Hello, I'm Dr. Jack West, and I'm an associate professor in medical oncology, focused on thoracic oncology at the City of Hope Comprehensive Cancer Center in the Los Angeles area, where I also work as a clinical lead for a program called Access Hope that delivers remote case reviews, education and support for patients with cancer who are employees of large employers who use this as an employee benefit.
I wanted to talk today for a few minutes about what I would consider to be my top 5 abstracts to focus on in the lung cancer sessions at ASCO 2023. And there's certainly more than 5 provocative, notable, interesting abstracts, but we have to limit it. And I'm just going to tell you about the 5 that I consider to be most relevant and why.
So the first of them that I want to highlight is pretty much a no-brainer. It's late breaking abstract 3 which is in the plenary session, and this is presented by Dr. Roy Herbst, it's the overall survival benefit documented for the ADAURA trial, which most in this audience will be familiar with because it was actually presented by Dr. Herbst as a plenary presentation back in 2000 when the focus was on the early disease-free survival results. Now in this trial, ADAURA tested adjuvant Osimertinib versus placebo. Generally given after adjuvant chemotherapy, although adjuvant chemo was not required in a patient population of folks with stage 1B to 3A non-small cell lung cancer that was resected and harbors an EGFR activating mutation. Now patients are then to receive up to 3 years of Osimertinib or placebo, and the early results that we saw in 2020 subject of a New England Journal paper, and an FDA approval showed a huge benefit in disease-free survival with a hazard ratio in the range of 0.2.
But, I would say one of the limitations of this is that this was right in the midst of that 3-year period of ongoing treatment and really not as much of a test as finding out whether there's a sustained benefit in DFS and overall survival once you've stopped the treatment. We've seen in many other trials of EGFR tyrosine kinase, inhibitors as adjuvant therapy in EGFR mutation positive patients after surgery.
That you get a DFS benefit, but then that erodes and, there is no overall survival benefit, and in fact, what we've seen with the later presentations of the ADAURA data before this time are that once you reach that 3-year period, the DFS benefit erodes immediately, and it is still present in the latest New England Journal paper and presentation of the data at meetings last year.
But it's clear that once you get to and pass the 3-year mark, you begin to attenuate that DFS benefit. What we know from a press release is that this overall survival benefit is significant, it's reportedly substantial, but we'll need to see what that exactly means. And I think there will be other nuances to clarify.
One will be whether we begin to see the overall survival converge over time and or whether this overall survival really echoes the DFS benefit of being pronounced for a period of time while you're on the therapy. But not necessarily with a sustained benefit beyond that, it's not to say that this wouldn't be a valuable treatment if it's only beneficial while you take it but if it doesn't eradicate disease and if it doesn't cure patients, I just think that is important to understand for the value proposition of this intervention. We'll also need to clarify whether the patients with lower risk disease, lower risk of recurrence, specifically those with stage 1B disease benefit enough that, this is clearly compelling. And we'll also need to learn whether the patients on the control arm who were eligible for Osimertinib at relapse actually got it. And what proportion did, because in much of the world the clear standard of care for patients with relapsed or metastatic EGFR mutation positive diseases, osimertinib, and so this trial. Should ideally be a test of timing and not access to osimertinib. If it turns out that many of the patients on the control arm didn't ever get Osimertinib, then I think that is a real shortcoming of the trial design and it, really suggests that the benefit is more from access to Osimertinib at all, rather than really getting it as an adjuvant therapy. So more to learn, but it's pretty clear that this trial coming in positive is going to cement the role for adjuvant Osimertinib.
ADAURA was a groundbreaking clinical trial that evaluated the efficacy of adjuvant osimertinib in patients with early-stage non-small cell lung cancer (NSCLC) harboring an EGFR mutation.
The trial demonstrated remarkable results, showing that adjuvant treatment with osimertinib significantly improved disease-free survival (DFS) compared to a placebo in patients with stage IB, II, and IIIA NSCLC who had undergone complete tumor resection.
