World Lung Cancer Day: Reviewing the Latest Updates of Targeted Agents

Patricia Rich, MD

Medical Oncologist

City of Hope Atlanta

Large strides are being made in lung cancer treatment each year, and pivotal clinical trials are in various stages of reporting and validating improved outcomes for patients. The 2023 American Society of Clinical Oncology Annual Meeting (ASCO) included presentations of different approaches to treatment including antibody-drug conjugates (ADCs), as well as targeted therapies for promising molecular targets.

Several presentations supported new therapies for early-stage non–small cell lung cancer (NSCLC) as adjuvant or neoadjuvant therapies. Follow-up data supported the adjuvant use of osimertinib (Tagrisso) for stage IB to IIIA NSCLC with an EGFR mutation, and several immunotherapies recently showed a role before and after surgical resection. ADCs, which have been used successfully in other cancer types, are demonstrating strong antitumor responses in recurrent NSCLC.

Although lung cancer already has many actionable mutations in the advanced setting, new targets are on the horizon, including MET amplification, CEACAM5, and Trop-2. These targets offer more ways to extend survival for these patients.

In an interview with Targeted Oncology^TM, Patricia Rich, MD, a medical oncologist at City of Hope Atlanta, discussed the data presented at ASCO 2023 and other recent trials that she found most exciting and important to the field of NSCLC treatment.

TARGETED ONCOLOGY: What are the newest data out of ASCO 2023 that you feel are changing treatment in NSCLC?

RICH: What was very interesting to me at ASCO was the ADAURA trial [NCT02511106]. We’ve been using osimertinib for EGFR-mutated NSCLC in the metastatic setting. Back in December of 2020, it was approved in earlier stages. That was a breakthrough…for patients with stage IB to IIIA who have undergone surgery. The patients who had the EGFR mutation, particularly exon 19 and 21, were receiving adjuvant chemotherapy, and then they were treated with osimertinib. The drug was approved based on disease-free survival.¹ At this ASCO, the overall survival [OS] data were presented, and…using osimertinib provided a 51% reduction in the risk of death.² That’s considerable, particularly in lung cancer, and the 5-year OS rate was reported as [88% compared with 78%] in patients who only received chemotherapy. That cemented using osimertinib for patients with early-stage lung cancer…if they had that mutation. Giving patients osimertinib for a year made a difference in survival.

Previously, CheckMate 816 [NCT02998528] had led to the approval of nivolumab [Opdivo], which is an immunotherapy, in combination with chemotherapy in the presurgical, neoadjuvant [setting] for resectable lung cancer that was stage IB to IIIA. The trial [regimen] was approved because when patients were taken into surgery, the pathological complete response rate was approximately 24% compared with patients who did not receive this, which was about 2%.³ Nivolumab in combination with chemotherapy was approved, and it was given as 3 cycles and then patients proceeded to surgery.

Now they have presented the phase 3 KEYNOTE-671 [NCT03425643] using pembrolizumab [Keytruda] with chemotherapy before and after surgery. They would receive some treatment, go to surgery, and then [continue treatment] after surgery, and it was shown that it reduced the risk of recurrence and death by 42% compared with chemotherapy alone, which was quite a bit lower.⁴

Based on the data in CheckMate 816 and what I saw in KEYNOTE-671 at ASCO this year, this sets a new standard for treatment for resectable NSCLC using chemoimmunotherapy. Once we know this, then we start saying, “What else can we do that would benefit patients?” There are studies looking at what if we combine 2 immunotherapies, for example, and there's a study called NEOpredict [NCT04205552] that compared combined nivolumab and relatlimab [vs nivolumab alone]. Although the difference was relatively low [relatlimab] is…a different target and in lung cancer right now it's all about targets.⁵

Another new trial was the AEGEAN trial [NCT03800134]...investigating combined chemotherapy with durvalumab [Imfinzi], which is also an immunotherapy. It was similar to KEYNOTE-671 where [treatment was given] before surgery and then after. AEGEAN was a positive trial.⁶ [Additionally], the Neotorch trial [NCT04158440] combined chemotherapy with a drug called toripalimab [Loqtorzi]. The interesting thing about this trial was that the benefit was good for patients who had a higher PD-L1, but patients with squamous [histology] benefited more than those with nonsquamous [histology].⁷ That is very intriguing.

These trials are changing the standard of care. Some of these data are not mature enough. With maturity, we'll answer which is the optimal regimen, for whom, and if there is an [optimal] sequencing.

What other types of treatment with important data were presented at ASCO 2023?

What I thought was very interesting, not only in lung cancer but in other cancers as well, is the ADCs. They are joining a drug molecule, like what we’re used to in chemotherapy, with an antibody to attack cancer cells. It increases the specificity to that cancer cell, and it spares normal cells. There is potential for improving response and reducing adverse events.

I looked at the DESTINY-Lung02 trial [NCT04644237], which is an example of this target mutation in HER2. We hear about HER2 mainly in breast, esophageal, and gastric cancers. In breast cancer…you are looking at amplification, [but] for lung cancer it's different because we're looking at the mutation in that receptor. They had an ADC that is being used in breast cancer, trastuzumab deruxtecan [Enhertu]. The DESTINY-Lung02 trial reported an overall response rate [ORR] of 58%, and for lung cancer, that is rather good.⁸ This is a response rate for previously treated patients [which] is significant because normally we [get ORR of] at most 20%. This drug was approved in August of 2022.⁹ Now we have multiple trials in the pipeline and [other ADCs] that will probably be approved. These trials will tell us about future applications of these treatments and in which stages. We start most of the time with metastatic [disease] and then we backtrack into earlier stages.

