As we’ve seen, myelosuppression remains a part of our management of patients with systemic cytotoxic chemotherapy. It’s probably here for the long term. Even targeted therapies or checkpoint inhibitors are often given along with, or in sequence with, myelosuppressive chemotherapy. It will remain the backbone of many cancer therapy regimens.

Particularly in the time of a pandemic, we’re trying to reduce exposure to the health care system, infectious complications, and the need for transfusions, given the limited resources in blood banks. Any strategy that may preserve marrow function in patients with a pending need for cytotoxic therapy for the cancer—which will not wait and needs to be treated—is imperative. This is clearly the time for exploring these new agents, such as trilaciclib.

Beyond the pandemic, as we resume more traditional care of patients, any strategies that reduce the impact of the cancer or treatment on the patient—their functioning, fatigue, the need to be seen in the hospital—or anything that reduces the cost of managing these complications needs to be given very serious consideration. Our goal to reduce the hematopoietic toxicities due to myelosuppression has to remain paramount in our treatment planning and our shared decision-making with patients. We need to do everything we can to maintain and improve their quality of life as they go through this very difficult time in battling cancer, in some cases the pandemic, and the toxicities of the treatments that they need to receive.

Obviously, trilaciclib is early in its clinical development. It’s been primarily studied in small cell lung cancer to date. I would say that in small cell lung cancer, the major data we’re missing are related to cost. It’s probably cost-effective by preventing the most frequent adverse effects. Then there’s quality of life. Because the most frequent adverse effect that bothers patients is fatigue, we need more data on the quality-of-life implications of myelopreservation. Outside small cell lung cancer, we need information on the antitumor effects of trilaciclib in other cancers. Besides the antitumor effects, we need the myelopreservation effects in other tumors. Chemotherapy administration is different in different therapies. For example, in small cell lung cancer, etoposide is given for 3 days in a row and topotecan for 5 days in a row, whereas in non–small cell cancer, almost all treatments are administered on 1 day. We need data for many types of chemotherapy administration. It’s highly likely that this would have myelopreservation effects irrespective of the schedule, but we need to study it appropriately for different schedules. There are many unanswered questions, and we all look forward to the results of clinical trials to answer these questions.

The unanswered questions in small cell lung cancer, which are being addressed in some ongoing trials, other than cost and quality-of-life benefits, are related to the immune benefits. As immunotherapy becomes more prevalent, we need to understand the potential beneficial effects of trilaciclib on immunotherapy, both by itself and in combination with other immunotherapies.

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Reducing the Impact of Chemotherapy-Induced Myelosuppression 

As I mentioned, chemotherapy is the mainstay of treatment in many cancers, including almost all solid and liquid tumors. Myelopreservation is important for all these tumors. One of the questions is, would it interfere with antitumor effects? This is not an issue in small cell lung cancer because they all have Rb [retinoblastoma protein] loss. But for many cancers in which there’s myelosuppression, you don’t have Rb loss. The question is whether trilaciclib could interfere with an antitumor effect in other settings where there’s not Rb loss. In fact, the clinical data suggest that’s not going to happen, presumably because cell cycle control is modulated by many proteins besides phospho-Rb [phosphorylated-Rb] and other cyclin-dependent kinases. It’s reasonable to study this in many cancers. The data, to date, have been primarily in breast cancer. In breast cancer, there are data to suggest antitumor and myelopreventive effects from trilaciclib. There are many ongoing trials—and there will likely be more—in diseases other than breast cancer, in which chemotherapy is the backbone. The future will extend beyond small cell lung cancer. Undoubtedly, non–small cell lung cancer will have some trials and breast cancer will have more trials, as will other solid and liquid tumors. We need data.

As I mentioned, there are trials underway to look at the impact of trilaciclib in cancer settings beyond small cell lung cancer. We anticipate that there might be ability to enhance chemotherapy delivery, as well as reduce the myelosuppression associated with cytotoxic chemotherapy. But there’s also the potential for an impact on the immune system. In a recent trial that was published in 

, which was a phase 2 trial of trilaciclib in patients with triple-negative breast cancer receiving conventional chemotherapy, trilaciclib did not show the same level of effect on myelosuppression. There was some, but it was not statistically significant.

However, in the secondary end points of this study, it was quite intriguing that there was a significant improvement in overall survival. There was a hazard ratio of 0.4, and highly significant reduction in mortality in patients receiving trilaciclib prior to their chemotherapy in triple-negative breast cancer. This was a phase 2 study that was relatively small and still needs to be confirmed.

The reasoning here is also under investigation. If the improvement in survival was not a result of reducing complications, it leaves the possibility that in some cases, there may have been more chemotherapy delivered, because there was some reduction in neutropenia, anemia, and so forth.

Perhaps more intriguing is the impact on the immune system. Again, the immune system is also preserved. There’s less impact on immune stem cells. In correlative studies done in triple-negative breast cancer, there were increased CD8 T cells. There was a strong correlation between overall survival and patients who have more immunogenic tumors.

This needs a lot more investigation, but obviously we want to confirm and then understand why there was a significant improvement in overall survival in the most difficult cancers to manage, speaking as a breast cancer oncologist. Anything that improves survival in triple-negative breast cancer has to be explored fully and taken advantage of if it is confirmed.