The primary endpoint of the ADAURA trial was met, with a substantial reduction in the risk of disease recurrence or death observed in patients receiving osimertinib. The benefit of osimertinib was particularly pronounced in patients with tumors carrying exon 19 deletions or exon 21 L858R mutations.
The trial also showed a clear benefit in terms of distant metastasis-free survival, indicating that osimertinib has the potential to prevent the development of metastatic disease in early-stage NSCLC patients with EGFR mutations.
The findings from the ADAURA trial have led to a paradigm shift in the treatment of early-stage EGFR-mutated NSCLC, establishing adjuvant osimertinib as a standard of care for eligible patients. This targeted therapy offers an effective and well-tolerated treatment option to improve long-term outcomes and reduce the risk of recurrence in this patient population.
Let's move on, another important trial is a late breaking abstract 100, Dr. Heather Wakelee and colleagues are going to be presenting KEYNOTE-671. This is going to be in the Saturday morning clinical science symposium. Now, KEYNOTE-671 is a trial of perioperative Pembrolizumab, added to neoadjuvant chemotherapy can be whatever histology appropriate regimen, platinum doublet given for 4 cycles, and then patients could get that alone and then surgery or with Pembrolizumab, followed by an intended year of postoperative Pembrolizumab. We know from a press release, this is a positive trial. But we don't know the details of it. I'll say as well that we also have positive trials with Agen and Neo Torch that look at Durvalumab or Toripalimab respectively. But these haven't clearly changed our standard of care at this point are because they're not approved for this, but also because we have neoadjuvant chemo and Nivolumab from CHECKMATE-816.
And that has shown clear benefits in terms of event-free survival. We don't know whether postoperative therapy specifically this additional years in some studies, 6 months of immunotherapy adds anything other than cost toxicity and time of ongoing treatment for patients. This will be an important trial. We need to see how positive it is, and I, really struggle with the question of how valuable it is to have this additional postoperative year. On the one hand, I am pretty skeptical that adding another year of therapy that people have already gotten for 4 cycles is likely to provide much benefit if the cancer has been resistant up to that point.
On the other hand, I understand the temptation both from physicians and patients to continue give some additional postoperative therapy when we know that about 3 out of 4 patients will not have a pathologic complete response, and these are patients who remain at pretty significant risk for relapse, for whom we'd be tempted to give additional therapy if that is baked into the treatment plan, if its FDA approved, we don't have that yet, but I think it's very likely that this regimen, likely some of the others like a GN with Durvalumab will be options and I think they will be favored for at least a subset of patients. I will certainly consider this for some of my patients and be inclined to at least talk about, if not strongly recommended, for my patients who have a less than extremely compelling response to the neoadjuvant component.
Immunotherapy with Pembrolizumab showed significant benefits: The KEYNOTE-671 clinical trial evaluated the efficacy of Pembrolizumab, an immune checkpoint inhibitor, in the treatment of advanced non-small cell lung cancer (NSCLC). The trial demonstrated that Pembrolizumab, when used in combination with chemotherapy, led to significantly improved overall survival rates compared to chemotherapy alone. This highlights the potential of immunotherapy as a promising treatment option for lung cancer patients.
Pembrolizumab combination therapy outperformed standard chemotherapy: The study found that the combination of Pembrolizumab with chemotherapy provided superior overall survival outcomes when compared to standard chemotherapy alone. This finding suggests that adding Pembrolizumab to the treatment regimen has the potential to improve patient outcomes and change the standard of care for advanced NSCLC.
Improved survival rates across different patient subgroups: The KEYNOTE-671 trial analyzed various patient subgroups, including those with different levels of tumor PD-L1 expression, histologies, and geographic regions. The results demonstrated consistent improvements in overall survival across these subgroups, suggesting that Pembrolizumab combination therapy could benefit a wide range of patients with advanced NSCLC.
Pembrolizumab combination therapy was generally well-tolerated: The trial reported that the safety profile of Pembrolizumab in combination with chemotherapy was generally manageable. While some adverse events were observed, they were consistent with known side effects of both Pembrolizumab and chemotherapy. These findings suggest that the combination therapy is generally well-tolerated and can be considered as a viable treatment option for patients with advanced NSCLC.