When we treat patients with targeted therapies like osimertinib, as with other drugs, resistance will develop. [ADCs] are what is next, most likely. It is the same thing when patients progress on chemotherapy, and they don't have an EGFR mutation. If they progress on immunotherapy, what do we do next? This will open the door to what we are going to do next. Some of these drugs have newer toxicity profiles that we must watch for, such as toxicity to the eyes. We are beginning to see some of these new toxicities.

What are some of the newer targets for patients with NSCLC?

When I first started practicing, more than 20 years ago, we did not have targets. We knew KRAS existed and then we knew about EGFR. Today we have a growing number of targets.

There are some newer targets that we have drugs for, particularly ADCs. One that caught my attention was Trop-2. That one is interesting because it is seen in about 65% of the patients with adenocarcinoma, and another 75% of patients with squamous carcinoma of the lung. It's not a rare target like ROS1 which is in 1% or less of the lung cancer population. The other target was c-MET. We have treatment approved for the MET exon 14 skipping mutation. Now [MET amplification] comes into play. Another one is HER3, a member of the HER family. Yet another one where we can have targeted drugs is CEACAM5. I used to see them reported when I was doing next-generation sequencing and it was not an actionable mutation at the time. Those 4 to me are novel targets that now may have treatments.

There was a phase 1 trial [TROPION-PanTumor01 (NCT03401385)] for the Trop-2 using a HER2-directed treatment [datopotamab deruxtecan] for treating metastatic NSCLC in previously treated patients. There were 3 dosages to choose from, so the phase 1 trial was to establish which dose is the best dose for patients. Based on the dose chosen they can proceed with phase 2 trials. The response rates in the phase 1 trial] were similar in the 3 dosage categories. The ORR for previously treated patients was about 28%.¹⁰ The interesting thing is that 40% of patients had stable disease. Therefore, 68% showed some benefit from the treatment. The drug had activity irrespective of the expression of the Trop-2 and that was an interesting finding because that may widen the patient population that may benefit from this drug.

There are at least 8 ongoing clinical trials for Trop-2. This is for metastatic disease. They are being used for patients irrespective of EGFR mutations, patients who progressed on chemotherapy, and patients who have PD-L1 [expression]—so a wide variety of our NSCLC population could likely benefit from this.

The [trial] for MET was interesting because we have more patients with MET amplifications than with the [MET exon 14 skipping] mutation. From ASCO 2022, there was a phase 1 trial [NCT02099058] for patients that failed osimertinib. This trial combined a drug called Teliso-V [telisotuzumab vedotin] with osimertinib. [If they] give them osimertinib and they progress, we can add a drug to hopefully bridge that resistance.

The LUMINOSITY trial [NCT03539536]…enrolled previously treated patients whose tumor overexpressed c-Met. [When] the patients progressed, they treated them. Patients were grouped by level of c-Met expression into high expression, intermediate, and no expression. They were all treated with telisotuzumab vedotin. What they found was they all had a level of response, [but] the highest level of response was for patients that had high MET amplification, which makes sense.¹¹ The ORR was 52.2% [for the c-Met high overexpressing population].¹² We're again expanding the treatment options for patients who received prior treatment, and who may have the MET amplification. There are multiple ongoing trials to look forward to review their results.

Another interesting target is CEACAM5, which is found in multiple cancers. It has a role in programmed cell death, and may be of value in many cancers. There are trials underway for different patient populations of lung cancer whose tumors are positive for CEACAM5, studying patients who did not have prior treatment and patients who had prior treatments and how they responded. Most of the patients studied are in the nonsquamous population. Studies are looking at the effectiveness of different treatment permutations in the metastatic setting, such as targeted monotherapy or in combination with chemotherapy or with immunotherapy.

_References:

_{1. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. News release. FDA. December 18, 2020. Accessed July 13, 2023. https://tinyurl.com/4dcryjvj}

_{2. Herbst RS, Tsuboi M, John T, et al. Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 17):LBA3. doi:10.1200/JCO.2023.41.17_suppl.LBA3}

_{3. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170}

_{4. Wakelee HA, Liberman M, Kato T, et al. KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC. J Clin Oncol. 2023;41(suppl 17):LBA100. doi:10.1200/JCO.2023.41.17_suppl.LBA100}

_{5. Schuler MHH, Cuppens K, Ploenes T, et al. A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small cell lung cancer (NEOpredict-Lung). Ann Oncol. 2022;33(suppl 7):LBA37. doi:10.1016/annonc/annonc1089}

_{6. Heymach JV, Harpole D, Mitsudomi T, et al. AEGEAN: a phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT005.}

_{7. Lu S, Wu L, Zhang W, et al. Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): Interim event-free survival (EFS) analysis of the phase III NEOTORCH study. J Clin Oncol. 2023;41(suppl 16):8501. doi:10.1200/JCO.2023.41.16_suppl.8501}

_{8. Goto K, Sang-We K, Kubo T, et al. LBA55 - Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{9. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed July 17, 2023. https://tinyurl.com/4f76ckvp}

_{10. Shimizu T, Sands J, Yoh K, et al. First-in-human, phase I dose-escalation and dose-expansion study of trophoblast cell-surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan in non-small-cell lung cancer: TROPION-PanTumor01. J Clin Oncol. 2023;JCO2300059. doi:10.1200/JCO.23.00059}

_{11. Camidge DR, Baijal S, Vasilopoulos A, et al. Impact of genomic alterations measured in circulating tumor DNA (ctDNA) on clinical response to telisotuzumab vedotin treatment in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 2023;41(suppl 16):9032. doi:10.1200/JCO.2023.41.16_suppl.9032}

_{12. Camidge DR, Bair J, Horinouchi H, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2022;40(suppl 16):9016. doi:10.1200/JCO.2022.40.16_suppl.9016}