CDK4/6 Inhibitors & Myelopreservation in Other Cancers

For small cell lung cancer, platinum doublet therapy has been the backbone of treatment for several decades. More recently, the combination of platinum doublet chemotherapy with etoposide and carboplatin, plus the addition of immunotherapy with either atezolizumab or durvalumab, has become the standard. But myelosuppression remains a huge problem. In the second-line setting, the standard treatment is chemotherapy. Again, in the second line, when people have already been exposed to prior chemotherapy, myelosuppression is a huge deal. There are other cell cycle-related inhibitors. One is called ALRN-6924, which is an MDM2 inhibitor. Like the cyclin-dependent kinases, MDM2 stimulates cell cycle progression. Preventing cell cycle progression with things other than trilaciclib might have very similar results. There’s 1 abstract from a phase 1 trial with this agent, which suggests that it can also lower the rates of grade 3 and 4 myelosuppression with neutropenia, anemia, and thrombocytopenia. But this drug is far behind in its development, compared with trilaciclib. Whether it would add to trilaciclib or be better than trilaciclib is not known, but the fact that it prevents trilineage myelosuppression suggests that this is a strategy that would work in patients treated with chemotherapy. In a way, it adds to the likelihood that trilaciclib will have benefit. It adds another trial and further suggests that this approach may have benefit.

CDK4/6 Inhibitors for SCLC: Trials of Interest

Trilaciclib could prevent the effectiveness of chemotherapy. In small cell lung cancer, essentially all of them have Rb [retinoblastoma protein] loss. The tumor cells with Rb loss are not going to be affected by a CDK4 or CDK6 inhibitor. There’s no reason to expect that trilaciclib would reduce the antitumor effect of chemotherapy. In fact, in the 3 clinical trials we’ve been talking about, there’s been no indication that there is any inhibition of the cytotoxic effect of chemotherapy on the tumor. Specifically, response rate and progression-free survival have not been affected, nor has overall survival been affected.

There are some other effects of trilaciclib, which could lead to increased antitumor activity. There’s some indication that trilaciclib has beneficial immune effects, and those have not been evaluated in clinical trials. But in the future, we’ll want to understand the immune effects of trilaciclib better and determine whether it has antitumor properties. For small cell lung cancer, once again, because of the Rb loss, it’s unlikely to make chemotherapy more effective. But if it did stimulate the immune system, that might be beneficial. At present, there’s no evidence of detriment to effective chemotherapy from the addition of trilaciclib, and the trilaciclib adverse effects have been minimal in the clinical trials to date.

There are a couple of questions remaining, of course. One of those questions is cost. Obviously, adding a drug adds cost, but giving intravenous antibiotics in an inpatient setting, visits to the emergency department, red blood cell transfusions, and platelet transfusions have consideration costs. We don’t have any cost analyses comparing the cost of a new drug with prevention. My guess is that it would be cost effective to prevent these, especially if the agent that prevented these things did not have major adverse effects itself and does not interfere with the effectiveness of chemotherapy. That seems to be the case for trilaciclib administration; however, we don’t have good cost-effectiveness studies to date.

We also need more quality-of-life analyses. As I mentioned, fatigue associated with myelosuppression is a major problem for patients. There’s a suggestion that these things may improve quality of life, but we need more data in that regard.

Chemotherapy-Induced Myelosuppression in SCLC: CDK4/6 Inhibition

A major question is whether there is a way to prevent all types of myelosuppression—neutropenia, anemia, and thrombocytopenia. If we had 1 drug that could affect all lineages, that would be really helpful, rather than worrying about 3 types of growth factors and 3 separate problems. Any cell has to divide. We have factors and proteins that cause the cell cycle to progress, and we have inhibitors of cell cycle progression. In general, the cyclin-dependent kinases are stimulating cell cycle progression from G1 through S, G2, and mitosis. If we could inhibit cell cycle progression before giving chemotherapy, that would reduce the adverse effects of chemotherapy, because chemotherapy is affecting proliferating cells much more than other cells. If we could inhibit cell cycle progression at the time, or just before, we give chemotherapy, it might markedly reduce the myelosuppression from chemotherapy.



Cell cycle–dependent kinases promote cell cycle and promote growth of all bone marrow cells. Inhibiting this just before chemotherapy might markedly reduce the myelosuppression induced by chemotherapy. CDK4 and CDK6 are 2 cell cycle-dependent kinases that stimulate cell cycle growth and proliferation. If we could inhibit CDK4 and CDK6 just prior to chemotherapy administration, it might markedly reduce myelosuppression from chemotherapy. Trilaciclib is a CDK4/6 inhibitor, and it might inhibit cell cycle progression. Therefore, if given before chemotherapy, it might markedly reduce the myelosuppression of chemotherapy.

Small cell lung cancer patients frequently have all types of myelosuppression due to chemotherapy. In the first line therapy of small cell lung cancer, the standard is etoposide and carboplatin, which frequently cause myelosuppression, including anemia, thrombocytopenia, neutropenia, and febrile neutropenia. In the second-line setting, topotecan is the only approved agent. That also very frequently causes neutropenia, thrombocytopenia, and anemia. Trilaciclib, the CDK4/6 inhibitor, has been studied in patients receiving standard first-line or second-line therapy. In the first line, there were 2 studies that gave etoposide-carboplatin or etoposide-carboplatin and atezolizumab. The patients receiving these first-line therapies were randomized to receive trilaciclib or placebo. In the second-line setting, patients receiving topotecan were also randomized to receive trilaciclib or placebo.

In the pooled analyses of these studies, there was no effect on the efficacy of the chemotherapy. That is, the progression-free survival and overall survival were the same in patients receiving placebo or trilaciclib. On the other hand, there was a marked reduction in myelosuppression. Grade 3/4 neutropenia was reduced from 77% to 43%. Days of febrile neutropenia in the first cycle were reduced from 4 to none. GCSF administration was reduced from 56% to 29%. Grade 3/4 anemia decreased from 32% to 20%. Red blood cell transfusion and platelet transfusions were reduced, but because these are not as frequent, they may have been reduced less. It was clear from these 3 trials that trilaciclib would reduce myelosuppression from neutrophils, red blood cells, and platelets. The fact that this was a striking reduction led to a breakthrough designation by the FDA to review these trilaciclib myelosuppression reduction trials.

Analyses of CDK4/6 Inhibitors for Myelopreservation

One of the more interesting recent developments for reducing the risk of myelosuppression is to utilize inhibitors of CDK4/6. Trilaciclib has recently been accepted for priority review by the FDA. Yesterday, notice came out from the FDA that they had accepted the application for new drug approval for review. While that’s undergoing review, there can be some compassionate access to this agent.