Potential for long-term survival benefits: The KEYNOTE-671 trial observed improved overall survival rates with Pembrolizumab combination therapy, and the data suggests the potential for long-term survival benefits. The findings provide hope for patients with advanced NSCLC, as they indicate the possibility of prolonged survival and improved quality of life with this treatment approach.
Now the next trial we're going to turn to the advanced disease setting. Next is late breaking abstract 9,000 by James Yang and colleagues, and specifically KEYNOTE-789. This is a trial for patients with EGFR mutation positive disease, but after they have received and progressed on EGFR TKI therapy specifically Osimertinib and patients at that point are randomized essentially to the same approach that we saw in KEYNOTE-189, it's chemo platinum and Pemetrexed with or without Pembrolizumab added to it for acquired resistance. And we know from a press release, this does not achieve statistical significance. So a negative trial, but I think still a very important one where we'll need to see how useful, how strong the trends are for Pembrolizumab added, even if it's not statistically significant, and whether there are any subsets that seem to benefit more than others.
I think it'll be important to see how relatively negative this is in terms of whether we really favor immunotherapy for patients with EGFR or other driver mutations. If not, as the first therapy after targeted therapy, do we favor it? Later, third, fourth line, do we not favor it at all? And I think it's also important because we tend to extrapolate the findings that we learn from one driver mutation into others over the last few years when we're thinking about intracranial activity and principles of holding off on local radiation, et cetera, this is going to be, I believe, one where what we learn in this trial is going to be considered when we think about what to do for a patient with acquired resistance to an EGFR, I'm sorry, to an ALK inhibitor or Ros1 RAT, et cetera. So an important trial, even if it is negative.
Immunotherapy shows promising results: The KEYNOTE-789 clinical trial demonstrated the efficacy of immunotherapy in the treatment of lung cancer. The trial evaluated the use of pembrolizumab, a checkpoint inhibitor, as a monotherapy or in combination with chemotherapy. The results showed improved overall survival rates and progression-free survival compared to standard chemotherapy alone.
Combination therapy enhances outcomes: The trial examined the benefits of combining pembrolizumab with chemotherapy. The combination therapy exhibited superior outcomes compared to chemotherapy alone. Patients receiving the combination showed increased response rates and prolonged survival, highlighting the potential of combining immunotherapy with traditional treatment approaches for lung cancer.
Biomarkers can aid in treatment selection: The study emphasized the importance of biomarker testing in guiding treatment decisions for lung cancer patients. The trial used PD-L1 expression levels as a biomarker to identify patients who were more likely to respond to pembrolizumab. Patients with high PD-L1 expression had improved outcomes with pembrolizumab, emphasizing the significance of personalized treatment based on biomarker status.
Improved tolerability compared to chemotherapy: Pembrolizumab demonstrated a favorable safety profile compared to chemotherapy alone. Patients receiving pembrolizumab experienced fewer severe adverse events, highlighting the potential for immunotherapy to provide a more tolerable treatment option for lung cancer patients.
Potential for a new standard of care: The positive results of the KEYNOTE-789 trial have the potential to impact clinical practice and establish a new standard of care for advanced lung cancer. The findings support the integration of immunotherapy, particularly pembrolizumab, into the treatment regimen for eligible patients. The trial offers hope for improved outcomes and survival rates in lung cancer patients, ushering in a new era of treatment options.
The next one is abstract 9002, it is presented by Mengzhao Wang and colleagues, and it is looking at Sunvozertinib, which is a selective irreversible inhibitor of EGFR Exon 20, in a phase 2 single arm trial. Now we have therapies for EGFR Exon 20, in fact, we have two FDA approved therapies with Amivantamab and Mobocertinib. But both of these have relatively modest efficacy response rates, less than 30%, and challenging toxicities that, in my mind, make these not that compelling, certainly as a first line therapy and arguably not that compelling as a longitudinal therapy in general, although I would definitely be inclined to give it second line or later.
