, progression-free survival (PFS) was significantly better than with the current most effective treatment for the mutation. 
This is a conclusion of the Phase 3 MARIPOSA study showing that amivantamab (Rybrevant®; Janssen Biotech), in combination with lazertinib (Leclaza®; Janssen Biotech), an oral, third-generation, EGFR-TKI being developed by Yuhan and Janssen Biotech for the treatment of NSCLC, compared to osimertinib (Tagrisso®; AstraZeneca) resulted in a 30% reduction in the risk of disease progression or death (Hazard Ratio [HR]=0.70; 95% Confidence Interval [CI], 0.58–0.85; p value P<0.001) in the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with either epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution
The results also showed a favorable trend in overall survival (OS) for amivantamab and lazertinib in these patients compared to osimertinib (HR=0.80; 95 percent CI, 0.61–1.05; P=0.11) at a first interim analysis.
In people who had already progressed on this current standard of care, the new targeted drugs, combined with chemotherapy, significantly improved PFS compared with chemotherapy alone. 
“We still need to see that the new combination leads to improved overall survival compared with current treatment. We also need to understand more about the effects in patients with brain metastases as it appears that one of the newer EGFR-targeting agents used in these studies has good penetration of brain tissue,” explained Curioni-Fontecedro.
“These studies show that patients now have a potentially new drug combination for their treatment that works partly by targeting EGFR mutations, and partly by directing immune cells to destroy cancer cells. The fact that the combination worked better than the current standard of care, not just better than placebo, shows tangible benefits for this new approach,” Mariamidze added.
Results of NSCLC studies presented at the ESMO Congress 2023 also suggest that using mutation-targeted treatment can reduce the need for chemotherapy in some patients, including those with some rarer tumor alterations for which targeted treatment options have previously been limited.
These include patients with operable, early stage anaplastic lymphoma kinase (ALK)-positive NSCLC,  those with RET-mutated advanced NSCLC,  and those with the less common, more difficult to treat EGFR mutation, Exon 20 insertion, advanced NSCLC. 
The primary analysis of the Phase III ALINA study demonstrating a statistically significant and clinically meaningful improvement in disease-free survival (DFS; primary endpoint). The study outcomes demonstrated that alectinib (Alecensa®; Genentech) reduces the risk of disease recurrence or death by 76% (hazard ratio [HR]=0.24, 95% CI: 0.13-0.43, p<0.0001) compared with platinum-based chemotherapy in people with completely resected Stage IB (tumor ≥4 cm) to IIIA (UICC/AJCC 7th edition) ALK-positive non-small cell lung cancer (NSCLC). A clinically meaningful improvement of central nervous system (CNS)-DFS was also observed (HR=0.22; 95% CI: 0.08-0.58). 
The safety and tolerability of alectinib in this trial were consistent with previous trials in the metastatic setting and no unexpected safety findings were observed. Overall survival data were immature at the time of this analysis and follow-up is ongoing to report a more mature estimate.
In two late-breaking oral presentations to be featured as part of the Presidential Symposium 1, investigators share interim analysis results from the Phase 3 LIBRETTO-431 and LIBRETTO-531 clinical studies. LIBRETTO-431 evaluated selpercatinib (Retevmo®; Lilly & Co) versus platinum-based chemotherapy – with or without pembrolizumab (Keytruda®; Merck & Co/MSD) – as an initial treatment for patients with RET fusion-positive non-small cell lung cancer (NSCLC). The LIBRETTO-531 study evaluated selpercatinib versus multikinase inhibitors (cabozantinib or vandetanib) in patients with advanced RET-mutant medullary thyroid cancer (MTC).
Immunotherapy + chemotherapy
In addition, study data reinforce the value of adding immunotherapy to chemotherapy in some types of NSCLC, including the use of this treatment before surgery for patients with operable cancers to shrink tumors and indicate likely response to further treatment after surgery (so called, neoadjuvant treatment). 
“We know that patients have a better prognosis if pre-surgical treatment of lung cancer leads to tumor disappearance on pathology reports after surgery (pCR-pathologic complete response) than if there are still obvious cancer cells present in post-surgical material. The new results show that adding immunotherapy to chemotherapy before surgery, and then continuing with maintenance immunotherapy for a year after surgery, is more effective than just giving chemotherapy before surgery,” Mariamidze said.
Even for patients with advanced or metastatic NSCLC who have relapsed following previous treatments and can only be given chemotherapy, there is good news. Directing chemotherapy more precisely at tumors using antibody-drug conjugates (ADCs), namely antibodies that recognize specific proteins commonly found in lung cancers significantly improved PFS compared to currently used chemotherapy.
