Authors: Renee Botello, MSc., Treatment and Trials Navigator; Andrew Ciupek, PhD, Associate Director, Clinical Research; Chief Scientific Officer Jennifer C. King, PhD; Shanada Monestime, PharmD, BCOP, Director, Community Engaged Research

Every person’s cancer is different, which is why we cannot use a one-size-fits-all approach to treatment. Precision medicine uses a person’s unique genetic profile to guide treatment decisions—and was a theme at this year’s ESMO and World Lung conferences. We’re recapping the latest news and key takeaways on precision medicine for late stage lung cancer—including oncogene targeted therapies, new targets for immuno-oncology, and more.

The Current Landscape of Oncogene Targeted Therapies

EGFR:

There was a focus on treating EGFR-positive NSCLC that has progressed after being treated with currently approved EGFR targeted therapies, with several presentations of new drug combinations and new EGFR targeted therapies.

  • Data from the CHRYSALIS-2 trial was presented looking at giving a combination of the new EGFR inhibitor called Lazertinib, the EGFR and MET targeted therapy Rybrevant (amivantamab)and chemotherapy to treat EGFR-positive NSCLC that had progressed after previous treatment with approved EGFR inhibitors. We saw promising results with an overall response rate of 50% including responses for patients who had their cancer spread to the brain.
  • Very early phase trial data was presented where a combination treatment with the EGFR targeted therapies Tagrisso (osimertinib) and Portrazza (necitumumab) along with the HER2 inhibitor trastuzumab was used to treat EGFR-positive NSCLC that was no longer responding well to standard targeted therapies. There was initial evidence that some patients might respond to treatment and the combination will be reviewed further in a larger trial.
  • Early data was presented on BBT-176, a new EGFR inhibitor that was designed to specifically work when EGFR C797X and/or T790M mutations develop – which can be ways that EGFR-positive NSCLC can become resistant to currently approved EGFR targeted therapies. Newer EGFR inhibitors that were designed to work against mechanisms of resistance are often called “4th generation EGFR inhibitors.” Responses were seen in patients with EGFR-positive lung cancer that had stopped responding to other approved EGFR targeted therapies and had one or both mutations that can be associated with EGFR targeted therapy resistance.
KRAS:

Several presentations provided early and promising data on treatments for lung cancer with a KRAS G12C mutation—both new KRAS G12C targeted therapies and new combination approaches with other targeted therapies or immunotherapy.

  • Early data was presented from a trial looking at using the combination of the KRAS inhibitor Lumakras (sotorasib) and a new targeted therapy, RMC-4603, for a protein called SHP2 to treat KRAS-G12C positive NSCLC after progression on other drugs like immunotherapy and chemotherapy or KRAS G12C targeted therapies. An overall response rate of 27% was reported that included cancers  previously treated with Lumakras. It was noted that the response rate was higher for cancers that had not been previously treated with another KRAS G12C targeted therapy.
  • Early clinical trial data for using a new KRAS G12C inhibitor called GDC-6036 to treat KRAS G12C-positive NSCLC that had received at least one prior treatment tand was not a KRAS G12C targeted therapy was presented. Promising initial results with an overall response rate of 46% was reported. The drug will be studied further especially to use in combination with other therapies.
  • Early data was presented from the CodeBreaK 100/101 trials which are looking at giving immunotherapy (either Tecentriq (atezeolizumab) or Keytruda (pembrolizumab)) with the KRAS G12C targeted therapy Lumakras (sotorasib) after progression on one other previous treatment that was not a KRAS G12C targeted therapy. A 29%overall response was observed. Giving Lumakras for a few doses before starting the immunotherapy seemed to reduce the amount of side effects that patients experienced.
  • Early data from a clinical trial for a new KRAS G12C inhibitor called D-1553 was presented. Patients in the trial had varying numbers of previous treatmentand had the cancer spread to different areas of the body, including the brain. An overall response rate of 38% was seen in this varied group. D-1553 will continue to be reviewedin larger clinical trials.
MET:
  • The VISION trial provided confirmation that the FDA approved MET Exon 14 skipping mutation targeted therapy, Tepmetko (tepotinib), has durable effectiveness for both a first treatment and  used after other treatments.  It also showed promising effectiveness against brain metastasis.
HER2:
  • Data was shared on a new HER2 exon 20 oral tyrosine kinase inhibitor (BI 1810631) being tested in a phase 1 study for patients with advanced solid tumors with HER2 aberrations. This agent binds to HER2 receptors while sparing EGFR signaling providing a novel mechanism in the oral formulation and could also reduce toxicities. Preclinical data suggest good tolerability and efficacy. The study is in progress and will determine the safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics and preliminary efficacy. This agent could potentially provide patients with an oral formulation for  fam-trastuzumab deruxtecan-nxki which is currently administered intravenously.
RET:
  • Data was presented on a new promising agent (TA0953/HM06) for patients with RET fusions including those with brain metastasis and those resistant to first-generation selective RET inhibitors. This agent is structurally different from other RET inhibitors. When compared to selpercatinib and pralsetinib, it is equipotent at inhibiting the growth of patient-derived and isogenic cell lines harboring different RET fusions. TA0953/HM06 also demonstrated superior brain penetration kinetics when compared to selpercatinib. This agent is currently being evaluated in a phase 1/ 2 clinical trial for patients with solid tumors driven by RET alterations (NCT04683250).
ROS1:

Several presentations highlighted novel agents being investigated in the era of ROS1-resistant mutations and brain metastases activity.

  • A new highly selective ROS1 inhibitor (NVL-520) is being investigated for patients with advanced ROS1-positive solid tumors, including those with ROS1 resistance mutations and brain metastases. This agent will aid in addressing the current gap of current ROS1 inhibitors (crizotinib and entrectinib) which can develop resistance and cause potential neurologic adverse events.. NVL-520 is a novel, brain-penetrant ROS1-selective kinase inhibitor that exhibits preclinical activity against a diverse array of ROS1 fusions and ROS1 mutations including G2032R, while sparing inhibition of TRK. This agent is currently being investigated in a phase 1 study (ARROS-1 Study) to determine the recommended dose and maximum tolerated dose.
  • Taletrectinib, is a new ROS1/ NTRK tyrosine kinase inhibitor with brain penetration activity. Previous studies have demonstrated activity against the ROS1 G2032R resistance mutation, CNS metastases, and NTRK-positive solid tumors. Updates were shared that this agent is currently undergoing a global phase 2 study to evaluate the efficacy and safety in patients who have ROS1 fusion-positive advanced metastatic NSCLC and other solid tumors. The study will primarily analyze response rates in ROS1 TKI naïve patients who received ≤ 1 prior line of systemic chemotherapyand patients who were previously treated and progressed on crizotinib or entrectinib plus ≤ one line of platinum and/or pemetrexed-based therapy for NSCLC.
  • Final results of the PRFOST trial evaluating lorlatinib at crizotinib failure in patients with ROS1-positive non-small cell lung cancer were presented. At data cut-off, the median progression-free survival was 8.9 months and the overall survival was 30.4 months. Results were also further categorized between patients with or without brain metastases. Patients without brain metastases had a longer progression-free survival (12.6 months vs. 8.5 months) and overall survival (34.2 months vs 30.4 months) compared to patients without brain metastases. Interestingly, results also demonstrated that patients with co-altered ROS1+/TP53+,  had a higher risk of progression and death compared to those without co-existing TP53+ mutations More aggressive strategies for this specific population are needed
  • An updated analysis on the efficacy and safety analysis of using entrectinib in patients with ROS1 fusion-positive NSCLC was presented. Results were integrated from three studies (STARTRK-1, STARTRK‑2 and ALKA-372-001) demonstrating continued intracranial efficacy and a manageable safety profile. For patients with baseline CNS metastases, the median intracranial response rate was 49%, intracranial duration of response was 12.9 monthsand intracranial progression-free survival was 12.0 months. Most treatment-related adverse events were mild and one patient died from a drug-related side effect. Side effects led to 36% of patients interrupting treatment, 35% requiring a lower dose, and 7% of patients having to discontinue treatment.
ALK:

Presentations focused on using alectinib in the neoadjuvant setting and the discovery of a new compound that could be used in patients who relapsed after lorlatinib.