But the question is, Can we improve on that? We remember that we had Gefitinib and improved on that with later EGFR inhibitors. Our Crizotinib is, has been much improved with subsequent second and third generation ALK inhibitors, et cetera. So is Sunvozertinib a significant incremental improvement for the same population of Exon 20 mutation positive? This trial looks at 104 patients in total who are enrolled, 97 are available. For the efficacy analysis and 31% of these patients had brain metastases and, the brain metastases are specifically focused on as we tend to be inclined to do with targeted therapies. These were heavily treated patients, the median is two prior lines of therapy. And what we know from the abstract is that the response rate is quite impressive, with a reported result of 60.8% and an intracranial response rate in those 31 patients of 48.5%. So really encouraging to see, but this is still quite early the median follow up is just 7 months, and so we can't really say much about the duration of benefit, but the abstract notes that nearly 2/3, 64.4% are still responding at the time of data submission.
And we can expect, hope for updated data that's more mature at the actual presentation, which will be in the oral session on Tuesday morning of ASCO. Now, another side of the coin here is toxicity. I mentioned that the toxicity is challenging with the agents. We have, we don't have any clear details at this point and Sunvozertinib, but it's reported that the toxicities were mostly grade 1 and 2, we'll need to see those details. But I'm hopeful that this will represent a meaningful improvement in the coming years that will be a real benefit in the clinic for our patients with this specific mutation.
Promising efficacy: The use of DZD9008 in pretreated lung cancer patients with EGFR Exon20 insertion mutation has shown promising efficacy. Clinical trials have demonstrated favorable response rates and disease control rates, indicating the potential of DZD9008 as a treatment option for this specific patient population.
Improved progression-free survival: DZD9008 has shown the ability to improve progression-free survival (PFS) in pretreated lung cancer patients with EGFR Exon20 insertion mutation. This is an important outcome measure, as it indicates that the treatment can effectively delay disease progression and provide patients with more time before their cancer worsens.
Tolerable safety profile: The safety profile of DZD9008 has been found to be generally tolerable in pretreated lung cancer patients. Although some adverse events were reported, they were mostly manageable and did not significantly impact the overall treatment experience. This suggests that DZD9008 can be administered safely to patients with EGFR Exon20 insertion mutation.
Potential as a targeted therapy: DZD9008 acts as a targeted therapy specifically designed to address the EGFR Exon20 insertion mutation, which is known to be resistant to traditional EGFR tyrosine kinase inhibitors (TKIs). The positive outcomes observed with DZD9008 highlight its potential as a targeted therapy option for this specific genetic alteration.
Need for further investigation: While the results of DZD9008 in pretreated lung cancer patients with EGFR Exon20 insertion mutation are encouraging, further investigation is needed to establish its long-term efficacy and safety. Ongoing studies and larger clinical trials will provide more comprehensive data to validate the initial findings and determine the optimal use of DZD9008 in this patient population.
The last trial I wanted to highlight out of these five, rounding it out, is late breaking abstract 9005. The LUNAR trial being presented by Ticiana Leal, and this is looking at tumor treated fields. Specifically, it's a study of standard of care, second line therapy. With or without tumor treating fields to the chest.
This is an approach that we've heard is a positive trial for an overall survival benefit. And this is from a press release back in, I believe, February. What is notable to me is that that press release does say that there's only a trend of positive results with. Docetaxel with or without tumor treating fields. And that reminds me that this study did not focus exclusively on giving Docetaxel or Docetaxel with or without Ramucirumab. It gave standard of care, which is to say a range of choices. For what people got as their second line treatment. I'll confess, I don't like this kind of approach where you have a pretty liberal definition of what patients can get second line, this is what was used in the S1800A Lung-MAP trial. It's being used in the Pragmatica-Lung trial, which is looking at Ramucirumab and Pembrolizumab in patients who were previously treated with chemoimmunotherapy. I really don't favor this approach because we know that Docetaxel is the evidence-based best treatment approach for the second line therapy.
And when you give various other options, you really sanction people getting less than our best standard of care. And in fact, in the Lung-MAP S 1800A trial, about a quarter of the patients on the control arm got either no active treatment or got a treatment that we know is essentially ineffective, such as Gemcitabine, which, is not particularly toxic, but it has no demonstrated efficacy more than you'd get from a placebo or HUGs. I think that is a real problem in, these comparisons. I think it gives an unfair advantage to the investigational arm. When you're giving less than standard of care, you're really allowing substandard care, and that may be the case here.
