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New Treatment Options Offer Hope For Patients With Non-small Cell Lung Cancer

More people with non-small cell lung cancer (NSCLC) are likely to benefit from new drugs that target molecular alterations in tumor cells, with less need for chemotherapy, following results of multiple landmark clinical trials reported for the first time in late-breaking presentations at the ESMO Congress 2023. 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 (8).

The results are very impressive and mean that we can expect major changes in first-line treatment for patients with NSCLC with these targetable tumour cell alterations, and in the way we care for patients whose previous treatment has stopped working. 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."

Professor Alessandra Curioni-Fontecedro, University of Fribourg, Switzerland

Dr Elene Mariamidze, Todua Clinic, Tbilisi, Georgia, agreed: "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."

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. 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 (2).

"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," commented 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," added Mariamidze.

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 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.

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 pointed out.

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, namely antibodies that recognize specific proteins commonly found in lung cancers significantly improved PFS compared to currently used chemotherapy (7).

"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," predicted Curioni-Fontecedro.

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," concluded Mariamidze.

Early-Stage NSCLC Standard Treatments

Experts discuss the current standard treatment options for patients diagnosed with early-stage NSCLC [non-small cell lung cancer].

David Carbone, MD, PhD: Drs Gillaspie and Jabbour, what are the current standard treatment options for patients diagnosed with early-stage lung cancer? Let's start with the surgical perspective.

Erin A. Gillaspie, MD, MPH, FACS: There are a couple particular trials I'd like to highlight, and I think one of the key things that I always say when people say early stage, depending on who you ask, we all define that a little bit differently. When I think of early stage, [it's] like stage I all the way through IIIa, because those people I can operate on. But what I'd actually like to do is chat just a tiny bit about the really early-stage folks. Historically we've always done a lobectomy to treat patients who are diagnosed with lung cancer; a lobectomy or more. It was based on a trial that actually came out in 1995 from the Lung Cancer Study Group that looked at lobar versus sublobar resections and not only did the sublobar resections have worse surgical outcomes [and] worse oncologic outcomes, it was just a catastrophe. They said lobectomy has to be the gold standard of care.

Fast-forward, we start having the NLST [National Lung Screening Trial] data coming out. We have better and better CT [computerized tomography] scans, our radiologists are finding earlier and earlier lung nodules, we have everybody getting CT scans [in] the emergency [departments], we have with tons of people coming in with incidental findings, and we're finding all these subsolid lesions. We're now doing lobectomy [and] sometimes finding a 3-mm or 4-mm solid component, invasive component. Dr Al-Turki, [MD] and colleagues put this brilliant trial together called CALGB [Cancer and Leukemia Group B] 140503, and what they did is they [randomly assigned] patients who had tumors 2 cm or less with nodes negative. They were tested pathologically, intraoperatively. We had to take out the nodes, take out the tumor, send it to pathology; they measured it, and we'd call in and find out if we were randomized to lobar versus sublobar. And sublobar, I should mention, does include wedge versus segmentectomy, and that's important to know because there are some differences with lymph node yield between those 2 different surgeries. After 15 years, the study finally finished not only accrual but follow-up, and they found a few important things. One, sublobar section was noninferior with regard to disease for overall survival, and oncologic outcomes were equivalent. Surgical outcomes, there was no increased morbidity with a sublobar section, which is great; the length of stay is approximately equivalent. Interestingly, they have similar patterns and rates of recurrence, so [there are] very similar outcomes for those 2 groups. We see another study being done sort of at the same time, JCOGO802; slight differences with that. Their sublevel was just segmented to me but [had] very, very similar findings. We've ushered in this new era of sublobar resections for very small lesions. Now as we start to broaden this and bring it into the real world, it will be really important to continue accumulating data because, to me, the most shocking part of this was the 35% recurrence rate for patients during the 7 years of follow-up, 35% for node-negative tumors that are 2 cm last. That's shocking. And that tells me that there's a huge component of biology that we're not accounting for. I suspect we're going to continue to see all of our molecular therapies or immune therapies moving into earlier settings, in particular for these sort of more biologically aggressive tumors.

David Carbone, MD, PhD: Do you tell your patients you've got it all?

Erin A. Gillaspie, MD, MPH, FACS: I don't. I sure don't, because I think it gives them a false sense of security, and sometimes that leads them to stop doing follow-up. I have a very frank and candid conversation with every single person. "Our margins are negative, we're super pleased with our resection, and we did aggressive lymphadenectomy, which is negative, but the most critical piece that we have to do right now for these small tumors is surveillance." I tell them, "You can make another one, or you could recur. There are 2 different scenarios. I say, "Your body, it figured out how to make a cancer. It could do it again." I think it's really important for patients to understand that.

David Carbone, MD, PhD: Too often I hear, "Oh, but my surgeon said, 'I got it all,'" and I'm with you. I'm also hoping that that screening and incidental pulmonary nodule programs will increase the number of these small nodules that we find since today most patients are diagnosed when they're not surgically resectable; [in screening programs], the majority are surgically treatable. You didn't mention [this], but also the surgical techniques have improved in the last decades. It's amazing how things have transitioned to these foot-long, rib-splitting scars to people coming out with 3 Band-Aids in 3 days [after] robotic surgery. Do you want to say a little bit about that?

Erin A. Gillaspie, MD, MPH, FACS: I'd love to. It's been a massive change and, you're right, it's been the last decade where we've seen this really just change dramatically because even as little as 10 years ago, the majority of cases were being done [with] open [surgery]. For most people that meant cutting through muscles, so the latissimus, we're shingling, we're taking out of part of [ribs], we're putting in huge retractors, and it's a big deal to recover from that, [from] chest surgery in general.