The principle here is that CDK4/6 inhibitors result in the transient arrest of normal cells in the G1 phase of the cell cycle. If given prior to chemotherapy, they may protect stem cells in the bone marrow, as well as the immune system, from chemotherapy damage. Chemotherapy primarily affects the rapidly proliferating cells, both healthy and tumor cells, by inducing this arrest in the in the G1 phase. Prior to giving the chemotherapy, it’s been demonstrated in both animal and human systems that it has the capacity to preserve hematopoietic stem cells, progenitor cells, and committed progenitors.

The trials that have been done based on phase 1 work resulted in a recommended phase 2 dose of trilaciclib. That dose is 240 mg/m2, given intravenously about 30 minutes prior to the chemotherapy. The initial trials have been done in small cell lung cancer with carboplatin and etoposide in 1 of the trials, and with atezolizumab for PD-L1–high patients with small cell lung cancer.

Small cell lung cancer has been used as a prototype or a target tumor for the development of supportive care for cytotoxic chemotherapy. It was used in the original, pivotal work for GCSF. It’s because it’s a rapidly proliferating, high-risk situation in which patients may progress very rapidly. It’s also a situation in which chemotherapy produces responses in a high proportion of patients, but with the ensuant toxicities that we talked about.

These trials, 3 of which were presented to the FDA, were reviewed recently by Jonathan Weiss in 

. As I said, it was previously given breakthrough status, and the new drug application has now been given priority review in patients with small cell lung cancer based on these major trials.

These are pretty exciting and compelling myelopreservation data by a first-in-class new agent. These trials were double-blind, placebo-controlled, randomized trials of either chemotherapy alone or chemotherapy preceded 30 minutes by the trilaciclib. Combined, they clearly demonstrate myelopreservation to a very high degree. Myelopreservation was the efficacy endpoint of these studies. grade 4 neutropenia was reduced from about 50% down to almost 0—I think 2%—across these trials. There was less febrile neutropenia. There was less need for GCSF rescue. Grade 3 to 4 anemia was also reduced. Remember, this is affecting all lineages of the hematopoietic stem cell.

Anemia fell; the risk of grade 3 to 4 anemia fell from 28% in the control group with chemotherapy alone to 19% with the trilaciclib administered prior to chemotherapy. Transfusion was also reduced from 21% to 13% across these trials. The use of erythroid-stimulating agents was cut about in half.

Finally, grade 3 to 4 thrombocytopenia fell from about 40% to nearly 0, with platelet transfusions required in only half as many patients when they received the trilaciclib. 

The good news, on top of all this, is that it appeared to have no effect on the antitumor activity of the chemotherapy or immunotherapy. There were no significant or severe adverse effects of concern associated with the trilaciclib.

This is really a win-win. We still need a full FDA approval. We need confirmation in other disease settings beyond small cell lung cancer, and there are other trials being completed in triple-negative breast cancer. There’s an ongoing trial in colorectal cancer. We’re going to have to see how all these data fall out, and whether the effects we see from trilaciclib in small cell lung cancer carry over to other solid tumors and malignancies.

The overall impact of this cannot be overstated. These dramatic reductions in myelosuppression, or the dramatic myelopreservation that’s been seen with trilaciclib in patient surveys, has been shown to significantly delay the deterioration of patient functional status in the symptoms associated with myelosuppression.

We also anticipate, although formal economic analyses are still needed, that there will be a significant reduction in cost and improved quality of life. With less neutropenia and febrile neutropenia, there will be less hospitalization, less need for growth factor support, and fewer transfusion requirements. All this should have a noticeable and significant impact on health care costs associated with supportive care of patients receiving cytotoxic chemotherapy.

Although the data are early and we need more data in other settings, there’s a reason for encouragement and optimism. We now have another strategy for reducing these complications and preserving marrow function across all 3 lineages.

CDK4/6 Inhibitors and Myelopreservation

The coronavirus pandemic has affected patients. Patients with lung cancer and other cancers are even more susceptible to infection by COVID-19 [coronavirus disease 2019], and their outcomes are worse. We try to keep cancer patients away from COVID-19 as much as possible. We’ve been trying to limit the exposure using telehealth visits and other methods. We have been getting blood counts frequently by home blood draws for our patients and trying to keep them out of the hospital as much as possible. The pandemic has also created some problems with blood supply and blood transfusions. Because of that, there have been some attempts to lower the threshold for treatments of anemia, for example, to preserve the red blood cell supply. Ordinarily, we transfuse people who have a hemoglobin count less than 8 g/dL, but there have been some guidelines to say that we should change that to 7 g/dL. With thrombocytopenia, there have been some recommendations to transfuse people with a platelet count of less than 10 g/dL instead of a platelet count of less than 20 g/dL.

Any treatment that would make it less common to have anemia or thrombocytopenia is particularly important during the pandemic. That is so transfusions of red blood cells and platelets are needed less often, and also so patients have febrile neutropenia and have to visit the hospital less often.

Obviously, the lives of our patients and our lives as health care providers have been profoundly impacted by the coronavirus pandemic. It has become a global pandemic and has had a profound impact on all of us. Globally, we now have more than 22 million patients infected with COVID-19, and there have been over 750,000 deaths as a result of this. In the United States, which unfortunately has the highest number of COVID-19 infections—around 5.6 million—there have been over 170,000 deaths from COVID-19.

We’ve warned, from the early data coming out of China and then Italy, that cancer patients are among the most vulnerable to COVID-19. Particularly, we’ve warned of the serious and sometimes often fatal complications of COVID-19 on top of their cancer.

We formed a consortium 3 or 4 months ago called the COVID-19 and Cancer Consortium. We’re gathering data throughout the United States, and now globally, on cancer patients infected by COVID-19. Our results were published in 

 2 months ago. They looked at the various risk factors for serious complications and the impact of cancer treatment in the first 1000 cancer patients with documented COVID-19.