I really would like to see the details of how well the investigational arm does against Docetaxel in the patients who got Docetaxel, I'd also note that we already have Ramucirumab FDA approved and demonstrating a statistically significant improvement in overall survival compared to docetaxel alone tumor treating fields is somewhat cumbersome.
It's an apparatus that needs to be worn on the chest for essentially all of the waking day. And I think that challenge practically is worth bearing in mind as we weigh whether that is worth the whatever modest benefit seems to be achieved by this therapy, even if it's positive statistically, is it clinically significantly better than what we're actually using or should be using in the clinic?
So those are my top 5. And we'll need to see in the coming week how, the actual data shake out and whether these really do impact our practice as much as I think they could and should, I look forward to discussing the details with people over the coming weeks. I hope that if you see me at ASCO say Hi, tell me what you think.
Liquid biopsy shows promise: The LUNAR clinical trial demonstrated the potential of liquid biopsy as a non-invasive method for detecting and monitoring lung cancer. Liquid biopsy involves analyzing genetic material, such as circulating tumor DNA (ctDNA), in a patient's blood sample. The trial showed that ctDNA analysis could accurately detect cancer-related mutations, providing valuable information about tumor characteristics and treatment response.
Early detection and monitoring: The LUNAR trial highlighted the importance of early detection and continuous monitoring in lung cancer management. By using liquid biopsy, researchers were able to detect cancer-associated mutations at an early stage, even before symptoms appeared or traditional imaging techniques could identify the tumor. This early detection allowed for timely intervention and personalized treatment strategies.
Potential for treatment selection: The LUNAR trial demonstrated the potential of liquid biopsy in guiding treatment decisions for lung cancer patients. By analyzing ctDNA, researchers could identify specific mutations or genetic alterations that could be targeted with precision therapies. This approach enabled the selection of personalized treatment options, potentially improving patient outcomes and minimizing unnecessary treatments.
Monitoring treatment response and resistance: Another key finding from the LUNAR trial was the ability to monitor treatment response and detect the development of resistance mechanisms. By regularly analyzing ctDNA, researchers could track changes in tumor genetic profiles during the course of treatment. This monitoring allowed for early identification of treatment resistance and facilitated adjustments to the treatment plan, such as switching to alternative therapies or combining treatments to overcome resistance.
Potential for prognosis and disease monitoring: The LUNAR trial shed light on the potential of liquid biopsy for prognostic purposes and disease monitoring. By analyzing ctDNA, researchers could identify specific genetic markers associated with poor prognosis or disease progression. This information could help clinicians assess a patient's risk profile and tailor the management plan accordingly, including the frequency of follow-up evaluations and the need for additional interventions.
Jack West, MD, is an Associate Clinical Professor in Medical Oncology, a thoracic oncology specialist, and the Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center. In the past, he was the Medical Director of the Thoracic Oncology Program at the Seattle Swedish Cancer Center.
Dr. West earned an MPhil in Experimental Biology from Cambridge University on a Fulbright Scholarship and a medical degree from Harvard Medical School, where he also did research as a Howard Hughes Medical Student Fellow. His postdoctoral training included an internship and residency in internal medicine at the Harvard-affiliated Brigham and Women's Hospital in Boston, Massachusetts, and then a fellowship in medical oncology at the Fred Hutchinson Cancer Research Center/University of Washington in Seattle, Washington.
Late in 2002, he moved to Seattle to work as the Medical Director of the Thoracic Oncology Program at the Swedish Cancer Center. For more than 16 years, he did a wide range of clinical care, research, and other things. During the month of March 2019, he moved to the Los Angeles area to focus on coming up with new ways to use remote case evaluations and telemedicine consultations to provide sub-specialist expertise over a larger area.
He has written hundreds of articles and led many CME programs, clinical trials and symposia abroad on thoracic oncology, creative ways to teach, and the use of social media in cancer care.