“The approach using these antibody-drug conjugates will make a big difference for the majority of patients with advanced or metastatic NSCLC who have stopped responding to first and second-line treatments, irrespective of whether they have targetable mutations. We need to know more about the side-effects of this approach but these findings are likely to change the standard of care for these patients,” Curioni-Fontecedro predicted.
In the pivotal TROPION-Lung01 Phase 3 trial, investigating datopotamab deruxtecan, an investigational TROP2-directed ADC designed Daiichi Sankyo and AstraZeneca, in the treatment of non-small cell lung cancer, showed a reduced the risk of disease progression or death by 25% compared to docetaxel (hazard ratio [HR]=0.75; 95% confidence interval [CI] 0.62-0.91; p=0.004) as assessed by blinded independent central review (BICR).
Furthermore, the median PFS was 4.4 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. Results also showed a confirmed objective response rate (ORR) of 26.4% in patients treated with datopotamab deruxtecan compared to an ORR of 12.8% with docetaxel.
In patients with non-squamous NSCLC, datopotamab deruxtecan demonstrated a clinically meaningful benefit, reducing the risk of disease progression or death by 37% compared to docetaxel (HR 0.63; 95% CI 0.51-0.78) as assessed by BICR. Median PFS was 5.6 months in patients treated with datopotamab deruxtecan versus 3.7 with docetaxel. A confirmed ORR of 31.2% was observed with datopotamab deruxtecan, including four complete responses (CRs), versus 12.8% with docetaxel which elicited no CRs. Datopotamab deruxtecan did not demonstrate a PFS benefit in patients with squamous NSCLC.
For the dual primary endpoint of overall survival (OS), interim results numerically favored datopotamab deruxtecan over docetaxel in the overall population (HR 0.90; 95% CI 0.72-1.13) and in patients with non-squamous tumors (HR 0.77 95% CI: 0.59-1.01), however, results did not reach statistical significance at the time of this data cut-off. The trial is ongoing and OS will be assessed at a final analysis.
Better understand the sequence of treatments
Following such promising NSCLC data presented at ESMO 2023, the next step for both Curioni-Fontecedro and Mariamidze is to better understand the sequence of treatments that will give the best outcomes for patients.
“We still face the dilemma of what we do after patients have had these promising new drugs and need further treatment. It will be very important to understand the sequencing of treatment now that we have so many more options for treating NSCLC so that we can achieve the best possible results for each patient,” said Curioni-Fontecedro.
“Very few patients benefit from one therapy alone, and most will need combinations of treatments at different times in their lung cancer care. We need further research to show when and how to target different mutations, possibly including new targets, and to help establish the ideal treatment plan for patients with lung cancer who develop extensive disease,” Mariamidze concluded.
 Abstract – LBA14. Cho BC et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from mariposa, a Phase 3, global, randomized, controlled trial will be presented by Byoung Chul Cho during Presidential 3 Session on Monday, 23 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA15. Passaro A et al. Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: mariposa-2, a phase 3, global, randomized, controlled trial will be presented by Antonio Passaro during Presidential 3 Session on Monday, 23 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA2. Solomon BJ et al. ALINA: efficacy and safety of adjuvant alectinib (Alecensa®; Genentech) versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer (NSCLC)will be presented by Ben J. Solomon during Presidential 1 Session on Saturday, 21 October 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA4. Loong HHF et al. Randomized phase 3 study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC will be presented by Herbert Ho Fung Loong during Presidential 1 Session on Saturday, 21 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA5. Girard N et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): primary results from papillon, a randomized phase 3 global study will be presented by Nicolas Girard during Presidential 1 Session on Saturday, 21 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA1 Cascone T et al. CHECKMATE 77T: Phase 3 study comparing neoadjuvant nivolumab (nivo) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant nivo or placebo for previously untreated, resectable stage II-IIIB NSCLC will be presented by Tina Cascone during Presidential 1 Session on Saturday, 23 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 Abstract – LBA12. Ahn M-J et al. Datopotamab deruxtecan (DATO-DXD) vs docetaxel in previously treated advanced/metastatic (ADV/MET) non-small cell lung cancer (NSCLC): results of the randomized Phase 3 study TROPION-LUNG01will be presented by Aaron E. Lisberg during Presidential 3 Session on Monday, 23 October, 16:30 to 18:15 (CEST) in Madrid Auditorium – Hall 6.
 ESMO. Non-small-cell lung cancer: A guide for patients.
Featured image: Lung radiography | Doctor examining a lung radiography