A few weeks ago, we updated the data with more than 2200 patients with cancer and COVID-19 in a virtual meeting of the American Association for Cancer Research. This was published in 

. All these data have led us to better understand the risk factors for getting COVID-19 and serious adverse outcomes in patients with cancer.

The guidelines for the use of supportive care for cancer patients have been appropriately modified, at least on an interim basis. The National Comprehensive Cancer Network, or NCCN, has issued interim recommendations for enhanced use of hematopoietic growth factors. Those include the supportive care that we have used routinely, but only for higher-risk patients. The recommendations broaden indications for the use of myeloid growth factors in patients who are at 20% or greater risk. Now they are recommended for patients whose risk is 10% or greater, and even in patients at lower risk if they have serious comorbidities.

The threshold for the use of these agents has been decreased. There is also a recommendation for using them, if they were not used prophylactically, in patients who develop febrile neutropenia to speed up the recovery of the myeloid precursors. The use of self-administration, which is not generally utilized, or on-body injectors, have become more routine.

There are cautions, because there has been evidence of cytokine release in some patients receiving myeloid growth factors. Since acute respiratory distress syndrome can be a complication of COVID-19, some caution needs to be used there. Even for anemia, the recommendations are now saying not to transfuse patients until their hemoglobin drops below 7 g/dL or platelets drop below 10,000 per mm3. Again, they are broadening the indications for use of the supportive care in that setting.

In the end, 1 of the impacts on patients is that some patients’ treatments have been delayed. Their treatments have been modified. The monitoring of their disease or screening for recurrence of their cancer have been delayed because of the pandemic. We all have to be aware of potential secondary effects of the pandemic on the management of other conditions that would normally bring patients to the doctor to be evaluated. Patients may be avoiding the health care system to minimize the risk of infection. But these will all have potential downstream ramifications with more advanced disease, or for response to our treatments in the long term.

Chemotherapy-Induced Myelosuppression & COVID-19

The myelosuppressive effects of systemic chemotherapy have a direct impact on the patient, the bone marrow, and the multiple lineages of the hematopoietic system. If neutropenia infection occurs, patients may need to be evaluated in the emergency department or even hospitalized. Although we try to manage many of these patients in the ambulatory setting, members of the more vulnerable populations—older patients, patients with comorbidities, or those with clear sepsis—still need to be hospitalized. Hospitalization, or at least emergency department evaluation, is often a consequence of chemotherapy-induced myelosuppression.

We’ve talked about fatigue. That’s what patients experience the most. But it’s usually because of the underlying anemia, infection, or even bleeding that might be occurring because of the chemotherapy-induced myelosuppression.

We try to intervene. Traditional strategies in recent years have involved the use of a myeloid growth factor given after the chemotherapy, but prior to the onset of severe neutropenia, to lessen the myelosuppression. It usually doesn’t prevent it, but it may reduce the nadir of neutrophil suppression or shorten the period of severe neutropenia.

Similarly, erythroid-stimulating agents have been utilized and continue to be utilized. However, they have come with additional concerns, based on some trials, that sometimes the adverse events from these agents may be worse than the anemia itself. That, for a while, was a black box warning around the use of erythroid-stimulating agents.

We’ve learned how to better use them and in which patients to use them, so these are available. But we generally don’t use them broadly anymore. If the anemia becomes profound, the patient may need to come in for a transfusion. Again, the issue will be at what threshold or cut point we should administer transfusion.

All this may eventually lead to dose reductions, dose delays, reduction in the relative dose intensity chemotherapy, or a change to a different regimen that’s less myelosuppressive. In the extreme and most unfortunate situation, it may result in the stopping of chemotherapy, either because the patient refuses to go on or because it’s not thought to be in the best interest of the patient.

Because myelosuppression is a common problem in chemotherapy treatment, there are several issues that arise. One is what’s going to happen in subsequent treatments with chemotherapy. In general, severe myelosuppression is going to lead to dose reductions. It may lead to transfusions. There are growth factors now that can help us with severe myelosuppression. Obviously, for patients with neutropenia, especially febrile neutropenia, we have the GCSF growth factors. For patients in whom anemia becomes the more common problem, we have the ESAs [erythropoietin-stimulating agents] to treat chemotherapy-induced anemia. We do have a growth factor for thrombocytopenia as well. That is used in patients with severe neutropenia, anemia, or thrombocytopenia. For severe anemia and thrombocytopenia, we also have blood transfusion.

We use these in a minority of patients, but the use of growth factors is not going away for patients who have severe effects. Unfortunately, each of these growth factors—myelosuppression for neutropenia, anemia, or thrombocytopenia—only affects that particular type of blood count. More recently, there have been some drugs that affect cell cycle and can prevent all types of myelosuppression. Those may supplant the individual types of growth factors, or just neutrophils, red blood cells, or platelets. We will be discussing new ways to prevent all sorts of myelosuppression—white blood cells, red blood cells, and platelets.

Management of Chemo-Induced Myelosuppression

 Chemotherapy, despite the excitement around targeted therapies and immunotherapies that we all share, remains the backbone of systemic cancer treatment today and is likely to remain as such for the foreseeable future. We know that about 1 million patients receive chemotherapy annually in the United States. Therefore, it is a treatment that we need to continue to fully understand. Most important, we need to manage the adverse effects that occur.

These are very active but very myelosuppressive agents. We know they attack stem cells, both healthy and diseased—tumor stem cells. They can damage hematopoietic progenitor cells at the origin of hematopoietic cells and right through committed precursors. Of course, it can have an impact on all lineages. The hematopoietic stem cells give rise to not only neutrophils and infection-fighting cells but red cells resulting in anemia. They give rise to platelets. If they’re severely low, it may lead to bleeding issues. This major dose-limiting toxicity of cytotoxic chemotherapy remains that of the damage to stem cells in all 3 lineages, and it’s important that we optimize the methods to preserve those healthy stem cells in the normal cells throughout the course of treatment to minimize these complications.