  • Preliminary data was shared from the ALK+ cohort of the NAUTIKA1 phase II study investigating the efficacy and safety of alectinib in the neoadjuvant setting in patients with ALK+ stage II, IIIA or select IIIB NSCLC. Patients were treated with alectinib prior to surgery, followed by chemotherapy and alectinib after surgery. Data demonstrated that patients who received alectinib were able to have surgery performed with a 100% resection rate, without delays or major complications. The majority of the side effects experienced were mild and one was moderate-severe in which the patient had an increased lab level that was resolved by reducing the dose of alectinib.
  • Preclinical activity data was shared on the discovery of a novel compound (NVL-655), demonstrating potent preclinical activity in an ALK-positive patient with a G1202R/T1151M, which circulated after lorlatinib-relapsed. In cell viability assays, NVL-655 showed highly potent activity against cells expressing EML4-ALK v3 G1202R/T1151M. By comparison, all approved ALK inhibitors, including lorlatinib, exerted only weak activity (IC­50 > 100 nM), consistent with the resistance observed clinically. This could potentially demonstrate potential clinical utility for ALK-positive patients with resistant compound mutations but requires further investigation.

New Targets for Immuno-Oncology: Checkpoint Inhibitor Combinations

The immunotherapies used regularly for both non-small cell and small cell lung cancers are a type of immunotherapy called “checkpoint inhibitors.”  They take the brakes off your immune system and help it fight the cancer. Almost all the currently approved drugs are focused on a checkpoint called “PD-1/PD-L1.”

An active area of research is focused on other checkpoints and how targeting new checkpoints might also be effective either alone or in combination with the PD-1/PD-L1 inhibitors. There is already one approved CTLA4 checkpoint inhibitor and data presented at the World Conference on Lung Cancer suggested that combinations of CTLA4 and PD-L1 checkpoint inhibitors plus chemotherapy might be a good option for lung cancers with the poorest prognosis based on biomarker testing.

There have been encouraging reports at meetings this year about early studies with checkpoints such as LAG3. One promising study used a protein that bound LAG3 (eftilagimod alpha) instead of a more classic antibody inhibitor. This new drug will be further tested in more clinical trials. Similarly, there are ongoing clinical trials in both NSCLC and SCLC testing other new drugs that target different checkpoints, including TIM3.

Unfortunately, not all checkpoint combinations seem to be effective. A few trials have looked at targeting TIGIT in both NSCLC and SCLC in combination with approved immunotherapies. They have not yet shown a benefit of adding the 2nd drug to the current therapy.

There are also multiple trials evaluating promising combinations of PD-1/PD-L1 immunotherapies with other types of therapy. We have seen reports of early promising data of immunotherapies combined with multiple drugs that affect DNA repair, with Cyramza (ramucirimab) which affects the environment around the tumor, and with different regimens of chemotherapy and radiation. Researchers continue to look for new biomarkers to help predict which therapies or combinations of therapies might work best for each individual cancer.

One new and different class of immunotherapies activates the immune system while also attaching to a specific target on the cancer. There is excitement about bringing this type of drug to the small cell lung cancer space, where  scientific advances have been minimal. One of these drugs, tarlatamab, targets a protein called DLL3 commonly found in small cell lung cancer. In an early study, this drug was shown to be safe and result in good responses for some patients.  This drug will now be tested in larger clinical trials.

Small Cell Lung Cancer: Steps Towards Unlocking Genetic Driven Therapy

In recent studies, identified transcriptional subtypes of small cell lung cancer (SCLC) provide a possible framework  to actively target and relay a personalized approach for the continuously aggressive disease. This is a promising step for SCLC   treatment given that unlike non-small cell lung cancer (NSCLC), SCLC does not have biomarkers which allow for targeted therapies. The four major transcriptional subtypes identified – based on gene activation of the ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P) and SCLC-Inflamed (SCLC-I) provide a game-changing framework that would create a targeted approach to the further development of personalized SCLC treatment.

How do the subtypes shift the landscape of SCLC treatment? To answer this question, scientists are using ongoing experiments to determine if different subtypes react differently to treatment. To date, there have been promising results suggesting that SCLC-I subtypes may have better responses to immunotherapy options and that subtypes SCLC-N and SCLC-P may be better treated with targeted inhibitors. However, there is still work to be done in validating these results for SCLC subtyping to become standard of care.

The varying expressions of the subtypes within the clinical trials offer a bigger outlook of the derived inflamed gene signatures within the SCLC diagnosis and the impact that immune checkpoint inhibitors have in their treatment response. The research continues to evaluate and understand the subtypes of SCLC, and although there is still an unfortunate gap in the targeted approach to SCLC treatment, the current research allows a path towards a personalized approach in treatment.