European Lung Cancer Congress, highlights of innovative treatments in the era of personalized medicine.

On 29 of March -1 of April took place the ESMO – European Lung Cancer Congress in Copenhagen, Denmark, that explored the new technologies and innovations for the management of lung tumors. There were promising clinical trials showing compelling data that may pave the way for changing the way in which patients are treated today.

A recurrent concept has been the one of magic bullets to kill cancer cells. In early 1900s the physician-scientist Paul Ehrlich envisioned the concept of ‘magic bullet’, drugs that go straight to their intended cell-structural targets and could deliver a toxic drug to certain cells while sparing others, ideally the healthy one that are not affected by tumoral alterations.

More than 100 later, this concept is becoming a reality in many solid tumors with a key role in lung cancer. TROP-2, C-met, HER2, HER3 are important molecules for our cells, which are expressed at higher level than normal tissue in lung cancer tumors. A new class of drugs, called antibody-drug conjugated, has been developed in the last decades to specifically recognize these molecules on cancer cells and kill them by releasing the chemotherapy cargo they have associated. Those are Datopotamab Deruxtecan (recognizing TROP-2), Telisotuzumab Vedotin (recognizing c-MET), Sacituzumab Govitecan (recognizing TROP-2), Patritumab Deruxtecan (recognizing HER-3), Trastuzumab Deruxtecan (recognizing HER2), among others, and are revolutionizing the area of Lung Cancer.

All the above have shown interesting efficacies in phase II clinical trials in advanced non-small cell lung cancer (NSCLC) tumors, which were already pretreated with other therapies. Similarly, Patritumab Deruxtecan has shown excellent efficacies in EGFR inhibitor-resistant EGFR mutated NSCLC tumors and Trastuzumab Deruxtecan in HER2 mutant or overexpressing NSCLC tumors. Phase III clinical trials as AVANZAR, TROPION LUNG07, CARMEN LC03, Teli MET NSCLC 01, Destiny-Lung 04, MK3475-D46 among others will confirm the efficacy results previously obtained. Also, some of them will elucidate if these drugs can be positioned as preferred treatment to be administered to patients who have not received any lines of therapy before, or after the standard of chemo/immunotherapy.

Besides the ongoing trials it would be exciting to see the further development of these molecules as they may be combined with multiple treatments, with the final goal of increasing efficacy of treatment and decrease their toxicity, for example optimizing chemotherapy doses.

Following personalized medicine, KRAS G12C inhibitors continuously show efficacy results in patients with KRASG12C mutations as in the EAP -436 study. The efficacy of Amivantamab, a bispecific monoclonal EGFR and C-met antibody (meaning that is able to recognize and block molecules at the same time), was also highlighted in Osimertinib resistant tumors in the CHRISALYS-1 study. This drug was granted with accelerated approval by the FDA in 2021 for a specific population of NSCLC which are characterized by a mutation in EGFR called exon 20 insertion. Those patients are resistant to standard drug used for treating patients with EGFR-mutation, but amivantamab seems to have solved this previous unmet need and it is now standard of care for them.

Of note, approximately 2% to 3% of patients with NSCLC have EGFR exon 20 insertion mutation. It would be interesting to follow the phase III trials in naïve patients harboring EGFR mutated tumors as in the MARIPOSA trial, or for patients with EGFR Exon 20 insertions as in the PAPILLON study. It would be also interesting to see the efficacy of the drug with novel combinations and in tumors harboring C-met mutations.

A strong debate is still ongoing regarding the use of neoadjuvant immunochemotherapy (meaning before the surgery, to reduce tumor size) or adjuvant immunochemotherapy (after the surgery). The checkmate 816 phase III trial showed a 3-year EFS rate of 57% for neoadjuvant nivolumab plus chemotherapy and 43% for the chemotherapy treatment arm and an Overall survival rate of 78% versus 64% respectively. We still need to see if checkmate 816 study will change the future clinical management of resectable NSCLC. Also, it would be compelling to see the results of the coming studies evaluating neoadjuvant immunochemotherapy followed by adjuvant immunotherapy or immunochemotherapy as KEYNOTE 671, IMPOWER 030, NCT05457776, CheckMate77T among others. Last and not least, it is also interesting to evaluate if immunotherapy in the (neo)adjuvant context may yield better results compared with adjuvant immunotherapy as it was shown in advance melanoma (NCT03698019).

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