Because the cytotoxic nature of chemotherapy has an impact on all 3 lineages, in addition to immune cells in the body and T cells in particular, it is imperative that we understand the risk of neutropenia, particularly febrile neutropenia, which is tantamount to an infection. If the neutropenia is severe, it can be life threatening. This often results in hospitalization. Although most patients survive those infections, we know that there is still, based on our national data of hospitalized patients with febrile neutropenia, a real mortality rate that may reach the 6%-to-8% range across all patients with cancer receiving chemotherapy.

In addition, a major adverse effect of chemotherapy is fatigue, and that often relates to anemia. Of course, it may be further worsened by the cancer itself or any bleeding associated with the cancer. But because the red cell precursors are impacted just like the neutrophils, anemia can be a problem that may require intervention with transfusions or other therapeutic interventions.

We are also concerned about thrombocytopenia, which is less common. We’re trying, as part of therapy, to suppress all these lineages by impacting the marrow itself. But if thrombocytopenia does occur and it becomes profound enough, bleeding risk is a real concern. We can give platelet transfusions, and they’re usually reserved for very low platelet counts. We now have some thrombopoietic agents that are available and FDA approved. But they’re not used until we see more severe levels of thrombocytopenia that put the patient at risk for bleeding complications.

The impact of cytotoxic chemotherapy on the immune system is something we’ve recognized more recently. We know cancer can suppress the immune system as well as other therapies like corticosteroids. We also now understand that cytotoxic therapy may impact the immune response to either the cancer or to infectious conditions.

All of these—anemia, neutropenia, thrombocytopenia, and immunosuppression—may result from cytotoxic chemotherapy, which remains the mainstay of cancer systemic therapy.

The cytotoxic effects of chemotherapy obviously have a direct impact on the patient. While we have focused on the clinical aspects and the complications that may ensue, the patient is the one who’s most profoundly impacted. Recent surveys have clearly demonstrated that across solid tumors—breast cancer, lung cancer, colorectal cancer—anemia, leukocytopenia, thrombocytopenia, and neutropenia all occur and are recognized by patients as the cause of many of their symptoms. In fact, the vast majority of patients surveyed receiving cytotoxic chemotherapy indicate that chemotherapy-induced myelosuppression can have either a moderate or severe impact on their quality of life. Two-thirds of these patients particularly report fatigue as the biggest issue.

These are really part of the patient experience of going through cytotoxic therapy. Again, this is something we want to lessen by trying to preserve stem cells. Clearly, the physical aspects that we see often relate to the fatigue, to the performance status of the patient. The likelihood of these factors having a profound impact in patients clearly relates to the clinical scenario, the stage of the disease, and then of course the intention of treatment, regardless of whether the intention is curative in patients with early stage responsive malignancies or more palliative, for which the main goal of therapy is to minimize the effect of the cancer and the treatment on the patient in preserving patient preferences.

All of these have an impact on quality of life. We can talk about cost a little later. But we can’t forget what a major impact this is on the patient who goes through cytotoxic therapy.

Chemotherapy Use & Chemotherapy-Induced Myelosuppression

There are various KRAS G12C direct inhibitors beyond AMG 510. MRTX849 is another one of these. It was explored in a phase 1 trial that looked at the safety and activity of this drug, and while we've seen fewer patients with lung cancer with 

 G12C mutations, we've certainly seen proof of concept that the drug is active. We've seen responses in 3 out of 5 patients in the last presentation for an objective response rate of 60%, recognizing that we would need to see more patients treated with this drug moving forward, but certainly, it's very exciting. It also shows that the strategy of direct inhibition of a specific mutated KRAS protein works across different molecules that target this mutated protein.

In terms of MRTX849, it's being studied in several clinical trials, including the KRYSTAL-1 trial, which is a phase 1/2 study with expansion cohorts looking at the direct KRAS G12C inhibitor MRTX849 stratified by histology, whether colorectal cancer, non–small cell lung cancer, or pancreatic adenocarcinoma. It's also looking at combination studies in certain histologic subsets that may have activity in combination, such as the PD-1 antibody pembrolizumab in non–small cell lung cancer, the EGFR TKI [tyrosine kinase inhibitor] afatinib in non–small cell lung cancer, and cetuximab in colorectal cancer. MRTX849 is a covalent G12C inhibitor that binds to the GDP downstate of 

 and in this trial there were some adverse events but, generally, it appeared to be well tolerated. Adverse events included mostly grade 1 toxicities, the most common being diarrhea and nausea. Two patients had grade 3 or higher toxicities in the initial clinical trial, including fatigue and decreased appetite. Overall, the drug was well tolerated with a low incidence of grade 3 and 4 toxicities.

KRAS G12C Inhibition in Advanced NSCLC: MRTX849

Thankfully, we now have a variety of different selective direct inhibitors of 

 G12C. As a reminder, it's a specific mutation that you're looking for. One of these drugs is AMG 510, which right now is named sotorasib, and it is in clinical trials for patients who have these G12C mutations, such as lung cancer, and other cancers that might harbor G12C, such as colorectal cancers. We've seen very good activity in 

 G12C-mutated lung cancers, and we’re seeing response rates that approach 50%. That’s a dramatic difference from the older strategies that target 

. This drug has been very exciting for the field in general. The design of these drugs is unique and has been made possible because of the particular configuration of the KRAS G12C mutant protein that’s unique relative to other proteins such as G12D or G12V. In a particular, there is an IL [interleukin] group on the cysteine of 

 G12C that can be targeted with these covalent inhibitors. In general, one thing we haven't mentioned is that these direct inhibitors target the protein and lock it in the inactive state, noting thatthe KRAS mutant protein, shuttles between these active and inactive states for it to trigger continuous downstream signaling.