David Carbone, MD, PhD: The med students are holding [instruments]…

Erin A. Gillaspie, MD, MPH, FACS: They'recranking out things a little bit further a little bit further. It's painful, and we were sending people out 5 to 7 days after surgery, [with] 30% of people having chronic pain for the rest of their lives, and that's horrible. People dreaded surgery. [Then] we saw 2 major surgeries [that] really changed things. One was VATS [video-assisted thoracoscopic surgery], [which] first started getting a little bit of traction around 1995, with some really wonderful surgeons taking the helm, [Thomas D'Amico, MD] being one of them, [RJ McKenna, MD], being one of them, and training other surgeons how to do surgeries, and being leaders and developing the new equipment to be able to do these surgeries. Better cameras, instruments that are angled to be able to go through ribs. Then, of course, we had the advent of robotics. One of the wonderful [things] about robotics is, again, really small incisions. Incisions are 8 mm and the robot wrists completely mirror what our hands are doing inside of the console. It was a little bit of a learning curve because we've now taken the surgeon out of the operative field, which was a little bit scary for everybody at first. If we had a bleed, how were you going to handle these things? But with [the] gaining of experience, practicing, all the muscle memory, actually it's very easy to be able to see and to manage things. We've trained our bedside teams to be able to respond to any of our needs, even in emergency situations. Most patients are going home [sooner]. I did 2 segmentectomies yesterday. They both went home this morning.

David Carbone, MD, PhD: It takes advantage of all those kids learning to play video games.

Erin A. Gillaspie, MD, MPH, FACS: Yes, that's right.

David Carbone, MD, PhD: They transitioned to the robot really well.

Erin A. Gillaspie, MD, MPH, FACS: That's right. My dad wouldn't let me play video games. Every time one of those articles comes out, I send it to him and I'm like, "You stunted my surgical growth."

David Carbone, MD, PhD: Things have advanced in radiation oncology as well. That's just amazing. You don't do those giant APP fields anymore with the … blocks and things. Tell us about managing early stage from your perspective.

Salma Jabbour, MD, FASTRO: The technology in radiation oncology is just tremendous. We are so lucky to have that for our patients. I think not only the things that Dr Carbone has mentioned in terms of our machines being able to be very precise, being able to move from all angles to really conform to the patient, but some of our techniques in planning the radiation have also hugely advanced in terms of being able to identify tumor motion. Making sure that that strong radiation beam is targeting the tumor very accurately to protect the normal lung. These are all very inherent techniques to our treatment planning these days and make it so very safe for the patient. With regard to management of early-stage lung cancer patients from the radiation oncology perspective, we have great therapies, some of which are really quite good for patients who can't have surgery or don't want to have it. We know that these techniques can rival surgery outcomes even in patients who we know have more comorbidities, and they really provide very good local control. But we are faced with many of the same issues as the surgeons. The [disease] can recur in the mediastinum lymph nodes and other parts of the lung. And that's the biggest threat. The patients do need very close monitoring. Thereafter our local control rates can be in the 90% range. We know we're doing very well with high doses of radiation in that specific area. These techniques have been well studied for about 2 decades now, thanks to the work of many investigators and the cooperative groups, the NCTN [National Clinical Trials Network], through which these trials were conducted and so very carefully studied, and patients were so very carefully studied. We know that these are really effective and useful therapies to the patients with low toxicity profiles. We have such great advantages to help our patients with radiation.

David Carbone, MD, PhD: We not only have major advances in the in the technology of surgery and radiation, but now we've layered on top of that immunotherapies.

Transcript is AI-generated and reviewed by AJMC editorial staff.

Lung Cancer Treatment Research Enters A New Era

Advances in lung cancer treatment highlight importance of tumour testing at diagnosis

Research presented at the ESMO Congress 2023 sets potential major changes in first-line treatment for patients with NSCLC with targetable tumour cell mutations

Lugano, Switzerland, 17 October 2023 – More people with non-small cell lung cancer (NSCLC) are likely to benefit from new drugs that target molecular alterations in tumour cells, with less need for chemotherapy, following results of multiple landmark clinical trials reported for the first time in late-breaking presentations at the ESMO Congress 2023 (1-7). Better outcomes were achieved with combinations of experimental new drugs targeting common and rare tumour 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 (8).

"The results are very impressive and mean that we can expect major changes in first-line treatment for patients with NSCLC with these targetable tumour cell alterations, and in the way we care for patients whose previous treatment has stopped working," said 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," she added.

Dr Elene Mariamidze, Todua Clinic, Tbilisi, Georgia, agreed: "We are entering an era of personalised 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."

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 tumour mutations (1,2). 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 (1). 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 (2).

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 tumour alterations for which targeted treatment options have previously been limited. These include patients with operable, early stage ALK-positive NSCLC (3), those with RET-mutated advanced NSCLC (4), and those with the less common, more difficult to treat EGFR mutation, Exon 20 insertion, advanced NSCLC (5).

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 tumours and indicate likely response to further treatment after surgery (so called, neoadjuvant treatment) (6).

"We know that patients have a better prognosis if pre-surgical treatment of lung cancer leads to tumour 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 pointed out.

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 tumours using antibody drug conjugates, namely antibodies that recognise specific proteins commonly found in lung cancers significantly improved PFS compared to currently used chemotherapy (7).

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