 Obviously, in an early phase 1/2 study, the goal is to determine the dose, safety, and early signs of efficacy. Those early signs of efficacy are generally, first, objective response rate. And then later, duration of response, progression-free survival, and overall survival.

Most molecular therapies have objective response rates as single agents of 50% or more and median progression-free survival of 9 to 10 months or more. The FDA has determined from other molecular drivers that chemotherapy and other standard treatments in the past have had response rates lower than 50%. The median progression-free survival is in the 4- or 5-month range. They have given accelerated approval to agents that have response rates over 50% and a median progression-free survival of 9 months or more.

These 2 agents do seem to have response rates that are appearing to be in the 50% or higher range. The median progression-free survival is too early to determine, but certainly, could be in the 9 month or more range. The safety profiles have been really good for these agents so far. The rates of grade 3 and 4 serious adverse events is quite low. So far, these agents seem to be as safe or safer than some of the other molecular therapies that we have. That's because normal cells don’t have 

 G12C mutations. These therapies seem to be highly specific and therefore, not causing serious adverse effects. For the grade 2 anemias and so on that have been reported, it's not clear whether those are due to the disease or due to the treatment at this point.

The CodeBreak 100 study is a phase 1/2 trial of the selective KRAS G12C inhibitor AMG 510, or sotorasib, for patients with 

mutated lung cancers and other cancers. In particular, we're looking for that G12C mutation. The goals of the study were to show the safety and activity of this molecule in this molecularly enriched population, and we certainly saw that the drug was not only active, but also safe. I think that's critical to know because 

 G12C doesn't exist in the normal human body, and so there is not a 

 G12C molecule that is harbored by normal tissues. Conceptually, in the design of these drugs you would have a good therapeutic window where you're able to hit the target hard, but not actually hit normal tissues to a substantial extent. You would see a high frequency of drug-related toxicities.

In terms of the development of AMG 510 in KRAS G12C inhibition, I do think it has the potential to be practice changing. In non–small cell lung cancer, overall response rates are about half, about 50%. I think we need to know more about duration of response and progression-free survival among a larger group of patients to see if it stacks up to osimertinib in 

-positive non–small cell lung cancer. We need those data to mature and get the result of larger trials. I'm hopeful it will be practice changing, even if it seems too early to say. I would note that there appears to be some differential activity based on histology. For example, activity in non–small cell lung cancer seems to be better than colorectal cancer where response rates are lower. That's where I think we need to look at the effects of histology and other comutations and how they may impact the activity of KRAS G12C inhibitors.

In terms of the practical implications of AMG 510 as your direct KRAS inhibitor, I do think it has the potential to be practice changing. I also think it's too early to say without further data, without the progression-free survival, duration of response, and having more data with that among a larger group of patients, to say how practice changing it will be and what those practical implications are.

 For these agents, toxicity has been pretty minimal. These have been well tolerated. There have been a couple of cases of diarrhea and anemia, and these have been well controlled and have not been dose-limiting. In fact, when it comes to anemia, it's not totally clear whether it's due to the drug or the disease, but diarrhea and anemia have been quite infrequent and easily managed and have not required discontinuation of the drug.

KRAS G12C Inhibition in Advanced NSCLC: AMG 510

 has long been known to be "undruggable" for a variety of factors. The KRAS protein itself was perceived to lack a good drug binding pocket outside of the nucleotide binding pocket of the RAS molecule. In addition, RAS does complex itself with GTP, or bind to GTP. In fact, it has a very high affinity for GTP, making it difficult for us to design GTP-competitive inhibitors, to outcompete the GTP molecule for that particular pocket. We've tried many different strategies in the past, and to name a few of them, there have been farnesyl transferase inhibitors that inhibit the localization of RAS to the membrane; those didn't work. We tried to leverage the fact that RAS activates downstream pathways, such as the MEK and ERK pathways, and have given either single-agent MEK or ERK inhibitors or combinations that hit these downstream pathways. While we've seen isolated responses in patients here and there, we haven't really seen a single series result in a very large number of patients who benefit from therapy.

KRAS G12C direct inhibitors have been an exciting development and potentially a transformational development in the treatment of non–small cell lung cancer. Several years ago, Kevan Shokat’s, PhD, laboratory and his colleagues identified small molecules that can irreversibly bind to the mutant reactive cysteine at residue 12. They identified a previously unappreciated binding pocket near the KRAS effector region. Small molecules binding to this pocket can inhibit KRAS by locking the protein in a GDP balance in inactive state. That development has spurred these new small molecule, direct KRAS G12C inhibitors that preliminarily looked to be able to induce responses and to be efficacious, particularly in non–small cell lung cancer. That's been an exciting development, that we're now able to take these small molecules to the clinic and see responses.

In terms of the rationale for identifying that cysteine at residue 12, it can target the binding pocket near the KRAS effector region where it locks the protein and its GDP bound in an active state. That underlies its activity as a direct KRAS inhibitor. I think once again that's an exciting development to be able to target that binding pocket.

 in that situation because the G12C substitutes a glycine for a cysteine. Potentially, EGFR inhibition may have some impact on wild-type 

 and that interaction may potentiate activity. That's being studied in future clinical trials.

In terms of tethering approach to drug design, that's a methodology to screen ligands that bind to targeted site proteins via a disulfide tether, where a native cysteine or an introduced cysteine can capture the ligands. That's a way to screen for these direct KRAS inhibitors of G12C. It's the drug development approach that was initially taken to identify these small molecule inhibitors of KRAS G12C.

, there are some covalent drugs that have been developed. These drugs covalently bind to the receptor and prevent GTP binding activation. These G12C agents that bind covalently are called AMG 510 and MRTX849. These are the first KRAS-specific drugs that have entered a clinical trial. Early clinical trial results have established safety, dose, and some efficacy of both of these agents. There's a limited number of patients, less than 30 for both drugs, so we don't actually have anywhere near enough data to have these drugs approved yet. We don't know the median progression-free survival, the overall survival, what it will be with these drugs. But we do know that these drugs can cause responses in 50% or more of 

Development of KRAS G12C-Targeted Therapy in NSCLC

Unfortunately, to date, we have not seen regulatory approval of a specific targeted therapeutic for 

-mutant lung cancers. We certainly hope that will change in the future, but for now, the systemic therapy options that are available to these patients include chemotherapy, immunotherapy, or a combination of both in the upfront setting, and the other second- and third-line options that are approved for non–small cell lung cancers in general.

In terms of EGFR TKIs [tyrosine kinase inhibitors] in 

-mutant non–small cell lung cancer, that's not really a practice that's used anymore. Afatinib is a second-generation EGFR TKI that's approved after platinum-based chemotherapy in squamous non-small cell lung cancer, based upon a modest benefit that was observed in lung adenocarcinoma. Erlotinib used to be approved in lung adenocarcinoma after progression on platinum-based chemotherapy, even without 

 mutation. Sometimes that was used, but it's really not used anymore and it doesn't particularly work in 

There are some interesting data, and I think what's more relevant now is ERBB pathway inhibition with EGFR and HER2 on impacting GDP and GTP loading, in terms of shifting KRAS and the GDP downstate that may help synergize in certain settings with direct KRAS G12C inhibitors. That's where I see the future heading, with EGFR TKIs and 

-mutant non–small cell lung cancer as part of a combinatorial approach, with direct KRAS inhibition or other combination treatments targeting the RAS/RAF/MAP kinase pathway, rather than as a single agent in 

mutant non–small cell lung cancer. With the changing landscape of much more effective therapies, its role has been substantially diminished.

 For many molecular drivers, the immunotherapies are less effective. If you look at 

, the immunotherapies don't seem to work so well. For 

 mutations, the immunotherapies tend to work at about the same frequency in the 

 mutations as in tumors that don't have any actionable driver.

Immunotherapy is a good option for patients who have 

mutations. If they're those, the selection would primarily be based on the PD-L1 expression. Whereas high PD-L1 patients with 

 mutations could receive a checkpoint inhibitor alone, and those with lower PD-L1 expression might receive checkpoint inhibitors plus chemotherapy.

There are some co-occurring molecular changes in 

 such as STK11 or PEAK1, where the chance that immunotherapy might work tends to be lower. The best thing to do in most cases is unknown, but the likelihood that immunotherapy will work in the presence of a 

 mutation plus a PEAK1 mutation, or an LKB1 mutation, may be lower, but we don't have a specific thing to do for them at the moment.

Systemic Therapy for KRAS+ Advanced NSCLC

 mutation on a patient’s molecular report after testing for lung cancer, it’s important to underscore that 

 mutations are really a heterogeneous group of different mutation types, meaning there are different amino acid changes that involve different residues along the 

 G12C mutation is the most common mutation. But in nonsmokers you see other mutations, such as the 

 G12D mutation, that are much more common. Beyond that, it can involve other amino acids, such as the amino acid 13 of the 

 protein. The difference is that we now have drugs for particular mutations or substitutions, such as 

 G12C, versus the other mutation types where we might employ different strategies altogether. The specific mutation that’s identified in a patient’s cancer may dictate the likelihood of us having a more exciting clinical trial for a patient, versus just more standard options for these patients on a targeted-therapy front.

 is found? The discussion we typically have is that previously, it was thought to be a poor prognostic feature, but with the evolution of immunotherapy and also these direct KRAS inhibitors, it’s really unclear if that’s true anymore. In terms of up-front treatment outside a clinical trial, the 

 mutation, I explain to patients that it’s the most common mutation we encounter in their type of lung cancer, and that immunotherapy can still be effective. For example, unlike the 

 lung cancer patients—especially the ones associated with smoking, such as G12C—can still derive good benefit from immunotherapy. But for 

, there’s really limited demonstration of effectiveness of immunotherapy, such as pembrolizumab and atezolizumab, especially as single agents.

I counsel them that they could still respond to immunotherapy or chemoimmunotherapy, stratified by what their PD-L1 status is. For example, PD-L1 high, they get pembrolizumab or chemotherapy with pembrolizumab. I also counsel them that we may have clinical trials for them. If they have 

 G12C, the direct inhibitor trials are very exciting and are in development. We also have trials targeting certain computations of 

. I emphasize that we have potentially excellent treatments for them, whether they are immunotherapy, chemoimmunotherapy, direct RAS inhibitors, or clinical trials with combination therapies.

Counseling Patients With NSCLC When KRAS is Detected

 In general, in the beginning, if the driving alteration was 

, it’s unlikely that the tumor cells would have 

. On the other hand, sometimes in the presence of an 

 drug, some of the cells will become resistant by developing 

 fusions, some cells, minimally, may become resistant by developing 

 mutation. If you have a patient with an 

 mutation, it will make sense in the future when we consider treating the patient with the 

For all these molecular alterations, 1 mechanism of resistance is they develop mutations that will prevent binding of the drug. In another way, it becomes resistant to development activation of another path, which may be 

. In some instances, there are other activating pathways such as the 

 mutations in patients with non–small cell lung cancer, and we’ve done this broadly for all cases, recognizing that we identified this gene a long time ago and well before the discovery of 

fusions. We’ve done this testing in the earlier phases also, in part because we know that these hot spot mutations tend to be mutually exclusive with these other drivers of oncogenesis—meaning, when you find a 

 mutation, there is a low likelihood that you might find another oncogenic driver. The 1 exception that we’ve learned about more recently is that 

 mutations can sometimes co-occur with other drivers like 

 mutation can be found either in a de novo or an acquired fashion. In general, for the other drivers, these tend not to coexist with those other driver states.

 In the old days, 1 strategy was to test 

 first because it’s the most common, and that worked for others only if 

 was negative. In my opinion, that’s not a particularly good strategy. Nowadays, basically every NGS [next-generation sequencing] panel will have 

 mutations as part of the panel because it’s the most common alteration since every panel has 

 mutations as part of the family nowadays.

If we do these tests sequentially, it will take a very long to find out how you’re going to treat a patient. Again, the old strategy was for some people to do 

 first. If it was positive, that’s the end. If it was negative, look for other alterations.

Right now, the common alterations are in the panels. Some panels are larger than others. The foundation, for example, has 400 genes that they’re looking for mutations. In our particular University of Colorado panel, we have only 40 genes, because those are the genes that are most common for which there is a potential treatment. In the foundation panel, there are many genes that may be mutated, but there is nothing you can do clinically. Even now, for many of the 

 mutations you find, there’s no sense to look for another if you have it, because there’s no specific treatment. Right now, the only specific treatments are basically based on G12C, for which there are some covalent drugs, binding drugs, that will prevent 

 My practice, particularly for stage IV metastatic lung adenocarcinoma, is to do broad genomic profiling up front, consistent with National Comprehensive Cancer Network Guidelines. The reason is that things have evolved from what we used to call the big 3: 

, where you can match to EGFR, ALK, and ROS1 TKIs [tyrosine kinase inhibitors], respectively. We have so many other agents now: MET exon 14 capmatinib is approved, 

 fusion, selpercatinib. With all these additional mutations, I approach it from the basis of getting broad genomic profiling to try to find targets that give us the highest percentage chances possible to find targets to match to effective drugs. Beyond that, at University of California, Davis Comprehensive Cancer Center, we have clinical trials for 

 [human epidermal growth factor receptor 2] and other molecular subtypes. It also broadens the scope to bring clinical trials to our patients.

I approach broad genomic profiling, particularly for lung adenocarcinoma. For squamous non–small cell lung cancer, particularly in patients who have a scant tissue specimen or have a never- or light-smoking history, I also pursue up-front genomic testing. At some point in squamous histology, I do get genomic testing if a patient has a heavy-smoking history. Often at University of California, Davis Comprehensive Cancer Center we get it as part of our Lung-MAP master protocol, which is a National Cancer Institute–sponsored clinical trial that looks at next-generation sequencing and includes squamous cell carcinoma to try to match the targeted therapy. The study helps support those getting that sequencing result by foundation medicine.

Testing for KRAS Mutations in NSCLC

 is an important proto-oncogene. In fact, there are 3 different types: 

. For lung cancer in particular, we’ve known that 

 hot spot mutations have existed since the late 1990s, and this was prior to the discovery of 

, in terms of its normal biology, functions as a sensor that integrates external stimuli in the wild-type state and then transduces those stimuli to the inside of the cell, thereby mediating processes such as cell growth and migration.

, in particular, can cycle between 2 different states: the on state, or the active confirmation, and the off state, or inactive confirmation. That cycling is mediated in part by binding to molecules such as GTP when the protein shuffles between these different states.

There are certain molecular alterations that drive cancer, and our belief is that those molecular alterations occur at the very earliest onset of the disease. Therefore, essentially, all the cancer cells have the same molecular alteration.

Of those molecular alterations, the most frequent ones are 

, and these are thought to be driver oncogenes, where all the cells have those particular 

 mutations. Therefore, they are potentially susceptible to treatment aimed at those particular alterations.

For every molecular alteration, there may be 1 or more than 1 molecular alteration that’s a driver. For example, 

 and most common molecular alterations are deletion 19 and a coin mutation that’s now L858R, but there are other molecular alterations in the 

 family. In a similar way, there is more than 1 

 mutation that can drive the tumor. The most common is what we call 

 mutations in other places, such as Q61. But the most common are G12C. The first specific 

 treatments that have been devised thus far are for 

Some lung cancers, even the most common, have this glycine substitution at G12C, and if one does any specific 

 mutation analysis or any next-generation sequencing analysis, one will find which 

 mutation they are, and whether a G12C is present or not. Again, this is really important because just like an 

, it may be that there are different drugs for different mutations. In 

, as far as we know, the prognosis is fairly similar across different 

 mutations, but the treatments may be completely different.

 G12B will have different drugs from what we will have for G12C. In fact, it’s highly unlikely. But if you have a 

 G12C mutation, all the cells will have that, and 1 treatment will likely be effective. Maybe that will be combinations in the future for that resistance. We don’t know how resistance is going to occur, but it’s highly likely that a specific treatment won’t kill all the cells, even though all the cells have that alteration.

 G12C, where there are a lot of exciting direct inhibitors in development, 

 mutations constitute about 25% of all solid tumors on average. That’s the same in lung adenocarcinoma. About half of those mutations, about 13%, have the 

 G12C amino acid substitution. To put that in context of newly diagnosed non–small cell lung cancer, there are about 228,000 new diagnoses of lung cancer per year estimated in the United States, the majority of those with metastatic disease. We’re looking at tens of thousands of patients per year who can be impacted by these direct KRAS inhibitor treatments. In terms of looking at that piece of pie of oncogene-driven subsets of non–small cell lung cancer, it’s probably the largest piece of pie that we could target. It’s exciting that we now have 

 inhibitors in development in clinical trials to address this large unmet need.

 mutations and other solid tumor types, the 

 mutations constitute about a quarter of all mutations across solid tumors. It’s frequently encountered in multiple cancer subtypes, such as colorectal cancer, pancreatic cancer, and others. The frequency between G12C and other 

 amino acid substitutions and that proportion varies by tumor type. But 

 mutations are encountered commonly throughout a broad spectrum of solid tumors.

KRAS Mutations in Solid Tumors

Arguably, in lung cancer, we’ve made as many therapeutic advances as in any cancers, and since lung cancer is the leading cause of cancer death in the United States and in the world, this is incredibly important.

Paul Bunn, MD, University of Colorado Cancer Center

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